WO2003018621A2 - Genes - Google Patents

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WO2003018621A2
WO2003018621A2 PCT/GB2002/003892 GB0203892W WO03018621A2 WO 2003018621 A2 WO2003018621 A2 WO 2003018621A2 GB 0203892 W GB0203892 W GB 0203892W WO 03018621 A2 WO03018621 A2 WO 03018621A2
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WIPO (PCT)
Prior art keywords
polypeptide
nucleic acid
hypoxia
recited
acid molecule
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PCT/GB2002/003892
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French (fr)
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WO2003018621A8 (en
Inventor
Susan Mary Kingsman
Jonathan White
Neil Raymond Ward
Robert Alan Harris
Stuart Naylor
Christopher Robert Mundy
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Oxford Biomedica (Uk) Limited
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Priority claimed from GB0120558A external-priority patent/GB0120558D0/en
Priority claimed from GB0124037A external-priority patent/GB0124037D0/en
Application filed by Oxford Biomedica (Uk) Limited filed Critical Oxford Biomedica (Uk) Limited
Priority to AU2002313559A priority Critical patent/AU2002313559A1/en
Publication of WO2003018621A2 publication Critical patent/WO2003018621A2/en
Publication of WO2003018621A8 publication Critical patent/WO2003018621A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • This invention relates to novel genes and gene products that are implicated in certain disease states.
  • hypoxia is intended to refer to an environment of reduced oxygen tension, as compared to the normal physiological environment for a particular organism, which is termed "normoxia”.
  • tissue oxygenation plays a significant regulatory role in both apoptosis and in angiogenesis (Bouck et al, 1996, Adv. Cancer Res. 69:135-174; Bunn et al, 1996, Physiol. Rev. 76:839-885; Dor et al, 1997, Trends Cardiovasc. Med., 7:289-294; Carmeliet et al, 1998, Nature 394:485-490).
  • Apoptosis see Duke et al, 1996, Sci.
  • Angiogenesis i.e. blood vessel growth, vascularization
  • hypooxygenated cells secrete factors that stimulate proliferation and migration of endothelial cells in an attempt to restore oxygen homeostasis (for review see Hanahan et al, 1996, Cell, 86:353-364).
  • Ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels.
  • solid tumours typically have a disorganised blood supply, leading to hypoxic regions.
  • myocardial ischaemia which encompasses several chronic and acute cardiac pathologies that involve the deprivation of the myocardium of its blood supply, usually through coronary artery occlusion.
  • a key component of ischaemia is hypoxia. Following transient ischaemia, the affected tissue may be subjected to reperfusion and re-oxygenation, and this is of significance in its own right.
  • Ischaemia/reperfusion is well known to induce cell death in myocardial tissue by apoptosis, leading to impaired function of the myocardium and infarction.
  • Many of the specific molecules required to execute the process of apoptosis are known, but not all of these molecules have been characterised in detail.
  • Cell death may also proceed by a distinct process called necrosis, which unlike apoptosis, is not initiated and controlled by specific and dedicated cellular and biochemical mechanisms (see Nicotera et al, Biochem Soc Symp. 1999; 66:69-73).
  • necrosis unlike apoptosis
  • hypoxia Other disease conditions involving hypoxia include stroke, atherosclerosis, retinopathy, acute renal failure, myocardial infarction and diseases involving infection of the airways (such as cystic fibrosis). Therefore, apoptosis and angiogenesis as induced by the ischaemic condition are also considered to be involved in these disease states. It is generally considered that understanding the mechanism by which cells respond to these diseases may be the key to the disease pathology and thus relevant to disease treatment. In a different but related approach, it is now recognised that angiogenesis is necessary for tumour growth and that retardation of this process provide a useful tool in controlling malignancy and retinopathies. For example, neoangiogenesis is seen in many forms of retinopathy and in tumour growth.
  • tumourigenic cells to undergo apoptosis are extremely desirable goals; particularly in the cancer field, it has been observed that apoptosis and angiogenesis-related genes provide potent therapeutic targets. It has also been observed that hypoxia plays a critical role in the selection of mutations that contribute to more severe tumourigenic phenotypes (Graeber et al, 1996 Nature, 379(6560):88-91).
  • the macrophage is a key cell type of the immune system, which has been shown to play a central role in the pathology of diseases which currently lack suitable treatments.
  • macrophages are known or suspected to be under the influence of hypoxia.
  • diseases include solid tumours (including ovarian and breast), dermal wounds, atherosclerosis, rheumatoid arthritis, proliferative retinopathy, cerebral malaria, peripheral arterial disease, chronic occlusive pulmonary disease (Lewis JS et al, 1999 J.Leukocyte Biol. 66: 889-900).
  • hypoxia inducible factor l ⁇ (HIF-l ⁇ or HIF-1 alpha) becomes activated in macrophages from the joint synovia of rheumatoid arthritis patients, consistent with previous reports of the rheumatoid synovium being hypoxic (Hollander AP et al, 2001 Arthritis and
  • RA are at least partly attributable to its exposure to hypoxia.
  • the macrophage is also a key cell type in promoting angiogenesis in response to hypoxia (Knighton DR et al, Science. 1983 221:1283-5), and tumour-infiltrated macrophages are key to the promotion of angiogenesis in cancer, and determining prognosis (Leek RD et al. 1997, 56:4625-4629).
  • HIF- 1 ⁇ a transcription factor that is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia.
  • This protein is considered a master regulator of oxygen homeostasis (see, for example, Semenza, (1998) Curr. Op. Genetics and Dev. 8:588-594).
  • HIF1 alpha is genetically knocked out, the hypoxia-inducible transcription of virtually all glycolytic enzymes has been shown to be inhibited. Glycolysis is an essential process which goes on in all mammalian cells.
  • HIF-1 ⁇ is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPAS1) or HIF-2 ⁇ , which shares 48% sequence identity with HIF-1 ⁇ ("Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.” Tian H, McKnight SL, Russell DW. Genes Dev. 1997 Jan l;l l(l):72-82.).
  • genes and regulatory elements identified as having a role in hypoxia may be used directly in therapeutic applications via gene therapy, via recombinant protein methods or via chemical mimetics or as targets for the development of agonists and antagonists such as antibodies, small chemical molecules, peptides, regulatory nucleic acids.
  • a novel gene and its encoded protein are provided, that have been identified and functionally annotated for the first time.
  • Some of these sequences are only identified as "hypothetical proteins" in the public databases. Each and every one of these sequences forms an embodiment of this aspect of the invention.
  • the invention also includes proteins whose amino acid sequences are encoded by a nucleic acid sequence recited in various ESTs deposited in the public databases or encoded by a gene identified from such an EST. At present, all of these EST sequences are functionally unannotated in the public databases. Each and every one of these sequences forms an embodiment of this aspect of the invention.
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261,
  • iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
  • polypeptide sequences recited in SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 and 531 were, prior to the present disclosure, unannotated in the literature and public sequence databases. Accordingly, until now, no biological function has been attributed to these polypeptide sequences; each of these sequences is generally labelled in the databases as a "hypothetical protein".
  • the novel Smartomics method, described below, has now elucidated a biological function for these polypeptides, in that they have been found to be differentially regulated under physiological conditions of hypoxia as mimicked by viral overexpression of HIF-1 ⁇ or EPAS1.
  • Smartomics The method used herein for the identification of hypoxia-induced and hypoxia repressed genes and proteins utilised an approach herein termed "Smartomics".
  • This method is a differential expression screening method for identifying genetic elements that are involved in a particular cellular process and is described in detail in co-pending, co-owned International patent application PCT/GBO 1/00758 entitled “Differential Expression Screening Method”. Simplistically put, the method involves comparing:
  • gene expression in a second cell of interest which cell comprises altered levels, relative to physiological levels, of a biological molecule implicated in the cellular process, due to the introduction into the second cell of a heterologous nucleic acid directing expression of a polypeptide; and identifying a genetic element whose expression differs, wherein gene expression in said first and/or second cell of interest is compared under at least two different environmental conditions relevant to the cellular process.
  • Gene expression is compared in both the first and the second cell of interest under at least two different environmental conditions relevant to the cellular process.
  • the object of the Smartomics methodology is to amplify and/or increase the signal to noise ratio of the differential response normally obtained so as to increase the likelihood of detecting gene products whose levels in a cell are low and/or whose expression normally changes by only a small amount.
  • the Smartomics method has been utilised herein to improve the discovery of genes activated or repressed in response to hypoxia in primary human macrophages. This involves augmenting the natural response to hypoxia, by experimentally introducing key regulators of the hypoxia response, namely HIF-1 ⁇ or EPAS1, into a population of primary human macrophages and comparing gene expression in these cells with that in control cells.
  • key regulators of the hypoxia response namely HIF-1 ⁇ or EPAS1
  • hypoxia adenoviral overexpression of HIF-1 ⁇ or EPAS1.
  • hypoxia-induced a cell overexpresses HIF-1 ⁇ or EPAS1 as compared to its expression level in normoxia, in the absence of overexpression.
  • polypeptides have been found to be hypoxia- induced: those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265 and 267; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374,
  • hypoxia-repressed as used herein is intended to mean that the polypeptide is expressed at a lower level when a cell is exposed to hypoxia conditions as mimicked by adenoviral overexpression of HIF-1 or EPAS1, as compared to its expression level under normoxia conditions: those polypeptides whose amino acid sequence is recited in SEQ ID Nos.: 515, 517, 519, 521, 523, 525, 527, 529 and 531; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ LD Nos.: 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or
  • hypoxic tissue should be taken to mean an environment of oxygen tension such that the oxygen content is between about 5% and 0.1% (v/v). In most cases, hypoxic tissue will have an oxygen content that is less than or equal to about 2%.
  • the term “normoxia” should be taken to mean conditions comprising a normal level of oxygen for the environment concerned. Normoxic tissue typically has an oxygen content above about 5%.
  • polypeptide sequences whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ LD Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or whose amino acid sequence is encoded by a gene identified from an EST recited in any one of these SEQ LD Nos.,
  • sequences in this group fall into a number of different categories.
  • the first of these are cDNA clones, for which a protein sequence has not been predicted by the depositor.
  • a second category is expressed sequence tag (EST) sequences that are represented in the UniGene database (http://www.ncbi.nlm.nih.gov/UniGene/), which contain modest or weak homology to known proteins when translated.
  • ESTs are single-pass sequence files of the 5' or 3' region of an organism's expressed genome as accessed via a force cloned cDNA library. EST sequences tend to be short and as a general rule are error-prone.
  • UniGene (see http://www.ncbi.nlm.nih.gov/Web/Newsltr/aug96.html for review) is an experimental system for automatically partitioning these EST sequences into a non-redundant set of gene-oriented clusters.
  • Each UniGene cluster contains sequences that represent a unique gene, as well as related information such as the tissue types in which the gene has been expressed and map location.
  • a third category of hits identified by the methods described herein is EST sequences that are contained in Unigene clusters, but which are not annotated and exhibit no homologies to proteins contained in the public databases.
  • the fourth and final category encompasses singleton EST sequence entries that are not incorporated as entries in the Unigene database and that only appear as single entries in the public databases.
  • Such polypeptides may have an amino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566.
  • this aspect of the invention also includes polypeptides that are encoded by a gene identified from an EST recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550,
  • Polypeptides of this aspect of the invention are intended to include fragments of polypeptides according to i) or ii) as defined above, provided that the fragment retains a biological activity that is possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii).
  • fragment refers to a polypeptide having an amino acid sequence that is the same as part, but not all, of an amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 and 531, an amino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos.
  • fragments may be isolated fragments, that are not part of or fused to other amino acids or polypeptides, or they may be comprised within a larger polypeptide, of which they form a part or region.
  • a fragment of the invention When comprised within a larger polypeptide, a fragment of the invention most preferably forms a single continuous region.
  • certain preferred embodiments relate to a fragment having a pre - and/or pro- polypeptide region fused to the amino terminus of the fragment and/or an additional region fused to the carboxyl terminus of the fragment.
  • several fragments may be comprised within a single larger polypeptide.
  • the polypeptides of the present invention or their immunogenic fragments can be used to generate ligands, such as polyclonal or monoclonal antibodies, that are immunospecific for the polypeptides.
  • ligands such as polyclonal or monoclonal antibodies
  • Such antibodies may be employed to isolate or to identify clones that express a polypeptide according to the invention or, for example, to purify the polypeptide by affinity chromatography.
  • Such antibodies may also be employed as diagnostic or therapeutic aids, amongst other applications, as will be apparent to the skilled reader.
  • immunospecific means that an antibody has substantially greater affinity for a polypeptide according to the invention than their affinity for related polypeptides.
  • the term "antibody” is intended to include intact molecules as well as fragments thereof, such as Fab, F(ab') 2 and scFv, which are capable of binding to the antigenic determinant in question.
  • the invention also includes functional equivalents of a polypeptide of i), ii) or (iii) as recited above.
  • a functionally-equivalent polypeptide according to this aspect of the invention may be a polypeptides that is homologous to a polypeptide whose sequence is explicitly recited herein. Two polypeptides are said to be "homologous” if the sequence of one of the polypeptides has a high enough degree of identity or similarity to the sequence of the other polypeptide. "Identity" indicates that at any particular position in the aligned sequences, the amino acid residue is identical between the sequences.
  • Similarity indicates that, at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences. Degrees of identity and similarity can be readily calculated according to methods known in the art (see, for example, Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993). Percentage identity, as referred to herein, is as determined using BLAST version 2.1.3 using the default parameters specified by the NCBI (the National Center for Biotechnology Information; http://www.ncbi.nlm.nih.gov/).
  • polypeptide sequence specifically identified herein, or with a fragment thereof, of greater than 50%.
  • More preferred polypeptides have degrees of identity of greater than 60%, 70%, 80%, 90%, 95%, 98% or 99%, respectively.
  • Functionally-equivalent polypeptides according to the invention are therefore intended to include natural biological variants (for example, allelic variants or geographical variations within the species from which the polypeptides are derived) and mutants (such as mutants containing amino acid substitutions, insertions or deletions) of the polypeptides whose sequences are explicitly recited herein.
  • Such mutants may include polypeptides in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code.
  • Typical such substitutions are among Ala, Val, Leu and lie; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gin; among the basic residues Lys and Arg; or among the aromatic residues Phe and Tyr.
  • variants in which several, i.e. between 5 and 10, 1 and 5, 1 and 3, 1 and 2 or just 1 amino acids are substituted, deleted or added in any combination.
  • silent substitutions, additions and deletions which do not alter the properties and activities of the protein.
  • conservative substitutions are also especially preferred.
  • “Mutant" polypeptides also include polypeptides in which one or more of the amino acid residues include a substituent group.
  • nucleic acid molecule that encodes a polypeptide according to any one of the aspects of the invention discussed above.
  • a nucleic acid molecule may consist of the nucleic acid sequence as recited in any one of SEQ LD Nos.
  • This aspect of the invention also includes a purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule as described above.
  • an expression vector that contains a purified and isolated nucleic acid molecule according to the aspects of the invention described above.
  • the invention also incorporates a delivery vehicle, such as a liposome, comprising a nucleic acid according to the above-described aspects of the invention.
  • the invention provides a host cell transformed with a vector of the above-described aspect of the invention.
  • the invention provides a ligand that binds specifically to a polypeptide according to the above-described aspects of the invention.
  • the ligand may be an antagonist ligand that inhibits the biological activity of the polypeptide, or may be an agonist ligand that activates the hypoxia-induced activity of the polypeptide to augment or potentiate a hypoxia-induced activity.
  • a ligand which binds specifically to, and which preferably inhibits the hypoxia-induced activity of, a polypeptide according to any one of the above-described aspects of the invention.
  • a ligand may, for example, be an antibody that is immunospecific for the polypeptide in question.
  • the invention provides a polypeptide, a nucleic acid molecule, vector or ligand as described above, for use in therapy or diagnosis of a disease or abnormal physiological condition.
  • a disease or abnormal physiological condition that is affected by hypoxia; examples of such diseases include cancer, ischaemic conditions (such as stroke, coronary arterial disease, peripheral arterial disease), reperfusion injury, retinopathy, neonatal stress, preeclampsia, atherosclerosis, inflammatory conditions (including rheumatoid arthritis) and wound healing.
  • the undesired cellular process involved in said diseases might include, but is not restricted to; tumorigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1,
  • iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common
  • polypeptides and nucleic acids include those polypeptide and nucleic acid sequences that are of known function, but which have not until now been implicated in the hypoxia response.
  • polypeptides which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in monocytes or macrophages.
  • pathologies include rheumatoid arthritis and other inflammatory conditions, atherosclerotic plaques and chronic occlusive pulmonary disease.
  • a substantially purified polypeptide which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 59 and 135; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with the response of a macrophage cell type to hypoxia conditions, including rheumatoid arthritis and other inflammatory conditions.
  • polypeptides The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary endothelial cells.
  • the polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 529 and 525.
  • polypeptide: i) comprises the amino acid sequence as recited in either one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in endothelial cells, such as the process of angiogenesis.
  • polypeptides The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary hepatocytes.
  • the polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 395, 235, 39, 95, 83 and 79.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in hepatocytes.
  • pathologies include ischaemia and other hepatic disorders.
  • polypeptides The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary myocytes.
  • the polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 5 and 167.
  • the expression of these polypeptides were found to be induced under conditions of hypoxia in skeletal muscle myocytes and cardiomyocytes.
  • a substantially purified polypeptide which polypeptide: i) comprises the amino acid sequence as recited in either one of SEQ ID Nos: 5 and 167; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in myocytes.
  • pathologies include peripheral arterial disease.
  • a substantially purified polypeptide which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos: 5 and 167; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cardiomyocyte cell type's response to hypoxia conditions including, but not limited to cardiac ischaemia.
  • Epithelial cells The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary epithelial cells.
  • the polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 61, 63, 195, 79, 475, 13, 383, 21 and 199.
  • the expression of these polypeptides were found to be induced under conditions of hypoxia in primary epithelial cells derived from mammary or renal tissues.
  • a substantially purified polypeptide which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 61, 63, 195, 79, 475, 13, 383, 21 and 199; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in epithelial cells.
  • pathologies include neoplasia, tumorigenesis and disruption of normal tissue homeostasis.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ LD Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a mammary or a renal cell type's response to hypoxia conditions including, but not limited to neoplasia and tumorigenesis and disruption of normal tissue homeostasis.
  • CYTOKLNES AND OTHER MOLECULES The expression of certain hypoxic regulated genes has been found to be responsive to cytokines and/or other molecules.
  • TNFalpha Polypeptides found to be responsive to TNF alpha are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 87, 227, 93, 83, 107, 111, 207, 231, 09, 01, 183, 483, 409, 395, 467, 235, 63, 255, 15, 39, 103, 121, 31, 153, 283, 169, 353, 201, 253, 239, 357, 243, 335, 249, 371, 293, 411, 351, 61, 181, 297, 485, 495, 507, 13, 59, 89, 385, 539, 519, 547, 135, 73, 533 and 451.
  • polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to TNFalpha including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic- associated pathology.
  • Such conditions and pathologies may in particular be infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, severe bacterial infection, septic shock, cerebral malaria, transplant rejection, allergic encephalomyelitis, cancer, gestational diabetes (GDM), insulin resistance syndrome, adult-onset diabetic patients, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, hyperandrogenism, alopecia areata, Japanese Guillain-Barre syndrome, mucocutaneous leishmaniasis, meningococcal disease, lepromatous leprosy, scarring trachoma and asthma.
  • Interleukin I beta ILI
  • Polypeptides found to be responsive to Interleukin 1 beta are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 91, 429, 505, 253, 533, 519, 503, 493, 411, 469, 535, 481, 409, 211, 59, 517, 563, 291, 479, 381, 525, 229, 225, 153, 325, 423, 217, 401, 353, 443, 331, 227, 475, 467, 373, 99, 483, 181, 135, 213, 83, 133, 87, 127 and 201.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 91,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to ILI including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypo
  • Such conditions and pathologies may in particular be conditions associated with an acute phase response, infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, cancer, high bone turnover, osteoporosis, cardiovascular disease, Alzheimer's disease, ulcerative colitis and Crohn's disease, lupus erythematosus, cerebral ischaemia, diabetes mellitus.
  • infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, cancer, high bone turnover, osteoporosis, cardiovascular disease, Alzheimer's disease, ulcerative colitis and Crohn's disease, lupus erythematosus, cerebral ischaemia, diabetes mellitus.
  • Polypeptides found to be responsive to a combination of lipopolysaccharide and gamma interferon are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 495, 91, 253, 455, 507, 453, 499, 91, 429, 493, 451, 383, 385, 547, 539, 481, 387, 155, 397, 59, 529, 409, 103, 503, 61, 427, 475, 69, 113, 63, 255, 55, 401, 157, 515, 505, 263, 127, 441, 485, 521, 83, 123, 367, 523, 215, 29, 525, 543, 447, 399, 491, 369, 141, 231, 413, 179, 405, 125, 135, 337, 27, 177, 335, 283, 257, 105, 147, 421, 237, 243, 375, 473, 545, 95, 17
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ ID Nos: 495, 91, 253, 455, 507, 453, 499, 91, 429, 493, 451, 383, 385, 547, 539,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to a combination of lipopolysaccharide and gamma interferon including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
  • IL-12 Polypeptides found to be responsive to IL-12 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 385, 451, 565, 381, 547, 539, 535, 283, 557, 291, 169, 507, 299, 505, 217, 371, 485, 145, 301, 35, 295, 293, 563, 269, 423, 177, 211, 367, 59, 271, 275, 77, 397, 405, 325, 561, 429, 487, 289, 353, 173, 553, 525, 13, 137, 241, 377, 517, 205, 519, 523, 495, 139, 281, 549, 157, 307, 215, 187, 237, 521, 411, 131, 41, 267, 187, 493, 49, 387, 153, 515, 347, 479, 143, 149, 233, 327, 489, 273, 37,
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ED Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent
  • Polypeptides found to be responsive to IL-15 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 451, 495, 539, 547, 385, 507, 429, 387, 493, 499, 455, 383, 447, 485, 515, 453, 397, 521, 303, 427,529, 491, 203, 481, 363, 167, 285, 401, 257, 421, 231, 187, 267, 213, 317, 113, 25, 241, 229, 153, 127, 85, 119, 177, 89, 87, 225, 251, 307, 227, 437, 183, 545, 467, 199, 107, 111, 207 and 83.
  • polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-15 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be atherosclerosis, rheumatoid arthritis and other inflammatory conditions.
  • Polypeptides found to be responsive to IL-17 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 385, 495, 539, 429, 451, 91, 87, 387, 547, 201, 287, 493, 203, 355, 533, 503, 183, 251, 351, 491, 177, 137, 77, 03, 95, 377, 303, 431, 367, 359, 563, 155, 297, 439, 113, 229, 453, 175, 261, 81, 109, 197, 545, 521, 141, 343, 285, 171, 541, 09, 513, 161, 417, 323, 25, 249, 337, 215, 15, 413 and 459.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-17 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be arthritis or chronic occlusive pulmonary disease..
  • Polypeptides found to be responsive to LL-13 are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125, 365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ LD Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common
  • Polypeptides found to be responsive to IL-4 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125, 365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-4 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be cancer, rheumatoid arthritis, Crohn's disease and other inflammatory diseases.
  • IL-10 for use in the diagnosis or therapy of conditions associated with a cell's response to IL-4 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology
  • Polypeptides found to be responsive to IL-10 are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 441, 117, 481, 121, 09, 59, 69, 403, 29, 529, 189, 519, 503, 505, 93, 347, 149, 137, 401, 427, 187, 11, 61, 81, 533, 335, 07,369, 243, 99, 411, 495, 181, 25, 145, 483, 545, 227, 193, 273, 133, 381, 393, 539, 353, 387, 507, 259, 379, 103, 203, 45, 265, 287, 323, 289, 301, 201, 283, 467, 87, 371, 83, 169, 31, 363 and 293.
  • polypeptide comprises the amino acid sequence as recited in any one of SEQ LD Nos: 441, 117, 481, 121, 09, 59, 69, 403, 29, 529, 189, 519, 503, 505, 93, 347,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-10 including, but not limited to tumorigenesis, angiogenesis
  • Polypeptides found to be responsive to superoxide are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 91, 253, 59, 481, 05, 503, 429, 385, 69, 493, 441, 507, 157, 231, 39, 409, 427, 61, 62, 475, 263, 529, 455, 453, 505, 311, 313, 401, 63, 255, 397, 143, 235, 167, 93, 103, 539, 547, 383, 451, 387, 433, 09, 523, 561, 33, 19, 85, 227, 297, 203, 549, 73, 509, 273, 339, 45, 361, 267, 513, 537, 395, 559, 307, 135, 489, 413, 159, 443, 423 and 425.
  • polypeptide i
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to superoxide including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic- associated pathology.
  • Such conditions and pathologies may in particular be ischaemia/reperfusion-associated tissue damage, rheumatoid arthritis and other inflammatory conditions linked to an inflamed rheumatoid synovium and conditions linked to inflammatory macrophage functions.
  • polypeptides found to be expressed higher in tumour compared to normal tissue are those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 100, 316, 126, 250, 164, 72, 388, 426, 128, 236, 260, 12, 546, 214, 254, 520, 90, 40, 154, 84, 118, 188, 406, 540, 490, 532, 188, 496, 362, 452, 168, 414, 384, 324, 472, 424, 308, 202, 244, 60, 534, 376, 470, 456, 412, 562, 158, 196, 408, 434, 508, 22, 410, 198, 208, 500, 476, 504, 200, 348, 162,
  • Polypeptides found to be expressed lower in tumour compared to normal tissue are those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94.
  • polypeptide comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ LD Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296, 218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis.
  • polypeptide comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis including well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated
  • polypeptide comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 100, 316, 126, 250, 164, 72, 388, 426, 128, 236, 260, 12, 546, 214, 254, 520, 90, 40, 154, 84, 118, 188,
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis;
  • the condition associated with tumorigenesis includes well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated adenocarcinoma, carcinoma endometrioid adenocarcinoma, poorly differentiated adenocarcinoma or invasive ductal carcinoma.
  • polypeptide comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis; wherein said substantially purified polypeptide is less highly expressed in tumour tissue associated with said condition compared to normal tissue, yet more preferably, normal adjacent tissue.
  • the condition associated with tumorigenesis includes well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated adenocarcinoma, carcinoma endometrioid adenocarcinoma, poorly differentiated adenocarcinoma or invasive ductal carcinoma.
  • COPD chronic obstructive pulmonary disease
  • Polypeptides found to be expressed at higher levels in COPD lungs compared to a healthy lung are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 167, 229, 133, 369, 181, 235, 349, 379, 321, 163, 91, 441, 83, 95, 39, 495, 87, 21, 225, 81, 69, 79, 227 and 437.
  • Polypeptides found to be expressed at lower levels in COPD lungs as compared to the healthy lung are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 405, 451, 533, 507, 215, 161 and 113.
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of chronic obstructive pulmonary disease.
  • ARTHEROSCLEROSIS Atherosclerosis if the process of thickening of arterial walls, leading to several pathologies including coronary artery disease, peripheral arterial disease, stroke, and a series of other related diseases. Macrophages in atherosclerotic lesions accumulate cholesterol in the form of modified LDLs, acting as a storage reservoir. The environment of the plaque is likely to involve hypoxia, and the response of macrophages to this is likely to contribute to their role in the disease process.
  • Polypeptides found to be expressed at higher levels in artherosclerotic arteries compared to normal arteries are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 413, 183, 87, 559, 425, 359, 513, 537, 11, 399, 421, 395, 91, 367, 417, 109, 197, 215, 187, 97. 03, 205, 285, 461, 245, 403, 551, 543, 525, 419, 447, 67, 75, 501, 93, 459, 113, 491, 155, 237 and 303.
  • Polypeptides found to be expressed at lower levels in artherosclerotic arteries compared to normal arteries are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 45, 203, 393, 99, 273, 07, 265, 373, 267, 363, 181, 483, 103, 385, 231, 335, 259, 83, 309, 311, 429, 545, 555, 123, 05, 425, 201, 19, 489, 365, 179, 321, 247, 421, 107, 111, 207, 235, 71, 463, 225, 451, 561, 33, 167, 209, 375, 507, 31, 63, 255, 193, 143, 61, 251, 239, 353, 289, 79, 283, 355, 293,13, 169, 301, 347, 01, 139, 453, 377, 371, 317, 77, 145, 437, 565, 29, 275, 295, 5
  • polypeptide i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
  • ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of atherosclerosis, coronary artery disease, peripheral arterial disease, stroke, other diseases associated with atherosclerotic plaques or lesions and other atherosclerosis related diseases.
  • the invention also provides a purified and isolated nucleic acid molecule that encodes a polypeptide according to this aspect of the invention, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
  • the sequences of these molecules are provided in SEQ ID NO: 1
  • this aspect of the invention includes redundant equivalents and fragments of the sequences explicitly recited in these SEQ ID Nos., and purified nucleic acid molecules which hybridize under high stringency conditions with such nucleic acid molecules, and vectors containing such nucleic acid molecules for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
  • This aspect of the invention also includes ligands which bind specifically to, and which preferably inhibit the hypoxia-induced activity of, a polypeptide listed in SEQ ID Nos.: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531, or to a polypeptide encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350,
  • the invention also provides a pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable camer.
  • the invention also provides a vaccine composition comprising a polypeptide, or a nucleic acid molecule as described above.
  • the invention also provides a method of treating a disease in a patient in need of such treatment by administering to a patient a therapeutically effective amount of a polypeptide, a nucleic acid molecule, vector, ligand or pharmaceutical composition as described above.
  • a polypeptide, a nucleic acid molecule, vector, ligand or pharmaceutical composition as described above.
  • the polypeptide, nucleic acid molecule, ligand, compound or composition administered to the patient should be an agonist.
  • the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an antagonist.
  • agonist is meant herein, any polypeptide, peptide, synthetic molecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity.
  • the invention also provides a polypeptide, nucleic acid molecule, vector, ligand or pharmaceutical composition according to any one of the above-described aspects of the invention, for use in the manufacture of a medicament for the treatment of a hypoxia- regulated condition.
  • the invention also provides a method of monitoring the therapeutic treatment of disease or physiological condition in a patient, comprising monitoring over a period of time the level of expression or activity of polypeptide, nucleic acid molecule, vector or ligand in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease or physiological condition.
  • the invention also provides a method of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by administering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or more of the nucleic acid molecules as described above.
  • the invention also provides a method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of the aspects of the invention described above in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition.
  • the invention provides such a method wherein the tissue is lung, ileum, colon, kidney, cervix, ovary or breast tissue and the hypoxia-regulated condition is squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, carinoma, endometrioid adenocarcinoma, or invasive ductal carcinoma.
  • Such a method of diagnosis may be carried out in vitro.
  • One example of a suitable method comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
  • a further example of a suitable method may comprises the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule whose sequence is recited in any one of SEQ D Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158
  • a still further example of a suitable method may comprise the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid primer under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154
  • a still further example of a suitable method may comprised the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of the above-described aspects of the invention from said tissue sample; and c) diagnosing the patient for the hypoxia-related condition by detecting the presence of a mutation which is associated with the hypoxia-related condition in the nucleic acid molecule as an indication of the hypoxia-related condition.
  • This method may comprise the additional step of amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
  • hypoxia-related conditions that may be diagnosed in this fashion include cancer, ischaemia, reperfusion, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, rheumatoid arthritis, cardiac arrest or stroke, for example, caused by a disorder of the cerebral, coronary or peripheral circulation.
  • the invention provides a method for the identification of a compound that is effective in the treatment and/or diagnosis of a hypoxia-regulated condition, comprising contacting a polypeptide, nucleic acid molecule, or ligand according to any one of the above-described aspects of the invention with one or more compounds suspected of possessing binding affinity for said polypeptide, nucleic acid molecule or ligand, and selecting a compound that binds specifically to said nucleic acid molecule, polypeptide or ligand.
  • a kit useful for diagnosing a hypoxia-regulated condition comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of the aspects of the invention described above; a second container containing primers useful for amplifying said nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of the hypoxia-regulated condition.
  • the kit may additionally comprise a third container holding an agent for digesting unhybridised RNA.
  • the invention provides an array of at least two nucleic acid molecules, wherein each of said nucleic acid molecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of the aspects of the invention described above.
  • Such an anay may contain nucleic acid molecules that either correspond to the sequence of, are complementary to the sequence of, or hybridise specifically to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
  • the nucleic acid molecules on the anay may consist of oligonucleotides of between twelve and fifty nucleotides, more preferably, between forty and fifty nucleotides.
  • the nucleic acid molecules on the array may consist of PCR-amplified cDNA inserts where the nucleic acid molecule is between 300-2000 nucleotides.
  • the invention provides an array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia-regulated condition as described above.
  • the invention also provides an anay of polypeptides, comprising at least two polypeptide species as recited above, wherein each polypeptide species is implicated in a hypoxia-regulated condition, or is a functional equivalent variant or fragment thereof.
  • Kits useful in the diagnostic methods of the invention may comprise such nucleic acid, antibody and/or polypeptide arrays.
  • a kit may also comprise one or more antibodies that bind to a polypeptide as recited above, and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide.
  • a genetically-modified non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of the aspects of the invention described above.
  • said genetically-modified animal is a transgenic or knockout animal.
  • the invention also provides a method for screening for a compound effective to treat a hypoxia-regulated condition, by contacting a non-human genetically-modified animal as described above with a candidate compound and determining the effect of the compound on the physiological state of the animal.
  • polypeptide refers to a chain (may be branched or unbranched) of two or more amino acids linked to each other by means of a peptide bond or modified peptide bond (isosteres).
  • the term polypeptide encompasses but is not limited to oligopeptides, peptides and proteins.
  • the polypeptide of the invention may additionally be either in a mature protein form or in a pre-, pro- or prepro-protein form that requires subsequent cleavage for formation of the active mature protein.
  • the pre-, pro-, prepro- part of the protein is often a leader or secretory sequence but may also be an additional sequence added to aid protein purification (for example, a His tag) or to conform a higher stability to the protein.
  • a polypeptide according to the invention may also include modified amino acids, that is, amino acids other than those 20 that are gene-encoded. This modification may be a result of natural processes such as post-translational processing or by chemical modification. Examples of modifications include acetylation, acylation, amidation, ADP-ribosylation, arginylation, attachment of a lipid derivative or phosphatidylinositol, ⁇ -carboxylation, covalent attachment of a flavin or haeme moiety, a nucleotide or nucleotide derivative, cyclisation, demethylation, disulphide bond formation, formation of covalent cross-links, formylation, glycosylation, GPI anchor formation, hydroxylation, iodination, lipid attachment, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemisation, selenoylation, sulphation, and ubiquitination. Modification of the polypeptide
  • a polypeptide according to the invention may either be isolated from natural sources (for example, purified from cell culture), or be a recombinantly produced polypeptide, or a synthetically produced polypeptide or a combination of all the above.
  • a polypeptide according to the invention, its functional equivalents and/or any immunogenic fragments derived from the polypeptide may be used to generate ligands including immunospecific monoclonal or polyclonal antibodies, or antibody fragments. These antibodies can then be used to isolate or identify clones expressing the polypeptide of the invention or to purify the polypeptide by affinity chromatography. Further uses of these immunospecific antibodies may include, but are not limited to, diagnostic, therapeutic or general assay applications. Examples of assay techniques that employ antibodies are immunoassays, radioimmunoassays (RIA) or enzyme linked immunosorbent assay (ELISA). In these cases, the antibodies may be labelled with an analytically- detectable reagent including radioisotopes, a fluorescent molecule or any reporter molecule.
  • RIA radioimmunoassays
  • ELISA enzyme linked immunosorbent assay
  • immunospecific refers to antibodies that have a substantially higher affinity for a polypeptide of this invention compared with other polypeptides.
  • antibody refers to a molecule that is produced by animals in response to an antigen and has the particular property of interacting specifically with the antigenic determinant that induced its formation. Fragments of the aforementioned molecule such as Fab, F(ab') 2 and scFv, which are capable of binding the antigen determinant, are also included in the term "antibody”.
  • Antibodies may also be modified to make chimeric antibodies, where non-human variable regions are joined or fused to human constant regions (for example, Liu et al, PNAS, USA, 84, 3439 (1987)). Particularly, antibodies may be modified to make them less immunogenic to an individual in a process such as humanisation (see, for example, Jones et al, Nature, 321, 522 (1986); Verhoeyen et al, Science, 239, 1534 (1988); Kabat et al, J.
  • humanised antibody refers to antibody molecules in which the amino acids of the CDR (complementarity-determining region) and selected other regions in the variable domains of the heavy and/or light chains of a non-human donor antibody have been substituted with the equivalent amino acids of a human antibody.
  • the humanised antibody therefore closely resembles a human antibody, but has the binding ability of the donor antibody.
  • Antibodies may also have a "bispecific" nature, that is, the antibody has two different antigen binding domains, each domain being directed against a different epitope.
  • Specific polyclonal antibodies may be made by immuno-challenging an animal with a polypeptide of this invention. Common animals used for the production of antibodies include the mouse, rat, chicken, rabbit, goat and horse.
  • the polypeptide used to immuno- challenge the animal may be derived by recombinant DNA technology or may be chemically-synthesised.
  • the polypeptide may be conjugated to a earner protein.
  • BSA bovine serum albumin
  • thyroglobulin thyroglobulin
  • keyhole limpet haemocyanin Serum from the immuno-challenged animal is collected and treated according to known procedures, for example, by immunoaffinity chromatography.
  • monoclonal antibodies can generally be made by methods known to one skilled in the art (see for example, Kohler, G. and Milstein, C, Nature 256, 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985) and Roitt, I. et al, Immunology, 25.10, Mosby- Year Book Europe Limited (1993)). Panels of monoclonal antibodies produced against the polypeptides of the invention can be screened for various properties, i.e., for isotype, epitope, affinity, etc. against which they are directed.
  • genes encoding the monoclonal antibodies of interest may be isolated from hybridomas, for instance using PCR techniques known in the art, and cloned and expressed in appropriate vectors. Phage display technology may be utilised to select the genes encoding the antibodies that have exhibited an immunospecific response to the polypeptides of the invention (see McCafferty, J., et al, (1990), Nature 348, 552-554; Marks, J. et al, (1992) Biotechnology 10, 779-783).
  • the polypeptides of the invention may also be used to search for interacting ligands. Methods for doing this include the screening of a library of compounds (see Coligan et al, Cunent Protocols in Immunology 1(2); Chapter 5 (1991), isolating the ligands from cells, isolating the ligands from a cell-free preparation or natural product mixtures.
  • Ligands to the polypeptide may activate (agonise) or inhibit (antagonise) its activity.
  • compounds may affect the levels of the polypeptide present in the cell, including affecting gene expression and/or mRNA stability.
  • Ligands to the polypeptide form a further aspect of the invention, as discussed in more detail above.
  • Preferced "antagonist” ligands include those that bind to the polypeptide of this invention and strongly inhibit any activity of the polypeptide.
  • Prefened “agonist” ligands include those that bind to the polypeptide and strongly induce activity of the polypeptide of this invention or increases substantially the level of the polypeptide in the cell.
  • the term "agonist” is meant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity.
  • antagonist is meant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharmacological receptor.
  • Ligands to a polypeptide according to the invention may come in various forms, including natural or modified substrates, enzymes, receptors, small organic molecules such as small natural or synthetic organic molecules of up to 2000Da, preferably 800Da or less, peptidomimetics, inorganic molecules, peptides, polypeptides, antibodies, structural or functional mimetics of the aforementioned.
  • Nucleic acid molecules Preferred nucleic acid molecules of the invention are those which encode the polypeptide sequences recited in any one of SEQ ID Nos. 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531, or which encode polypeptides encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356,
  • nucleic acid molecules examples include those listed in SEQ ID Nos. 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548,
  • Nucleic acid molecules of this aspect of the invention may be used in numerous methods and applications, as described generally herein.
  • a nucleic acid molecule preferably omprises of at least n consecutive nucleotides from any one of the sequences disclosed in SEQ LD Nos: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382,
  • a nucleic acid molecule of the invention also includes sequences that are complementary to the nucleic acid molecule described above (for example, for antisense or probing purposes).
  • a nucleic acid molecule according to this aspect of the invention may be in the form of RNA, such as mRNA, DNA, such as cDNA, synthetic DNA or genomic DNA.
  • the nucleic acid molecule may be double-stranded or single-stranded.
  • the single-stranded form may be the coding (sense) strand or the non-coding (antisense) strand.
  • a nucleic acid molecule may also comprise an analogue of DNA or RNA, including, but not limited to modifications made to the backbone of the molecule, such as, for example, a peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • PNA refers to an antisense molecule that comprises an oligonucleotide of at least five nucleotides in length linked to a peptide backbone of amino acid residues, preferably ending in lysine. The terminal lysine confers solubility to the composition. PNAs may be pegylated to extend their lifespan in a cell, where they preferentially bind complementary single-stranded DNA and RNA and stop transcript elongation (Nielsen, P.E. et al. (1993) Anticancer Drug Des. 8:53-63).
  • a nucleic acid molecule according to this aspect of the invention can be isolated by cloning, purification or separation of the molecule directly from a particular organism, or from a library, such as a genomic or cDNA library.
  • the molecule may also be synthesised, for example, using chemical synthetic techniques such as solid phase phosphoramidite chemical synthesis.
  • RNA may be synthesized in vitro or in vivo by transcription of the relevant DNA molecule. Due to the degeneracy of the genetic code, differing nucleic acid sequences may encode the same polypeptide (or mature polypeptide).
  • nucleic acid molecules included in this aspect of the invention include any molecule comprising a variant of the sequence explicitly recited.
  • variants may include variant nucleic acid molecules that code for the same polypeptide (or mature polypeptide) as that explicitly identified, that code for a fragment of the polypeptide, that code for a functional equivalent of the polypeptide or that code for a fragment of the functional equivalent of the polypeptide.
  • variant nucleic acid molecules that are derived from nucleotide substitutions, deletions, reanangements or insertions or multiple combinations of the aforementioned.
  • Such molecules may be naturally occuning variants, such as allelic variants, non-naturally occuning variants such as those created by chemical mutagenesis, or variants isolated from a species, cell or organism type other than the type from which the sequence explicitly identified originated.
  • Variant nucleic acid molecules may differ from the nucleic acid molecule explicitly recited in a coding region, non-coding region or both these regions.
  • Nucleic acid molecules may also include additional nucleic acid sequence to that explicitly recited, for example, at the 5' or 3' end of the molecule.
  • Such additional nucleic acids may encode for a polypeptide with added functionality compared with the original polypeptide whose sequence is explicitly identified herein. An example of this would be an addition of a sequence that is heterologous to the original nucleic acid sequence, to encode a fusion protein.
  • Such a fusion protein may be of use in aiding purification procedures or enabling techniques to be canied out where fusion proteins are required (such as in the yeast two hybrid system).
  • Additional sequences may also include leader or secretory sequences such as those coding for pro-, pre- or prepro- polypeptide sequences. These additional sequences may also include non-coding sequences that are transcribed but not translated including ribosome binding sites and termination signals.
  • a nucleic acid molecule of the invention may include molecules that are at least 70% identical over their entire length to a nucleic acid molecule as explicitly identified herein in SEQ ID Nos.: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528,
  • a nucleic acid molecule according to this aspect of the invention comprises a region that is at least 80% identical over its entire length to a nucleic acid molecule as explicitly identified herein in these SEQ ID Nos., preferably at least 90%, more preferably at least 95% and most preferably at least 98% or 99% identical.
  • Further preferred embodiments include nucleic acid molecules that encode polypeptides that retain substantially the same biological function or activity as the polypeptide explicitly identified herein.
  • the nucleic acid molecules of the invention can also be engineered using methods generally known in the art. These methods include but are not limited to DNA shuffling; random or non-random fragmentation (by restriction enzymes or shearing methods) and reassembly of fragments; insertions, deletions, substitutions and reanangements of sequences by site-directed mutagenesis (for example, by PCR). These alterations may be for a number of reasons including for ease of cloning (such as introduction of new restriction sites), altering of glycosylation patterns, changing of codon preferences, splice variants changing the processing, and/or expression of the gene product (the polypeptide) in general or creating fusion proteins (see above).
  • Nucleic acid molecules of the invention may also include antisense molecules that are partially complementary to a nucleic acid molecule as explicitly identified herein in SEQ LD Nos.: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 5
  • antisense molecules including oligonucleotides
  • hybridisation refers to any process by which a strand of nucleic acid binds with a complementary strand of nucleic acid by hydrogen bonding, typically forming Watson-Crick base pairs.
  • one of the nucleic acid populations is usually immobilised to a surface, whilst the other population is free. The two molecule types are then placed together under conditions conducive to binding.
  • stringency of hybridisation refers to the percentage of complementarity that is needed for duplex formation. "Stringency” thus refers to the conditions in a hybridization reaction that favour the association of very similar molecules over association of molecules that differ. Conditions can therefore exist that allow not only nucleic acid strands with 99-100% complementarity to hybridise, but sequences with lower complementarity (for example, 50%) to also hybridise.
  • High stringency hybridisation conditions are defined herein as overnight incubation at 42°C in a solution comprising 50% formamide, 5XSSC (150mM NaCI, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5x Denhardts solution, 10% dextran sulphate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1X SSC at approximately 65°C.
  • Low stringency conditions involve the hybridisation reaction being carried out at 35°C (see Sambrook et al [supra]).
  • the conditions used for hybridization are those of high stringency.
  • Some trans- and c/s-acting factors that may affect the binding of two complementary strands include strand length, base composition (GC pairs have an extra hydrogen bond and are thus require more energy to separate than AT pairs) and the chemical environment.
  • monovalent cations such as Na +
  • chemical denaturants such as formamide and urea destabilise the duplex by disruption of the hydrogen bonds.
  • Use of compounds such as polyethylene glycol (PEG) can increase reassociation speeds by increasing overall DNA concentration in aqueous solution by abstracting water molecules.
  • Denhardt's reagent or BLOTTO are chemical agents often added to block non-specific attachment of the liquid phase to the solid support. Increasing the temperature will also increase the stringency of hybridisation, as will increasing the stringency of the washing conditions following hybridisation (Sambrook et al. [supra]).
  • Labelling methods include, but are not limited to radiolabelling, fluorescence labelling, chemiluminescent or chromogenic labelling or chemically coupling a modified reporter molecule to a nucleotide precursor such as the biotin-streptavidin system. This can be done by oligolabelling, nick-translation, end-labelling or PCR amplification using a labelled polynucleotide. Labelling of RNA molecules can be achieved by cloning the sequences encoding the polypeptide of the invention into a vector specifically for this purpose. Such vectors are known in the art and may be used to synthesise RNA probes in vitro by the addition of an appropriate RNA polymerase such as T7, T3 or SP6 and labelled nucleotides.
  • an appropriate RNA polymerase such as T7, T3 or SP6 and labelled nucleotides.
  • Hybridisation assays include, but are not limited to dot-blots, Southern blotting, Northern blotting, chromosome in situ hybridisation (for example, FISH [fluorescence in situ hybridisation]), tissue in situ hybridisation, colony blots, plaque lifts, gridded clone hybridisation assays, DNA microanays and oligonucleotide microanays. These hybridisation methods and others, may be used by a skilled artisan to isolate copies of genomic DNA, cDNA, or RNA encoding homologous or orthologous proteins from other species.
  • the invention therefore also embodies a process for detecting a nucleic acid molecule according to the invention, comprising the steps of: (a) contacting a nucleic probe with a biological sample under hybridising conditions to form duplexes: and (b) detecting any such duplexes that are formed.
  • probe refers to a nucleic acid molecule in a hybridisation reaction whose molecular identity is known and is designed specifically to identify nucleic acids encoding homologous genes in other species.
  • the probe population is the labelled population, but this is not always the case, as for example, in a reverse hybridisation assay.
  • a use of a probe is to find nucleic acid molecules with an equivalent function to those that are explicitly identified herein, or to identify additional family members in the same or other species. This can be done by probing libraries, such as genomic or cDNA libraries, derived from a source of interest, such as a human, a non- human animal, other eukaryote species, a plant, a prokaryotic species or a virus.
  • the probe may be natural or artificially designed using methods recognised in the art (for example, Ausubel et al, [supra]).
  • a nucleic acid probe will preferably possess greater than 15, more preferably greater than 30 and most preferably greater than 50 contiguous bases complementary to a nucleic acid molecule explicitly identified herein.
  • isolated DNA from cDNA libraries will be incomplete in the region encoding the polypeptide, normally at the 5' end.
  • Methods available for subsequently obtaining full-length cDNA sequence include RACE (rapid amplification of cDNA ends) as described by Frohman et al, (Proc. Natl. Acad. Sci. USA 85, 8998-9002 (1988)), and restriction-site PCR, which uses universal primers to retrieve unknown nucleic acid sequence adjacent to a known locus (Sarkar, G. (1993) PCR Methods Applic, 2:318-322).
  • "Inverse PCR” may also be used to amplify or to extend sequences using divergent primers based on a known region (Triglia, T. et al, (1988) Nucleic Acids Res. 16:8186).
  • capture PCR which involves PCR amplification of DNA fragments adjacent to a known sequence in human and yeast artificial chromosome DNA
  • libraries that have been size- selected to include larger cDNAs.
  • random-primed libraries are preferable, in that they will contain more sequences that contain the 5' regions of genes. Use of a randomly primed library may be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA.
  • Genomic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.
  • a nucleic acid molecule according to the invention may be used for chromosome localisation.
  • a nucleic acid molecule is specifically targeted to, and can hybridise with, a particular location on an individual human chromosome.
  • the mapping of relevant sequences to chromosomes is an important step in the confirmatory conelation of those sequences with the gene-associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be conelated with genetic map data. Such data are found in, for example, McKusick, Mendelian Inheritance in Man (available on-line through Johns Hopkins University Welch Medical Library).
  • the relationships between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes). This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localised by genetic linkage to a particular genomic region, any sequences mapping to that area may represent associated or regulatory genes for further investigation.
  • the nucleic acid molecule may also be used to detect differences in the chromosomal location due to translocation, inversion, etc. among normal, canier, or affected individuals.
  • Nucleic acid molecules of the present invention are also valuable for tissue localisation. Such techniques facilitate the determination of expression patterns of the polypeptide in tissues by detection of the mRNAs that encode them. These techniques include in situ hybridisation techniques and nucleotide amplification techniques, such as PCR. Results from these studies provide an indication of the normal functions of the polypeptide in the organism, as well as highlighting the involvement of a particular gene in a disease state or abnormal physiological condition. In addition, comparative studies of the normal expression pattern of mRNAs with that of mRNAs encoded by a mutant gene provide valuable insights into the role of mutant polypeptides in disease. Such inappropriate expression may be of a temporal, spatial or quantitative nature. Vectors
  • the nucleic acid molecules of the present invention may be incorporated into vectors for cloning (for example, pBluescript made by Stratagene) or expression purposes.
  • Vectors containing a nucleic acid molecule explicitly identified herein (or a variant thereof) form another aspect of this invention.
  • the nucleic acid molecule may be inserted into an appropriate vector by any variety of well known techniques such as those described in Sambrook et al. [supra].
  • the encoding gene can be placed under the control of a control element such as a promoter, ribosome binding site or operator, so that the DNA sequence encoding the desired polypeptide is transcribed into RNA in the transformed host cell.
  • Vectors may be derived from various sources including, but not limited to bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses for example, baculoviruses and SV40 (simian virus), vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, or combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, including cosmids and phagemids.
  • Human, bacterial and yeast artificial chromosomes may also be employed to deliver larger fragments of DNA than can be contained and expressed in a plasmid.
  • retroviruses include but are not limited to: murine leukaemia virus (MLV), human immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukaemia virus (Mo-MLV), FBR murine osteosarcoma virus (FBR MSV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukaemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29), and Avian erythroblastosis virus (AEV).
  • MMV murine leukaemia virus
  • HMV human immunodeficiency virus
  • EIAV equine infectious anaemia virus
  • MMTV mouse mammary tumour virus
  • RSV Rous sarcoma virus
  • FuSV Fujinami sarcoma
  • Lentiviruses can be divided into primate and non-primate groups.
  • primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto-immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV).
  • the non-primate lentiviral group includes the prototype "slow virus” visna/maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV) and the more recently described feline immunodeficiency virus (FIV) and bovine immunodeficiency virus (BIV).
  • lentivirus family and other types of retroviruses are that lentiviruses have the capability to infect both dividing and non-dividing cells (Lewis et al 1992 EMBO. J 11: 3053-3058; Lewis and Emerman 1994 J. Virol. 68: 510-516).
  • other retroviruses - such as MLV - are unable to infect non-dividing cells such as those that make up, for example, muscle, brain, lung and liver tissue.
  • a vector may be configured as a split-intron vector.
  • a split intron vector is described in PCT patent applications WO 99/15683 and WO 99/15684.
  • adenoviruses can be used to transduce target cells to become transient retroviral producer cells that could stably infect neighbouring cells.
  • retroviral producer cells engineered to express an antigen of the present invention can be implanted in organisms such as animals or humans for use in the treatment of angiogenesis and/or cancer.
  • Poxvirus vectors are also suitable for use in accordance with the present invention.
  • Pox viruses are engineered for recombinant gene expression and for the use as recombinant live vaccines. This entails the use of recombinant techniques to introduce nucleic acids encoding foreign antigens into the genome of the pox virus. If the nucleic acid is integrated at a site in the viral DNA which is non-essential for the life cycle of the virus, it is possible for the newly produced recombinant pox virus to be infectious, that is to say to infect foreign cells and thus to express the integrated DNA sequence.
  • the recombinant pox virus prepared in this way can be used as live vaccines for the prophylaxis and/or treatment of pathologic and infectious disease.
  • prefened vectors are vaccinia virus vectors such as MVA or NYVAC. Most prefened is the vaccinia strain modified virus ankara (MVA) or a strain derived therefrom.
  • MVA vaccinia strain modified virus ankara
  • Alternatives to vaccinia vectors include avipox vectors such as fowlpox or canarypox known as ALVAC and strains derived therefrom which can infect and express recombinant proteins in human cells but are unable to replicate.
  • Bacterial vectors may be also used, such as salmonella, listeria and mycobacteria.
  • Vectors containing the relevant nucleotide sequence may enter the host cell by a variety of methods well known in the art and described in many standard laboratory manuals (such as Sambrook et al, [supra], Ausubel et al, [supra], Davis et al, Basic Methods in Molecular Biology (1986)). Methods include calcium phosphate transfection, cationic lipid-mediated transfection, DEAE-dextran mediated transfection, electroporation, microinjection, scrape loading, transduction, and ballistic introduction or infection.
  • host cells are often dependent on the vector type used as a carrier for the nucleic acid molecule of the present invention.
  • Bacteria and other microorganisms are particularly suitable hosts for plasmids, cosmids and expression vectors generally (for example, vectors derived from the pBR322 plasmid), yeast are suitable hosts for yeast expression vectors, insect cell systems are suitable host for virus expression vectors (for example, baculovirus) and plant cells are suitable hosts for vectors such as the cauliflower mosaic virus (CaMV) and tobacco mosaic virus (TMV).
  • Other expression systems include using animal cells (for example, with the Lenti VectorsTM, Oxford BioMedica) as a host cell or even using cell-free translating systems.
  • shuttle vectors may be maintained in a variety of host cells.
  • An example of such a vector would be pEG 202 and other yeast two-hybrid vectors which can be maintained in both yeast and bacterial cells (see Ausubel et al, [supra] and Gyuris, J., Cell, 75, 791-803).
  • Suitable bacterial hosts include Streptococci, Staphylococci, Escherichia coli, Streptomyces and Bacillus subtilis cells.
  • Yeast and fungal hosts include Saccharomyces cerevisiae and Aspergillus cells.
  • Mammalian cell hosts include many immortalised cell lines available from the American Type Culture Collection (ATCC) such as CHO (Chinese Hamster Ovary) cells, HeLa cells, BHK (baby hamster kidney) cells, monkey kidney cells, C127, 3T3, BHK, HEK 293, Bowes melanoma and human hepatocellular carcinoma (for example, Hep G2) cells.
  • ATCC American Type Culture Collection
  • Insect host cells that are used for baculovirus expression include Drosophila S2 and Spodoptera Sf9 cells. Plant host cells include most plants from which protoplasts be isolated and cultured to give whole regenerated plants. Practically, all plants can be regenerated from cultured cells or tissues, including but not limited to all major species of sugar cane, sugar beet, cotton, fruit and other trees, legumes and vegetables. Expression systems
  • expression vectors that comprise a nucleic acid molecule as described above.
  • Expression vectors and host cells are preferably chosen to give long term, high yield production and stable expression of the recombinant polypeptide and its variants.
  • Expression of a polypeptide can be effected by cloning an encoding nucleic acid molecule into a suitable expression vector and inserting this vector into a suitable host cell.
  • the positioning and orientation of the nucleic acid molecule insert with respect to the regulatory sequences of the vector is important to ensure that the coding sequence is properly transcribed and translated.
  • control and other regulatory sequences may be ligated onto the nucleic acid molecule of this invention prior to its insertion into the expression vector.
  • the sequence of the nucleic acid molecule may have to be adjusted in order to effect correct transcription and translation (for example, addition of nucleotides may be necessary to obtain the correct reading frame for translation of the polypeptide from its encoding nucleic acid molecule).
  • a nucleic acid molecule of the invention may comprise control sequences that encode signal peptides or leader sequences. These sequences may be useful in directing the translated polypeptide to a variety of locations within or outside the host cell, such as to the lumen of the endoplasmic reticulum, to the nucleus, to the periplasmic space, or into the extracellular environment. Such signals may be endogenous to the nucleic acid molecules of the invention, or may be a heterologous sequence. These leader or control sequences may be removed by the host during post-translational processing.
  • a nucleic acid molecule of the present invention may also comprise one or more regulatory sequences that allow for regulation of the expression of polypeptide relative to the growth of the host cell.
  • these regulatory signals may be due to a heterologous sequence from the vector. Stimuli that these sequences respond to include those of a physical or chemical nature such as the presence or absence of regulatory compounds, changing temperatures or metabolic conditions.
  • Regulatory sequences as described herein are non-translated regions of sequence such as enhancers, promoters and the 5' and 3' untranslated regions of genes. Regulatory sequences interact with host cellular proteins that cany out translation and transcription. These regulatory sequences may vary in strength and specificity. Examples of regulatory sequences include those of constitutive and inducible promoters.
  • an inducible promoter is the hybrid lacZ promoter of the Bluescript phagemid (Stratagene, LaJolla, CA) or pSportlTM plasmid (Gibco BRL).
  • the baculovirus polyhedrin promoter may be used in insect cells.
  • An example of a prefened expression system is the lentivirus expression system, for example, as described in International patent application WO98/17815.
  • Vectors frequently have marker genes that can be easily assayed. Thus, vector uptake by a host cell can be readily detected by testing for the relevant phenotype. Markers include, but are not limited to those coding for antibiotic resistance, herbicide resistance or nutritional requirements.
  • Markers however, only indicate that a vector has been taken up by a host cell but does not distinguish between vectors that contain the desired nucleic acid molecule and those that do not.
  • One method of detecting for the said nucleic acid molecule is to insert the relevant sequence at a position that will disrupt the transcription and translation of a marker gene.
  • a marker gene can be placed in tandem with a sequence encoding a polypeptide of the invention under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
  • More direct and definitive methods to detect the presence of the nucleic acid molecule of the present invention include DNA-DNA or DNA-RNA hybridisation with a probe comprising the relevant antisense molecule, as described above. More direct methods to detect polypeptide expression include protein bioassays for example, fluorescence activated cell sorting (FACS), immunoassay techniques such as ELISA or radioimmunoassays.
  • FACS fluorescence activated cell sorting
  • immunoassay techniques such as ELISA or radioimmunoassays.
  • a nucleic acid molecule according to the invention may be used to create a transgenic animal, most commonly a rodent.
  • the modification of the animal's genome may either be done locally, by modification of somatic cells or by germ line therapy to incorporate inheritable modifications.
  • Such transgenic animals may be particularly useful in the generation of animal models for drug molecules effective as modulators of the polypeptides of the present invention.
  • polypeptide purification A polypeptide according to the invention may be recovered and purified from recombinant cell cultures by methods including, but not limited to cell lysis techniques, ammonium sulphate precipitation, ethanol precipitation, acid extraction, anion or cation chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography, high performance liquid chromatography (HPLC) or fast performance liquid chromatography (FPLC).
  • HPLC high performance liquid chromatography
  • FPLC fast performance liquid chromatography
  • Many expression vectors are commercially available that aid purification of the relevant polypeptide. These include vectors that join the sequence encoding the polypeptide to another expressed sequence creating a fused protein that is easier to purify. Ways in which these fused parts can facilitate purification of the polypeptide of this invention include fusions that can increase the solubility of the polypeptide, joining of metal chelating peptides (for example, histidine-tryptophan modules) that allow for purification with immobilised metals, joining of protein A domains which allow for purification with immobilised immunoglobulins and the joining of the domain that is utilised in the FLAGS extension/affinity purification system (Immunex Corp., Seattle, WA). Fusion of the polypeptide of this present invention with a secretion signal polypeptide may also aid purification. This is because the medium into which the fused polypeptide has been secreted can subsequently be used to recover and purify the expressed polypeptide.
  • these extraneous polypeptides often comprise a cleavable linker sequence which allows the polypeptide to be isolated from the fusion.
  • Cleavable linker sequences between the purification domain and the polypeptide of the invention include those specific for Factor Xa or for enterokinase (Invitrogen, San Diego, CA).
  • One such expression vector provides for expression of a fusion protein containing the polypeptide of the invention fused to several histidine residues preceding a thioredoxin or an enterokinase cleavage site. The histidine residues facilitate purification by IMAC (immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp.
  • Another aspect of this invention includes assays that may be canied out using a polypeptide or nucleic acid molecule according to the invention. Such assays may be for many uses including the development of drug candidates, for diagnostic purposes or for the gathering of information for therapeutics.
  • the polypeptide is to be expressed for use in screening assays, generally it is prefened that it be produced at the surface of the host cell in which it is expressed. In this event, the host cells may be harvested prior to use in the screening assay, for example using techniques such as fluorescence activated cell sorting (FACS) or immunoaffinity techniques. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the expressed polypeptide. If polypeptide is produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
  • FACS fluorescence activated cell sorting
  • polypeptide of the invention can be used to screen libraries of compounds in any of a variety of drug screening techniques. Such compounds may activate (agonise) or inhibit
  • antagonise the level of expression of the gene or the activity of the polypeptide of the invention and form a further aspect of the present invention.
  • suitable compounds are those which are effective to alter the expression of a natural gene which encodes a polypeptide of the invention or to regulate the activity of a polypeptide of the invention.
  • Agonist or antagonist compounds may be isolated from, for example, cells, cell-free preparations, chemical libraries or natural product mixtures. These agonists or antagonists may be natural or modified substrates, ligands, enzymes, receptors or structural or functional mimetics. For a suitable review of such screening techniques, see Coligan et al., Cunent Protocols in Immunology l(2):Chapter 5 (1991).
  • Potential agonists or antagonists include small organic molecules, peptides, polypeptides and antibodies that bind to the polypeptide of the invention and thereby modulate its activity. In this fashion, binding of the polypeptide to normal cellular binding molecules may be potentiated or inhibited, such that the normal biological activity of the polypeptide is enhanced or prevented.
  • the polypeptide of the invention that is employed in such a screening technique may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly.
  • screening procedures may involve using appropriate cells or cell membranes that express the polypeptide that are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response.
  • the functional response of the cells contacted with the test compound is then compared with control cells that were not contacted with the test compound.
  • Such an assay may assess whether the test compound results in a signal generated by activation of the polypeptide, using an appropriate detection system.
  • Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist in the presence of the test compound is observed.
  • simple binding assays may be used, in which the adherence of a test compound to a surface bearing the polypeptide is detected by means of a label directly or indirectly associated with the test compound or in an assay involving competition with a labelled competitor.
  • competitive drug screening assays may be used, in which neutralising antibodies that are capable of binding the polypeptide specifically compete with a test compound for binding. In this manner, the antibodies can be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide. Assays may also be designed to detect the effect of added test compounds on the production of mRNA encoding the polypeptide in cells.
  • an ELISA may be constructed that measures secreted or cell-associated levels of polypeptide using monoclonal or polyclonal antibodies by standard methods known in the art, and this can be used to search for compounds that may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues. The formation of binding complexes between the polypeptide and the compound being tested may then be measured.
  • Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the polypeptide of interest (see International patent application WO84/03564).
  • This method large numbers of different small test compounds are synthesised on a solid substrate, which may then be reacted with the polypeptide of the invention and washed.
  • One way of immobilising the polypeptide is to use non-neutralising antibodies. Bound polypeptide may then be detected using methods that are well known in the art. Purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques.
  • a polypeptide according to the invention may be used to identify membrane-bound or soluble receptors, through standard receptor binding techniques that are known in the art, such as ligand binding and crosslinking assays in which the polypeptide is labelled with a radioactive isotope, is chemically modified, or is fused to a peptide sequence that facilitates its detection or purification, and incubated with a source of the putative receptor (for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids).
  • a source of the putative receptor for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids.
  • the efficacy of binding may be measured using biophysical techniques such as surface plasmon resonance and spectroscopy.
  • Binding assays may be used for the purification and cloning of the receptor, but may also identify agonists and antagonists of the polypeptide, that compete with the binding of the polypeptide to its receptor. Standard methods for conducting screening assays are well understood in the art.
  • a typical polypeptide-based assay might involve contacting the appropriate cell(s) or cell membrane(s) expressing the polypeptide with a test compound.
  • a polypeptide according to the invention may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. Any response to the test compound, for example a binding response, a stimulation or inhibition of a functional response may then be compared with a control where the cell(s) or cell membrane(s) was/were not contacted with the test compound.
  • a binding response could be measured by testing for the adherence of a test compound to a surface bearing a polypeptide according to the invention.
  • the test compound may aid polypeptide detection by being labelled, either directly or indirectly.
  • the polypeptide itself may be labelled, for example, with a radioisotope, by chemical modification or as a fusion with a peptide or polypeptide sequence that will facilitate polypeptide detection.
  • a binding response may be measured, for example, by performing a competition assay with a labelled competitor or vice versa.
  • a competition assay is a competitive drug screening assay, where neutralising antibodies that are capable of specifically binding to the polypeptide compete with a test compound for binding. In this manner, the antibodies may be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide.
  • Alternative binding assay methods are well known in the art and include, but are not limited to, cross-linking assays and filter binding assays. The efficacy of binding may be measured using biophysical techniques including surface plasmon resonance and spectroscopy.
  • High throughput screening is a type of assay which enables a large number of compounds to be searched for any significant binding activity to the polypeptide of interest (see patent application WO84/03564). This is particularly useful in drug screening.
  • many different small test compounds are synthesised on to a solid substrate.
  • the polypeptide is then introduced to this substrate and the whole apparatus washed.
  • the polypeptide is then immobilised by, for example, using non-neutralising antibodies.
  • Bound polypeptide may then be detected using methods that are well known in the art.
  • Purified polypeptide may also be coated directly onto plates for use in the aforementioned drug screening techniques.
  • Assay methods that are also included within the terms of the present invention are those that involve the use of the genes and polypeptides of the invention in overexpression or ablation assays. Such assays involve the manipulation of levels of these genes/polypeptides in cells and assessment of the impact of this manipulation event on the physiology of the manipulated cells. For example, such experiments reveal details of signaling and metabolic pathways in which the particular genes/polypeptides are implicated, generate information regarding the identities of polypeptides with which the studied polypeptides interact and provide clues as to methods by which related genes and proteins are regulated.
  • Another aspect of this invention provides for any screening kits that are based or developed from any of the aforementioned assays.
  • a further aspect of the invention provides a pharmaceutical composition suitable for modulating the biological response to hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable carrier.
  • a composition containing a polypeptide, nucleic acid molecule, ligand or any other compound of this present invention (herein known as X) is considered to be "substantially free of impurities" (herein known as Y) when X makes up more than 85% mass per mass of the total [X+Y] mass.
  • X comprises at least 90% of the total X+Y mass. More preferably X comprises at least 95%, 98% and most preferably 99% of the total X+Y mass.
  • Canier molecules may be genes, polypeptides, antibodies, liposomes or indeed any other agent provided that the canier does not itself induce toxicity effects or cause the production of antibodies that are harmful to the individual receiving the pharmaceutical composition.
  • Further examples of known earners include polysaccharides, polylactic acids, polyglycolic acids and inactive virus particles.
  • Caniers may also include pharmaceutically acceptable salts such as mineral acid salts (for example, hydrochlorides, hydrobromides, phosphates, sulphates) or the salts of organic acids (for example, acetates, propionates, malonates, benzoates).
  • Pharmaceutically acceptable carriers may additionally contain liquids such as water, saline, glycerol, ethanol or auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like. Carriers may enable the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slunies, suspensions to aid intake by the patient. A thorough discussion of pharmaceutically acceptable caniers is available in Remington's Pharmaceutical Sciences
  • the amount of component X in the composition should also be in therapeutically effective amounts.
  • therapeutically effective amounts used herein refers to the amount of agent needed to treat, ameliorate, or prevent (for example, when used as a vaccine) a targeted disease or condition.
  • An effective initial method to determine a "therapeutically effective amount” may be by canying out cell culture assays (for example, using neoplastic cells) or using animal models (for example, mice, rabbits, dogs or pigs).
  • animal models may also yield other relevant information such as preferable routes of administration that will give maximum effectiveness. Such information may be useful as a basis for patient administration.
  • a "patient” as used in herein refers to the subject who is receiving treatment by administration of X. Preferably, the patient is human, but the term may also include animals.
  • the therapeutically-effective dosage will generally be dependent on the patient's status at the time of adminstration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug combinations, reaction sensitivities and the patient's tolerance or response to the therapy. The precise amount can be determined by routine experimentation but may ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 mg/kg (mass of drug compared to mass of patient) to 50 mg/kg, preferably 0.05 mg/kg to 10 mg/kg. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • Uptake of a pharmaceutical composition of the invention by a patient may be initiated by a variety of methods including, but not limited to enteral, intra-arterial, intrathecal, intramedullary, intramuscular, intranasal, intraperitoneal, intravaginal, intravenous, intraventricular, oral, rectal (for example, in the form of suppositories), subcutaneous, sublingual, transcutaneous applications (for example, see WO98/20734) or transdermal means.
  • compositions of the invention may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • Direct delivery of the compositions can generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue.
  • the compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule.
  • One approach comprises administering to a patient an inhibitor compound (antagonist) along with a pharmaceutically acceptable canier in an amount effective to inhibit the function of the polypeptide, such as by blocking the binding of a ligand, substrate, enzyme, receptor, or by inhibiting a second signal, and thereby alleviating the abnormal condition.
  • an antagonist molecule may, for example, be an antibody.
  • antibodies are chimeric and/or humanised to minimise their immunogenicity, as previously described.
  • soluble forms of the polypeptide that retain binding affinity for the ligand, substrate, enzyme, receptor, in question may be administered to the patient to compete with the biological activity of the endogenous polypeptide.
  • the polypeptide may be administered in the form of a fragment that retains a portion that is relevant for the desired biological activity.
  • expression of the gene encoding the polypeptide can be inhibited using expression blocking techniques, such as by using antisense nucleic acid molecules (as described above), either internally generated or separately administered.
  • Modifications of gene expression may be effected by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5' or regulatory regions (signal sequence, promoters, enhancers and introns) of the gene encoding the polypeptide.
  • inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules.
  • the complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.
  • Such oligonucleotides may be administered or may be generated in situ from expression in vivo.
  • RNA interference (Elbashir, SM et al., Nature 2001, 41 1, 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed. Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA, reducing or ablating target protein expression.
  • expression of a polypeptide according to the invention may be prevented by using a ribozyme specific to the encoding mRNA sequence for the polypeptide.
  • Ribozymes are catalytically active RNAs that can be natural or synthetic (see for example Usman, N, et al, Cun. Opin. Struct. Biol (1996) 6(4), 527-33). Synthetic ribozymes can be designed to specifically cleave mRNAs at selected positions thereby preventing translation of the mRNAs into functional polypeptide. Ribozymes may be synthesised with a natural ribose phosphate backbone and natural bases, as normally found in RNA molecules. Alternatively the ribozymes may be synthesised with non-natural backbones, for example, 2'-O-methyl RNA, to provide protection from ribonuclease degradation and may contain modified bases.
  • Efficacy of the gene silencing approaches assessed above may be assessed through the measurement of polypeptide expression (for example, by Western blotting), and at the RNA level using TaqMan-based methodologies.
  • RNA molecules may be modified to increase their intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of non-traditional bases such as inosine, queosine and butosine, as well as acetyl-, methyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine and uridine that are not as easily recognised by endogenous endonucleases.
  • a particular disease state is partially or completely due to a lowered level of biological activity from a polypeptide according to the invention
  • various methods may be used.
  • An example of such a method includes administering a therapeutically effective amount of compound that can activate (i.e. an agonist) or cause increased expression of the polypeptide concerned. Administration of such a compound may be via any of the methods described previously.
  • Gene Therapy Another aspect of the present invention provides for gene therapy methods involving nucleic acid molecules identified herein.
  • Gene therapy may be used to affect the endogenous production of the polypeptide of the present invention by relevant cells in a patient.
  • gene therapy can be used permanently to treat the inappropriate production of a polypeptide by replacing a defective gene with the corrected therapeutic gene.
  • Treatment may be effected either in vivo or ex vivo.
  • Ex vivo gene therapy generally involves the isolation and purification of the patient's cells, introduction of the therapeutic gene into the cells and finally, the introduction of the genetically-altered cells back into the patient.
  • In vivo gene therapy does not require the isolation and purification of patient cells prior to the introduction of the therapeutic gene into the patient. Instead, the therapeutic gene can be packaged for delivery into the host.
  • Gene delivery vehicles for in vivo gene therapy include, but are not limited to, non-viral vehicles such as liposomes, replication- deficient viruses (for example, adenovirus as described by Berkner, K.L., in Cun. Top. Microbiol.
  • naked DNA may be directly injected into the bloodstream or muscle tissue as a form of in vivo gene therapy.
  • a nucleic acid molecule encoding a polypeptide of the invention is engineered for expression in a replication-defective retroviral vector.
  • This expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding the polypeptide, such that the packaging cell now produces infectious viral particles containing the gene of interest.
  • producer cells may be administered to a patient for engineering cells in vivo and expression of the polypeptide in vivo (see Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics (1996), T Strachan and A P Read, BIOS Scientific Publishers Ltd).
  • a further embodiment of the present invention provides that the polypeptides or nucleic acid molecules identified may be used in the development of vaccines.
  • vaccine development can involve the raising of antibodies against such agents.
  • vaccine development can involve the raising of antibodies or T cells against such agents (as described in WO00/29428).
  • Vaccines according to the invention may either be prophylactic (i.e. prevents infection) or therapeutic (i.e. treats disease after infection).
  • Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid, usually in combination with pharmaceutically-acceptable caniers as described above. Additionally, these caniers may function as immunostimulating agents ("adjuvants").
  • the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H. pylori, and other pathogens.
  • Vaccination processes may involve the use of heterologous vectors eg: prime with MVA and boost with DNA.
  • vaccines comprising polypeptides are preferably administered parenterally (for instance, subcutaneous, intramuscular, intravenous, or intradermal injection).
  • parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents.
  • the vaccine formulations of the invention may be presented in unit-dose or multi-dose containers.
  • sealed ampoules and vials may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use.
  • the dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.
  • the technology refened to as jet injection may also be useful in the formulation of vaccine compositions.
  • polypeptides can be delivered by viral or non-viral techniques.
  • Non-viral delivery systems include but are not limited to DNA transfection methods.
  • transfection includes a process using a non-viral vector to deliver a antigen gene to a target mammalian cell.
  • Typical transfection methods include electroporation, nucleic acid biolistics, lipid-mediated transfection, compacted nucleic acid- mediated transfection, liposomes, immunoliposomes, lipofectin, cationic agent-mediated, cationic facial amphiphiles (CFAs) (Nature Biotechnology 1996 14; 556), multivalent cations such as spermine, cationic lipids or polylysine, 1, 2,-bis (oleoyloxy)-3-(trirnethylammonio) propane (DOTAP)-cholesterol complexes (Wolff and Trubetskoy 1998 Nature Biotechnology 16: 421) and combinations thereof.
  • CFAs cationic facial amphiphiles
  • Viral delivery systems include but are not limited to adenovirus vectors, adeno-associated viral (AAV) vectors, herpes viral vectors, influenza, retroviral vectors, lentiviral vectors or baculoviral vectors, Venezuelan equine encephalitis virus (VEE), poxviruses such as: canarypox virus (Taylor et al 1995 Vaccine 13:539-549), entomopox virus (Li Y et al 1998 Xllth International Poxvirus Symposium pl44. Abstract), penguine pox (Standard et al. J Gen Virol. 1998 79:1637-46) alphavirus, and alphavirus based DNA vectors.
  • AAV adeno-associated viral
  • herpes viral vectors influenza
  • retroviral vectors lentiviral vectors
  • baculoviral vectors Venezuelan equine encephalitis virus (VEE)
  • poxviruses such as: can
  • this aspect of the invention includes the use of genetically-based vaccines, for example, those vaccines that are effective through eliciting the expression of a particular gene (either endogenous or exogenously derived) in a cell, so targeting this cell for destruction by the immune system of the host organism.
  • genetically-based vaccines for example, those vaccines that are effective through eliciting the expression of a particular gene (either endogenous or exogenously derived) in a cell, so targeting this cell for destruction by the immune system of the host organism.
  • a nucleic acid molecule identified herein may be detected or isolated from a patient's tissue and used for diagnostic purposes.
  • tissue refers to blood, urine, any matter obtained from a tissue biopsy or any matter obtained from an autopsy. Genomic DNA from the tissue sample may be used directly for detection of a hypoxia-related condition.
  • the DNA may be amplified using methods such as polymerase chain reaction (PCR), the ligase chain reaction (LCR), strand displacement amplification (SDA), or other amplification techniques (see Saiki et al, Nature, 324, 163-166 (1986); Bej, et al, Crit. Rev. Biochem. Molec. Biol., 26, 301-334 (1991); Birkenmeyer et al, J. Virol. Meth., 35, 117-126 (1991) and Brunt, J., Bio/Technology, 8, 291-294 (1990)).
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • SDA strand displacement amplification
  • Such diagnostics are particularly useful for prenatal and even neonatal testing.
  • a method of diagnosis of disease using a polynucleotide may comprise assessing the level of expression of the natural gene and comparing the level of encoded polypeptide to a control level measured in a normal subject that does not suffer from the disease or physiological condition that is being tested.
  • the diagnosis may comprise the following steps: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule of the invention and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of differing levels of the hybrid complex in the patient sample compared to levels of the hybrid complex in the control sample is indicative of the dysfunction.
  • a further aspect of the invention comprises a diagnostic method comprising the steps of: a) obtaining a tissue sample from a patient being tested for disease; b) isolating a nucleic acid molecule according to the invention from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation in the nucleic acid molecule which is associated with disease.
  • an amplification step such as PCR
  • An example of this includes detection of deletions or insertions indicative of the dysfunction by a change in the size of the amplified product in comparison to the normal genotype.
  • Point mutations can be identified by hybridising amplified DNA to labelled RNA of the invention or alternatively, labelled antisense DNA sequences of the invention. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase digestion or by assessing differences in melting temperatures.
  • the presence or absence of the mutation in the patient may be detected by contacting DNA with a nucleic acid probe that hybridises to the DNA under stringent conditions to form a hybrid double-stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion conesponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation in the corresponding portion of the DNA strand.
  • Point mutations and other sequence differences between the reference gene and "mutant" genes can be identified by other well-known techniques, such as direct DNA sequencing or single-strand conformational polymorphism, (see Orita et al, Genomics, 5, 874-879 (1989)).
  • a sequencing primer may be used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR.
  • the sequence determination is performed by conventional procedures with radiolabelled nucleotides or by automatic sequencing procedures with fluorescent-tags.
  • Cloned DNA segments may also be used as probes to detect specific DNA segments. The sensitivity of this method is greatly enhanced when combined with PCR.
  • point mutations and other sequence variations, such as polymorphisms can be detected as described above, for example, through the use of allele-specific oligonucleotides for PCR amplification of sequences that differ by single nucleotides.
  • DNA sequence differences may also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (for example, Myers et al, Science (1985) 230:1242). Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and SI protection or the chemical cleavage method (see Cotton et al, PNAS. USA (1985) 85: 4397-4401).
  • mutations such as microdeletions, aneuploidies, translocations, inversions, can also be detected by in situ analysis (see, for example, Keller et al, DNA Probes, 2nd Ed., Stockton Press, New York, N.Y., USA (1993)), that is, DNA or RNA sequences in cells can be analysed for mutations without need for their isolation and/or immobilisation onto a membrane.
  • FISH is presently the most commonly applied method and numerous reviews of FISH have appeared (see, for example, Trachuck et al, Science, 250, 559-562 (1990), and Trask et al, Trends, Genet., 7, 149-154 (1991)).
  • an array of oligonucleotide probes comprising a nucleic acid molecule according to the invention can be constructed to conduct efficient screening of genetic variants, mutations and polymorphisms.
  • Anay technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability (see for example: M.Chee et al, Science (1996), Vol 274, pp 610-613).
  • the array is prepared and used according to the methods described in WO95/11995 (Chee et al); Lockhart, D. J. et al. (1996) Nat. Biotech. 14: 1675-1680); and Schena, M. et al (1996) PNAS 93: 10614-10619).
  • Oligonucleotide pairs may range from two to over one million.
  • the oligomers are synthesized at designated areas on a substrate using a light-directed chemical process.
  • the substrate may be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support.
  • an oligonucleotide may be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application W095/251116 (Baldeschweiler et al).
  • a "gridded" anay analogous to a dot (or slot) blot may be used to anange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures.
  • An array such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536 or 6144 oligonucleotides, or any other number between two and over one million which lends itself to the efficient use of commercially-available instrumentation.
  • diseases may be diagnosed by methods comprising determining, from a sample derived from a subject, an abnormally decreased or increased level of polypeptide or mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods.
  • nucleic acid amplification for instance PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods.
  • Assay techniques that can be used to determine levels of a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art and are discussed in some detail above (including radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays).
  • a diagnostic method which comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
  • Protocols such as ELISA, RIA, and FACS for measuring polypeptide levels may additionally provide a basis for diagnosing altered or abnormal levels of polypeptide expression.
  • Normal or standard values for polypeptide expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably humans, with antibody to the polypeptide under conditions suitable for complex formation The amount of standard complex formation may be quantified by various methods, such as by photometric means.
  • Antibodies which specifically bind to a polypeptide of the invention may be used for the diagnosis of conditions or diseases characterised by expression of the polypeptide, or in assays to monitor patients being treated with the polypeptides, nucleic acid molecules, ligands and other compounds of the invention.
  • Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for the polypeptide include methods that utilise the antibody and a label to detect the polypeptide in human body fluids or extracts of cells or tissues.
  • the antibodies may be used with or without modification, and may be labelled by joining them, either covalently or non-covalently, with a reporter molecule.
  • reporter molecules A wide variety of reporter molecules known in the art may be used, several of which are described above. Quantities of polypeptide expressed in subject, control and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.
  • Diagnostic assays may be used to distinguish between absence, presence, and excess expression of polypeptide and to monitor regulation of polypeptide levels during therapeutic intervention. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials or in monitoring the treatment of an individual patient.
  • a diagnostic kit of the present invention may comprise:
  • a diagnostic kit may comprise a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to the invention; a second container containing primers useful for amplifying the nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease.
  • the kit may further comprise a third container holding an agent for digesting unhybridised RNA.
  • a diagnostic kit may comprise an anay of nucleic acid molecules, an anay of antibody molecules, and/or an anay of polypeptide molecules, as discussed in more detail above.
  • kits will be of use in diagnosing a disease or susceptibility to disease, particularly inflammation, oncology, or cardiovascular disease.
  • Smartomics The method used in the following examples for the identification of hypoxia-induced genes and proteins utilised an approach herein termed "Smartomics".
  • This method is a differential expression screening method for identifying genetic elements that are involved in a particular cellular process and is described in detail in co-pending, co-owned International patent application PCT/GBO 1/00758 entitled "Differential Expression Screening Method”. Simplistically put, the method involves comparing:
  • gene expression in a second cell of interest which cell comprises altered levels, relative to physiological levels, of a biological molecule implicated in the cellular process, due to the introduction into the second cell of a heterologous nucleic acid directing expression of a polypeptide; and identifying a genetic element whose expression differs, wherein gene expression in said first and/or second cell of interest is compared under at least two different environmental conditions relevant to the cellular process.
  • gene expression is compared in both the first and the second cell of interest under at least two different environmental conditions relevant to the cellular process.
  • the object of the Smartomics methodology is to amplify and/or increase the signal to noise ratio of the differential response normally obtained so as to increase the likelihood of detecting gene products whose levels in a cell are low and/or whose expression normally changes by only a small amount.
  • the Smartomics method has been utilised herein to improve the discovery of genes activated or repressed in response to hypoxia in primary human macrophages. This involves augmenting the natural response to hypoxia, by experimentally introducing a key regulator of the hypoxia response, namely hypoxia inducible factor l ⁇ (HIF-1 ⁇ ), into a population of primary human macrophages and comparing gene expression in these cells with that in control cells.
  • a key regulator of the hypoxia response namely hypoxia inducible factor l ⁇ (HIF-1 ⁇ )
  • HIF-l ⁇ is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPASl) or HIF-2 ⁇ , which shares 48% sequence identity with HIF-1 ⁇ (“Endothelial PAS domain protein 1 (EPASl), a transcription factor selectively expressed in endothelial cells.” Tian H, McKnight SL, Russell DW. Genes Dev.
  • the cunent example also utilises overexpression of EPASl, as an independent means of improving discovery of hypoxia-responsive genes, to overexpression of HIF-1 ⁇ . It also illustrates an embodiment of the Smartomics invention, whereby differences in the response to HIF-l ⁇ or EPASl (or other mediators of the hypoxia response) may be identified, with the goal of identifying therapeutic target molecules more suitable for specific and efficient treatment of disease.
  • FIG. 1 Northern blots performed to confirm overexpression of HLF-l ⁇ and EPASl using adenoviral gene transfer in transduced macrophages.
  • RNA loading was as follows Lanes 1,2: Macrophages transduced with the adenovirus AdApt ires-GFP. Lanes 3,4 Macrophages transduced with the adenovirus AdApt HLF-l ⁇ -ires-GFP. Lanes 4,5 Macrophages transduced with the adenovirus AdApt EPASl -ires-GFP. In lanes 1,3,5 the macrophages were maintained in normoxia (20% O ). In lanes 2,4,6 the macrophages were maintained in hypoxia (0.1% O ).
  • Hybridisation probes were complimentary to the genes HIF-1 ⁇ (A), EPAS 1 (B) and 28s ribosomal RNA (C).
  • FIG. 3 Analysis of Lactate Dehydrogenase A expression with Smartomics.
  • section A thumbnail images of spots conesponding to the lactate dehydrogenase-A (LDH-A) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure.
  • Each strip of 6 images corresponds to a discrete anay position or experiment, over the range of RNA samples.
  • Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O 2 ).
  • Anay location Identity of the spot as defined by Research Genetics. Clone: IMAGE identification.
  • the histogram (section B) shows the average of the figures shown and error bars are standard deviation, gfp: cells transduced with AdApt ires-GFP.
  • Hif-la Cells transduced with AdApt Hif-l ⁇ -ires-GFP.
  • Epasl Cells transduced with AdApt Epasl -ires-GFP.
  • Figure 4 Analysis of Glyceraldehyde 3-phosphate dehydrogenase expression with Smartomics.
  • section A thumbnail images of spots conesponding to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene are shown.
  • Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure.
  • Each strip of 6 images conesponds to a discrete anay position or experiment, over the range of RNA samples.
  • Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O 2 ).
  • Anay location Identity of the spot as defined by Research Genetics. Clone: IMAGE identification.
  • the histogram (section B) shows the average of the figures shown and enor bars are standard deviation, gfp: cells transduced with AdApt ires-GFP.
  • Hif-la Cells transduced with AdApt Hif-l ⁇ -ires-GFP.
  • Epasl Cells transduced with AdApt Epasl -ires- GFP.
  • Figure 5 Analysis of Platelet derived growth factor beta expression with Smartomics.
  • section A thumbnail images of spots conesponding to the Platelet derived growth factor beta (PDGF Beta) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure.
  • Each strip of 6 images conesponds to a discrete array position or experiment, over the range of RNA samples.
  • Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O 2 ).
  • Anay location Identity of the spot as defined by Research Genetics. Clone: IMAGE identification.
  • gfp cells transduced with AdApt ires-GFP.
  • Hif-la Cells transduced with AdApt Hif-l ⁇ - ires-GFP.
  • Epasl Cells transduced with AdApt Epasl -ires-GFP.
  • FIG. 6 Analysis of Monocyte Chemotactic Protein- 1 expression with Smartomics.
  • section A thumbnail images of spots corresponding to the Monocyte Chemotactic Protein- 1 (MCP-1) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure.
  • Each strip of 6 images conesponds to a separate experiment, over the range of RNA samples.
  • Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O 2 ).
  • Anay location Identity of the spot as defined by Research Genetics. Clone: IMAGE identification.
  • the histogram (section B) shows the average of the figures shown and error bars are standard deviation, gfp: cells transduced with AdApt ires-GFP.
  • Hif-la Cells transduced with AdApt Hif-l ⁇ -ires-GFP.
  • Epasl Cells transduced with AdApt Epasl -ires-GFP.
  • Figure 7 Discovery of a novel gene (EST acc:N64734 (LMAGE:293336)) using Smartomics.
  • section A thumbnail images of spots conesponding to the EST from UniGene cluster EST acc:N64734 (IMAGE:293336) are shown.
  • Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. For this gene, contrast levels are at maximum.
  • Each strip of 6 images conesponds to a separate experiment, over the range of RNA samples.
  • Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O 2 ).
  • Anay location Identity of the spot as defined by Research Genetics. Clone: IMAGE identification.
  • the histogram (section B) shows the average of the figures shown and enor bars are standard deviation, gfp: cells transduced with AdApt ires-GFP.
  • Hif-la Cells transduced with AdApt Hif-l ⁇ -ires-GFP.
  • Epasl Cells transduced with AdApt Epasl -ires-GFP.
  • FIG 8 Virtual Northern blot hybridisation to validate discovery of EST acc:N64734 (IMAGE:293336) by Smartomics.
  • A) Hybridisation probe IMAGE clone 1674154 (ace: AI051607) which conesponds to the same gene as EST acc:N64734.
  • B) Hybridisation probe ⁇ actin.
  • Lanes 1-6 are the RNA samples used in Figures 3-7, from cells transduced with adenovirus.
  • Lanes 7-10 are from non-transduced macrophages with (lanes 9,10) or without (lanes 7,8) prior activation. Histograms show relative mRNA expression levels, from phosphorimager analysis, relating to the Northern blots positioned above. Figures are relative expression ratios compared to gfp (20% O 2 ).
  • Example 1 The use of Smartomics for the identification of hypoxia-regulated genes in macrophages
  • HIF-l ⁇ or EPASl foreign gene sequences
  • primary macrophages may be achieved by recombinant adenovirus.
  • a commercially available system was used herein to produce adenoviral particles involving the adenoviral transfer vector AdApt, the adenoviral genome plasmid AdEasy and the packaging cell line Per-c6 (Introgene, Leiden, The Netherlands). The standard manufacturer's instructions were followed.
  • AdApt ires- GFP Three derivatives of the AdApt transfer vector have been prepared, named AdApt ires- GFP, AdApt HLF-l ⁇ -ires-GFP and AdApt EPASl -ires-GFP.
  • AdApt was modified such that inserted genes (i.e. HIF-1 ⁇ or EPASl) expressed from the powerful cytomegalovirus (CMV) promoter were linked to the green fluorescent protein (gfp) marker, by virtue of an internal ribosome entry site (ires). Therefore presence of green fluorescence provides a convenient indicator of viral expression of HIF- 1 ⁇ or EPAS 1 in transduced mammalian cells.
  • CMV cytomegalovirus
  • AdApt standard molecular biology methods were used to construct the derivatives of AdApt, which included reverse transcriptase PCR (RT-PCR), transfer of DNA fragments between plasmids by restriction digestion, agarose gel DNA fragment separation, "end repairing" double stranded DNA fragments with overhanging ends to produce flush blunt ends, and DNA ligation. Subcloning steps were confirmed by DNA sequencing. These techniques are well known in the art, but reference may be made in particular to Sambrook et al, Molecular Cloning, A Laboratory Manual (2000) and Ausubel et al, Short Protocols in Molecular Biology (1999) 4th Ed, John Wiley & Sons, Inc.
  • RT-PCR reverse transcriptase PCR
  • AdApt ires-GFP was made by inserting the encephalomyocarditis virus EMCV ires followed by the green fluorescent protein gene (GFP), into the end-repaired Hpal restriction site of AdApt, immediately downstream of and in the same orientation as the CMV promoter. Both EMCV ires and gfp sequences are widely used and can be obtained from commonly available plasmids.
  • SEQ ID NO:A recites the exact nucleotide sequence of the joined ires-GFP which was inserted into the AdApt plasmid.
  • AdApt HIF-1 ⁇ -ires-GFP was derived from AdApt ires-GFP by inserting the protein coding sequence of human HIF-l ⁇ between the CMV promoter and the ires-GFP elements of AdApt ires-GFP.
  • human HLF-l ⁇ cDNA was cloned by RT-PCR from human mRNA, and the sequence was verified by comparison to the published HIF- l ⁇ cDNA nucleotide sequence (Genbank accession U22431).
  • HEF-l ⁇ sequence was ligated as an end-repaired fragment into the end-repaired Agel restriction site of AdApt ires-GFP [this is also the Agel restriction site of the parental vector AdApt immediately downstream of the CMV promoter].
  • SEQ ID NO: B The exact DNA sequence containing HLF-l ⁇ that was inserted into AdApt ires-GFP is shown in SEQ ID NO: B.
  • AdApt EPAS 1-ires-GFP was derived from AdApt ires-GFP by inserting the protein coding sequence of human EPAS 1 between the CMV promoter and the ires-GFP elements of AdApt ires-GFP.
  • human EPASl cDNA was cloned by reverse transcriptase PCR (RT-PCR) from human mRNA, and the sequence was verified by comparison to the published EPASl cDNA nucleotide sequence (GenBank accession U81984).
  • the EPASl sequence was ligated as an end-repaired fragment into the end- repaired Agel restriction site of AdApt ires-GFP [this is also the Agel restriction site of the parental vector AdApt immediately downstream of the CMV promoter].
  • the exact DNA sequence containing EPAS 1 which was inserted into AdApt ires-GFP is shown in SEQ LD NO:C
  • adenoviral transfer vectors AdApt HIF-1 ⁇ -ires-GFP and AdApt EPASl -ires-GFP were verified prior to production of adenoviral particles, for their ability to drive expression of functionally active HIF-1 ⁇ or EPASl protein from the CMV promoter in mammalian cells. This was achieved by transient transfection luciferase-reporter assays as described (Boast K, Binley K, Iqball S, Price T, Spearman H, Kingsman S, Kingsman A, Naylor S. Hum Gene Ther. 1999 Sep l;10(13):2197-208. "Characterisation of physiologically regulated vectors for the treatment of ischemic disease.”).
  • adenoviral preparations were quantitated by spectrophotometry, yielding values of viral particles (VP) per milliliter.
  • monocytes were derived from peripheral blood of healthy human donors. 100ml bags of buffy coat from the Bristol Blood Transfusion Centre (Bristol, UK) were mixed with an equal volume of RPMI1640 medium (Sigma). This was layered on top of 10ml ficol-paque (Pharmacia) in 50ml centrifuge tubes and centrifuged for 25 min at 800 x g. The interphase layer was removed, washed in MACS buffer (phosphate buffered saline pH 7.2, 0.5% bovine serum albumin, 2mM EDTA) and resuspended at 80 microliter per 10n7 cells.
  • MACS buffer phosphate buffered saline pH 7.2, 0.5% bovine serum albumin, 2mM EDTA
  • the macrophages were washed and resuspended in DMEM (Gibco, Paisley, UK) supplemented with 4% fetal bovine serum (Sigma). 4xl0 6 cells were plated into individual 10cm Primeria (Falcon) tissue culture dishes in a total volume of 8 ml per plate, with 6x10° adenoviral particles per ml. Following culture for 16 hr, during which the macrophages adhere to the plate and are infected by the adenoviral particles, the medium is removed and replaced by AIM V medium supplemented with 2% human AB serum. A further 24 hr period of culture is allowed prior to experimentation, to allow gene expression from the transduced adenovirus.
  • adenoviral particles The above dosage of adenoviral particles was determined to be the minimum amount required to achieve transduction of the majority (over 80%) of the macrophage population, using green fluorescence as a marker of gene transfer. This was confirmed using a separate adenoviral construct containing the LacZ reporter gene. By selecting the minimum dose of virus, possible non-specific effects of viral transfer are minimised.
  • Gene discovery can be implemented by comparing gene expression profiles between these "cell types". According to conventional methods available in the literature, one would make comparisons between cell types 2 and 1. By implementing the Smartomics method, several other possibilities are seen. Firstly, a comparison can be made between cell types 3 or 5 and cell type 1. Here, the stimulus of overexpressing key molecules involved in the hypoxia response may exceed the natural response the hypoxia, as seen for cell type 2. Secondly, in a prefened embodiment of the invention, a comparison can be made between cell types 4 or 6 and cell type 1. In this situation, the natural response to hypoxia is being augmented or boosted by overexpressing key molecules involved in the hypoxia response.
  • RNA samples extracted from cell types 1-6 as described above were analysed by Northern blotting ( Figure 1).
  • the RNA samples (8ug total RNA per lane) were electrophoresed on a formaldehyde denaturing 1% agarose gel, then transferred to a nylon membrane (Hybond-N, Amersham, UK), and sequentially hybridised with 33 P- labelled DNA probes complementary in nucleotide sequence to HIF-l ⁇ ( Figure la), EPASl ( Figure lb) or 28S ribosomal RNA ( Figure lc).
  • RNA expression profiles from the RNA samples isolated from the six "cell types” were obtained using Research Genetics Human GeneFilters Release 1 (GF200) (Research Genetics, Huntsville, AL). This method uses pre-made arrays of DNA complementary to 5,300 genes covering a range of levels of characterisation, including sequences which only match unannotated ESTs or cDNA sequences of unknown function.
  • the anays are nylon in composition, and are spotted with DNA derived from specific IMAGE consortium cDNA clones (http://image.llnl.gov/image/).
  • the anays are hybridised to RNA samples which have been radioactively labelled with the isotope 33 P to measure the abundance of individual genes within the RNA samples. Multiple RNA samples are labelled and hybridised in parallel to separate copies of the anay, and spot hybridisation signals are compared between the RNA samples. Key issues in anay-based mRNA expression analysis are sensitivity and reliability. Cunently two other methods are available; glass microanays and DNA chips, both of which utilise fluorescently labelled RNA (Bowtell DD. Nat Genet.
  • Pair-wise comparisons were made between condition 2 and condition 1 condition 3 and condition 1 condition 4 and condition 1 condition 5 and condition 1 condition 6 and condition 1
  • condition 1 i.e. cell type 1
  • Results were output as expression profiles of individual genes, showing normalised signal intensity and expression ratio.
  • a key advantage of analysis in Pathways 3.0 is that high magnification thumbnail images of individual spots are displayed. This allows visual verification that the area being measured truly covers the region containing the hybridised anay spot, and that the spot is real and not a background artefact.
  • thumbnail images are not normalised to compensate for global differences, and are limited in image quality. Greyscale images are inherently limited in their capacity to depict quantitative differences in intensity. Digital images generated by the Storm phosphorimager cover a linear dynamic range of 100,000 for a single pixel, whereas printed images can only be depicted as 256 shades of grey.
  • LDH-A lactate dehydrogenase A gene
  • the lactate dehydrogenase A (LDH-A) gene is known in the art to be activated by hypoxia (Webster KA. Mol Cell Biochem. 1987 Sep;77(l): 19-28. "Regulation of glycolytic enzyme RNA transcriptional rates by oxygen availability in skeletal muscle cells.”).
  • Figure 3 it can be seen that in response to hypoxia alone (gfp 0.1% O 2 ) there is on average a 2.24-fold increase in mRNA expression compared to normoxia (gfp 20% O ).
  • HIF-l ⁇ is responsible for mediating the hypoxia-induced activation of LDH-A (Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Genes Dev. 1998 Jan 15;12(2): 149-62 "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.”).
  • overexpression of HIF-l ⁇ in a stable manner using viral gene transfer techniques, both with or without simultaneous hypoxia causes secondary changes in gene expression which are markedly greater than the natural hypoxia response.
  • the response to hypoxia of LDH- A is also improved by overexpressing EPASl (Figure 3; EPASl), though this is less dramatic than overexpressing HIF-1 ⁇ .
  • the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene is known in the art to be activated by hypoxia (Webster KA. Mol Cell Biochem. 1987 Sep;77(l): 19-28. "Regulation of glycolytic enzyme RNA transcriptional rates by oxygen availability in skeletal muscle cells.”).
  • hypoxia Webster KA. Mol Cell Biochem. 1987 Sep;77(l): 19-28. "Regulation of glycolytic enzyme RNA transcriptional rates by oxygen availability in skeletal muscle cells.”
  • HIF-l ⁇ is responsible for mediating the hypoxia-induced activation of GAPDH (Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Genes Dev. 1998 Jan 15; 12(2): 149-62 "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.”).
  • overexpression of HLF-l ⁇ in a stable manner using viral gene transfer techniques, both with or without simultaneous hypoxia causes secondary changes in gene expression which are markedly greater than the natural hypoxia response.
  • Platelet derived growth factor beta (PDGF ⁇ ) is also known in the art to be activated by hypoxia (Kourembanas S, Hannan RL, Faller DV. J Clin Invest. 1990 Aug;86(2):670-4 "Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells.”).
  • hypoxia gfp 0.1% O 2
  • monocyte chemotactic protein 1 (MCP-1) is known in the art to respond to hypoxia in a negative fashion, by decreasing mRNA expression (Negus RP, Turner L, Burke F, Balkwill FR. J Leukoc Biol 1998 Jun;63(6):758-65. "Hypoxia down- regulates MCP-1 expression: implications for macrophage distribution in tumors").
  • MCP-1 monocyte chemotactic protein 1
  • HIF-1 ⁇ or EPASl potentiates hypoxia-induced gene repression, as exemplified by MCP-1, is totally without precedent in this field.
  • the structure of both HIF-1 ⁇ and EPASl proteins is that they contain transactivation domains but not known transcriptional repressor domains (Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. J Biol Chem. 1997 Apr 25;272(17): 11205-14. "Activation of hypoxia-inducible factor- 1; definition of regulatory domains within the alpha subunit.”).
  • FIG. 7 shows the expression profile of a gene discovered using the described method, conesponding to an EST not previously known to be induced by hypoxia (GenBank accession N64734; IMAGE clone 293336). Thumbnail array spot images are shown at maximal contrast, such that the background signal is apparent. It can be seen that in response to hypoxia alone (gfp 0.1% O 2 ) there is on average a 1.4-fold increase in mRNA expression compared to normoxia.
  • RNA samples used for array hybridisation.
  • An additional four RNA samples were also processed, derived from non-transduced macrophages cultured in normoxia and hypoxia (6 hours at 0.1% O 2 ) both with and without pre-treatment for 16 hours with 100 ng/ml Lipopolysaccharide (E.coli 026:B6 Sigma, UK) and 1000 u/ml human gamma interferon (Sigma, UK).
  • This combination of factors causes macrophage activation, a process key to the physiological and pathophysiological actions of the macrophage.
  • HIF-l ⁇ may be induced by stimuli other than hypoxia, which are pertinent to human disease, including thrombin (Gorlach A. et al; Circ Res.
  • HLF-l ⁇ is frequently activated in human cancer cells in the absence of hypoxia (Wiesener MS et al; Cancer Res. 61:5215-22).
  • Tables 1 and 2 expression data is presented for genes identified by the procedure mentioned above. Adenoviral overexpression of HIF-l ⁇ was always done in combination with exposing cells with hypoxia to obtain the maximum dose of this transcription factor. For adenoviral overexpression of EPAS, as demonstrated in Figures 3-7, a maximal dose of this transcription factor does not require simultaneous exposure to hypoxia.
  • IMAGE clone Accession denotes the GenBank EST accession number of the IMAGE clone represented on the gene array.
  • Column 2 (title) denotes the name commonly associated with the gene.
  • Column 3 (Nucl Seq ID) denotes the patent identification number of the nucleotide sequence.
  • Column 4 (Nucleotide Accession) refers to the longest nucleotide sequence corresponding to the IMAGE clone as determined by standard bioinformatics procedures.
  • Column 5 Prot Seq ID
  • Column 6 (Protein Accession) refers to the GenBank accession number of the protein sequence as determined by standard bioinformatics procedures.
  • IMAGE clones were obtained from the UK MRC HGMP Resource Centre (Hinxton, Cambridge CB10 1SB, UK) and were re-isolated as individual colonies and sequenced to verify the correct identity of the clone. In the majority of cases, the same IMAGE clone identified from the Research Genetics Human GeneFilters was selected, but in some instances these clones were not available and alternatives were selected, corresponding to the same gene.
  • the custom gene array is a single colour type array, and contains a selection of additional IMAGE clones corresponding to genes which were empirically determined not to be affected by hypoxia and which are highly expressed in a wide range of human tissues and cell types.
  • spot intensities were divided by the mean of all the reference genes shown below, each of which was present in quadruplicate on each array.
  • IMAGE clone plasmid miniprep DNA was prepared and PCR amplified with flanking vector primers of the sequences GTTTTCCCAGTCACGACGTTG and TGAGCGGATAACAATTTCACACAG. This was then purified and concentrated by ethanol precipitation, and the presence of a single band and DNA concentration were determined by agarose gel electrophoresis and by digital imaging methods.
  • PCR product was normalised to 0.5 mg/ ml by dilution.
  • Arrays were fabricated onto Hybond N+ (Amersham) membranes using a BioRobotics TAS arrayer (Biorobotics, Cambridge CB37LW, UK) with a 500 micron pin tool. Using 384-well source plates and a 2x2 arraying format this array was relatively low density, thereby eliminating problems of spot-to-spot signal bleed. Also the large pin size and high source plate DNA concentration improves the sensitivity of detection.
  • Post-arraying denaturation/ neutralisation was essentially as described by Bertucci F et al., 1999 (Oncogene 18: 3905-3912).
  • the cDNA was then denatured by heating and added to the pre-hybridisation, which was continued for 18-20hr. Washing steps were done as follows: 2xSSC/ 1% SDS 2x20min at 50 degrees and 0.5xSSC/ 1% SDS lOmin at 55 degrees. Arrays were exposed to Amersham Low Energy phosphor screens for 24hr and scanned using a phosphorimager at 50 micron resolution. Image analysis was done using ArrayVision software (Imaging Research Ine). Tab delimited data files were exported and a full analysis performed using GeneSpring software (Silicon Genetics).
  • Example 3 Tissue-specific hypoxia regulation of gene expression by an analysis of a series of primary human cell cultures
  • RNA samples which were induced or repressed preferentially in particular cell type(s) were identified by hybridisation of the RNA samples to the custom gene array, as described previously.
  • Each RNA sample was hybridised to duplicate or triplicate arrays, to ensure reproducible data, and was analysed using GeneSpring software. Data from replicate arrays were merged during analysis to generate mean values. Data normalisation was achieved per-array using the aforementioned list of control genes, such that differences in RNA labelling or hybridisation due to experimental variation were corrected by referencing each gene to the mean value of the reference genes on the same array. Also, for each gene, expression values were obtained which represent the value in each experimental condition
  • Tables are presented below containing quantitative data regarding the expression of certain genes found to be induced in response to hyopxia preferentially in certain cell types.
  • the expression values contained in these tables represent the ratio of the expression in cell types compared to the median value of that gene throughout all cell types and oxygen conditions. For instance, in this analysis a normalised expression value of 0.5 therefore represents 2-fold underexpression and a normalised expression value of 0.333 therefore represents 3-fold underexpression compared to the median level.
  • monocytes and macrophages are similar cell types, the latter derived from the former, they will be analysed together.
  • the following genes were observed to be induced preferentially in monocytes/ macrophages, illustrating specific utility in the diagnosis and treatment of diseases involving the hypoxic macrophage as detailed in Example 1:
  • beta-Fc-gamma receptor II (Sen ID: 59/60) Clone:plN2
  • NK cell receptor CSl (Se ⁇ ID: 103/104) Clone:p2L12
  • Beta-Fc-gamma receptor II (SeqTD:- 59/60) encodes a well known receptor relevant to rheumatoid arthritis (Blom A.B. et al Arthritis Res 2000, 2:489-503) and the current clinical treatment of human inflamatory conditions (Samuelson A. et al Science 2001, 291:484-486).
  • IRCl also known as CMRF-35H or CMRF-35-H9; Seq D:-135/136
  • ITIMs immunoreceptor tyrosine-based inhibitory motifs
  • genes were found to be preferentially induced by hypoxia in hepatocytes, a cell type of the liver and relavant to the treatment of hepatic disorders involving ischaemia.
  • Hermanskv-Pudlak syndrome tvne-3 protein (Se ⁇ ID: 235/236) Clone:p2H2
  • heat-shock protein 40 (Se ⁇ ID: 79/80) Clone:plL2
  • the responses of two myocyte cell types to hypoxia was determined using the custom array.
  • the response of skeletal muscle myocytes to hypoxia is of particular interest to the treatment of peripheral arterial disease and the response of cardiomyocytes to hypoxia is of particular interest to the treatment of cardiac ischaemia.
  • Genes which respond to hypoxia in both these cell types may encode natural protective factors which may be utilised in the design of new therapies, and are listed below.
  • the responses to hypoxia of primary epithelial cells derived from mammary and renal tissues was determined using the custom array.
  • the response of epithelial cell types to hypoxia is of particular interest because normal tissue homeostatsis is maintained in several key organs by a balance of gene products at the epithelial: stromal interface involving recepto ⁇ ligand, celhmatrix (basement membrane), and other interactions. Disruption of this homeostasis, as may occur in response to hypoxia, leading to inappropriate reawakening of developemental remodelling processes may be a contributing factor in several pathologies including the processes of neoplasia and tumorigenesis.
  • Example 4 Effects on gene expression when cells are treated with cytokines and/or other molecules
  • an induction ration of -2.0 represents a two-fold decrease in expression and an induction ration of -3.0 represents a three-fold decrease in expression.
  • down-regulation is expressed as a fraction (for example in example 3; 0.5 represents a two-fold decrease in expression and 0.333 represents a three-fold decrease in expression).
  • 0.5 represents a two-fold decrease in expression
  • 0.333 represents a three-fold decrease in expression
  • Tumor necrosis factor alpha is a key cytokine implicated in a wide range of infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, severe bacterial infection, septic shock, cerebral malaria, transplant rejection, allergic encephalomyelitis, cancer, gestational diabetes (GDM), insulin resistance syndrome, adult-onset diabetic patients, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Crohn disease, hyperandrogenism, alopecia areata, Japanese Guillain-Barre syndrome, mucocutaneous leishmaniasis, meningococcal disease, lepromatous leprosy, scarring trachoma and asthma.
  • TNF alpha The significance of TNF alpha to human disease is clearly well established in the art. To investigate whether genes identified as hypoxia regulated may also respond to TNF alpha, cultures of primary macrophages were treated with lOOng/ml recombinant human TNF alpha and RNA was extracted after 24hr. The following genes were found to change in expression in response to TNF alpha.
  • Interleukin 1 beta mediates the panoply of host reactions collectively known as acute phase response and is a key cytokine implicated in a wide range of infectious, auto- immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, cancer, high bone turnover, osteoporosis, cardiovascular disease, alzheimer's disease, ulcerative colitis and Crohn's disease, lupus erythematosus, cerebral ischaemia, diabetes mellitus.
  • genes identified as hypoxia regulated may also respond to LL1
  • cultures of primary macrophages were treated with lOOng/ml recombinant human LL1 and RNA was extracted after 6 and 24hr. The following genes were found to change in response to this treatment, as determined using the custom gene array.
  • lipopolysaccharide and gamma interferon are commonly used way of stimulating macrophages to mimic acute bacterial infection, and causes the macrophage to assume a highly activated cellular phenotype.
  • LPS Lipopolysaccharide
  • IFN gamma Interferon
  • the macrophage is a key cell type in rheumatoid arthritis (RA) involved in inflammation associated with the synovium. As well as being exposed to hypoxia these macrophages are exposed to a range of cytokines. These include TNF alpha and IL-1 beta which are significant to a wide range of inflammatory conditions; and genes which respond to these factors have been presented above.
  • RA rheumatoid arthritis
  • LL-12 is expressed by infiltrating macrophages and synovial cells in RA patients (Sakkas L.I. et al Cell Immunol 1998 188: 105-110) and the principal targets of this cytokine are T- cells.
  • responses of macrophages to this cytokine will be relevant considering the association of this cytokine with RA, in which the macrophage plays a critical role.
  • genes identified as hypoxia regulated may also respond to IL-12, cultures of primary macrophages were treated with 100 ng /ml recombinant human IL-12 (obtained from Preprotech) and RNA was extracted after 6 and 48 hours. The genes listed below were found to change in response to this treatment, as determined using the custom gene array.
  • LL-15 is implicated in several diseases in which macrophages and hypoxia both feature as elements of the inflammatory state, such as in atherosclerosis (Wuttge DM et al Am J Pathol. 2001 159:417-23) and rheumatoid arthritis (Mclnnes IB et al Immunol Today. 1998 19:75-9).
  • atherosclerosis Wangtge DM et al Am J Pathol. 2001 159:417-23
  • rheumatoid arthritis Mclnnes IB et al Immunol Today. 1998 19:75-9
  • T-cells effects have also been shown on monocytes (Badolato R et al Blood. 1997 90:2804-9). Therefore genes which respond to both hypoxia and LL-15 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
  • IL-17 has been shown to mediate inflammation and joint destruction in arthritis (Lubberts et al J.Immunol 2001 167: 1004-1013). IL-17 has also been shown to stimulate macrophages to release other key pro-inflammatory cytokines (Jovanovic et al J Immunol 1998 160:3513-21). Therefore genes which respond to both hypoxia and IL-17 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
  • the cytokines IL4 and ILI 3 are produced by Th2 cells, and have very similar actions, being implicated in immune reactions associated with strong antibody and allergic responses.
  • the effects of these cytokines are opposite to those of Thl type cytokines (such as gamma interferon), which are implicated in immune reactions associated with strong cell mediated reactions.
  • Thl type cytokines such as gamma interferon
  • these two classes of cytokines are believed to antagonise one another.
  • genes which are suppressed in response to LL4 or ILI 3 may indicate a pro-inflamatory role in Thl responses (such as found in cancer, RA, and Crohn's disease) where they are likely to be induced, whereas genes which are induced in response to IL4 or IL13 are likely to have an anti-inflammatory role in Thl responses.
  • the following genes were found to change in expression in response to these cytokines at lOOng/ml for 24 hours in primary human monocyte-derived macrophages.
  • the cytokine IL-10 is a key anti-inflammatory cytokine which causes general downregulation of macrophage effector functions.
  • Several hypoxia-regulated genes in this specification are responsive to this cytokine, implicating them in inflammatory macrophage functions.
  • Genes which responded to lOOng/ml LL-10 at 24 hr in primary human macrophages are presented below.
  • Superoxide radicals have frequently been associated with ischaemia reperfusion and several studies have shown that ischaemia/ reperfusion-associated tissue damage is largely due to superoxide radicals (reviewed in Salvemini D 2002; Nature Reviews Drug Discovery 1 : 367-374). Superoxide radicals are also generated in the inflamed rheumatoid synovium, possibly as a result of ischaemia / reperfusion (Allen R.E. et al 1989, The Lancet. 2:282-3; Allen R.E. et al 1987, Annals Rheum. Dis. 46:843-845). Several cell types including macrophages respond to superoxide radicals is a highly pro-inflammatory way.
  • One of the utilities of the genes identified herein relates to the diagnosis and treatment of human tumors, on the basis that hypoxia is frequently found in tumors, resulting in features of the course and treatment of the disease. For instance, tumor angiogenesis is required for growth of tumors, and this is regulated by factors induced by hypoxia.
  • A Lung tissue affected with well differentiated squamous cell carcinoma derived from a 78 year old male. Comparison to normal adjacent lung tissue from the same patient.
  • D Colon tissue affected with moderately differentiated adenocarcinoma derived from a 74 year old female. Comparison to normal adjacent colon tissue from the same patient.
  • E Kidney tissue affected with carcinoma derived from a person of unknown age and sex. Comparison to normal adjacent kidney tissue from the same patient.
  • G Cervix tissue affected with endometrioid adenocarcinoma derived from a 70 year old female. Comparison to normal adjacent cervix tissue from the same patient.
  • H Ovary tissue affected with adenocarcinoma derived from a 50 year old female. Comparison to normal adjacent ovary tissue from the same patient.
  • I Ovary tissue affected with poorly differentiated adenocarcinoma derived from a 60 year old female.
  • J Ovary tissue affected with moderately differentiated adenocarcinoma derived from a 41 year old female. Comparison to normal adjacent ovary tissue from the same patient.
  • Negative values represent gene suppression or down-regulation as compared to adjacent normal tissue. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression.
  • Example 6 Gene expression changes associated with chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • Negative values represent gene suppression or down-regulation as compared to the healthy donor. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression.
  • Atherosclerosis is the process of thickening of arterial walls, leading to several pathologies including coronory artery disease, peripheral arterial disease, stroke, and a series of other related diseases. It is well established in the art that macrophages are central to the formation and development and rupture of atherosclerotic plaques (Nature Drug Discovery Reviews; Feb 2002; 122-130.). For example transgenic mice which are deficient in proteins required for the accumulation of macrophages in atherosclerotic plaques (i.e. CCR2 or MCPl) display a resistance to this disease following feeding on high fat diets.
  • Macrophages in atherosclerotic lesions accumulate cholesterol in the form of modified LDLs, acting as a storage resevoir.
  • the environment of the plaque is likely to involve hypoxia (Gainer J.L. Atherosclerosis 1987 68:263-266), and the response of macrophages to this is likely to contribute to their role in the disease process.
  • Vps39/Nam6-like protein The Oxford BioMedica clone p2G21 represents Vps39/Nam6-like protein .
  • the protein sequence encoded by Vps39/Vam6-like protein is represented in the public databases by the accession AAK58862 and is described in this patent by Seq ID 1.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF334400 and is described in this patent by Seq ID 2.
  • Vps39/Vam6-like protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Vps39/Vam6-like protein is induced in response to TNFalpha, by a factor of 2.19 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • Vps39/Nam6-like protein is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Vps39/Vam6-like protein was down-regulated 2.7, 1.64 and 1.75 fold in the three diseased patients compared to the control group. This indicates that Vps39/Vam6-like protein plays a role in the process of atherogenesis.
  • Vps39/Vam6-like protein contains a citron homology domain which is a regulatory domain involved in macromolecular interactions and an alpha helical repeat region which shares homology to the Clathrin repeat.
  • the Oxford BioMedica clone p2Ll represents Kell blood group.
  • the protein sequence encoded by Kell blood group is represented in the public databases by the accession AAH03135 and is described in this patent by Seq LD 3.
  • the nucleotide sequence is represented in the public sequence databases by the accession BC003135 and is described in this patent by Seq ID 4.
  • Kell blood group is up-regulated by greater than 2-fold by Epas.
  • the Kell blood group contains a Peptidase family M13 domain.
  • the Oxford BioMedica clone p2H10 represents 27.2KDA protein C21ORF7.
  • the protein sequence encoded by C21ORF7 is represented in the public databases by the accession P57077 and is described in this patent by Seq ID 5.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_020152 and is described in this patent by Seq ID 6.
  • C21ORF7 is up-regulated by greater than 2-fold by Epas.
  • C21ORF7 is preferentially induced by hypoxia in myocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for cardiac ischaemia and ischemic limbs.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • C21ORF7 is induced by a factor of 4.73 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • C21ORF7 is repressed by a factor of 1.67 in response to IL-13 and 2.04 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone plM21 represents 5'-AMP-acitivated protein kinase, beta-2 subunit (AMPK).
  • AMPK 5'-AMP-acitivated protein kinase, beta-2 subunit
  • the protein sequence encoded by AMPK is represented in the public databases by the accession 043741 and is described in this patent by Seq ID 7.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005399 and is described in this patent by Seq ID 8.
  • AMPK is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. AMPK is repressed by a factor of 1.56 in response to EL- 10, indicating a negative role in the response to IL-10.
  • AMPK Inhibitors of AMPK may delay disease progression, and AMPK levels may be a prognostic marker.
  • the Oxford BioMedica clone p2G12 represents MMP-2.
  • the protein sequence encoded by MMP-2 is represented in the public databases by the accession P08253 and is described in this patent by Seq ID 9.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004530 and is described in this patent by Seq LD 10.
  • MMP-2 cleaves collagen-like sequences. MMP-2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, MMP-2 is induced in response to TNFalpha, by a factor of 2.3 fold, indicating a positive role in pro- inflammatory responses involving this factor.
  • the cytokine Interleukin- 10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions.
  • MMP-2 is induced by a factor of 2.49 in response to IL-10, indicating a positive role in the response to LL-10. MMP-2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. MMP-2 contains a number of conserved domains including a Matrix Metalloprotease N-terminal domain, Zinc-dependent metalloprotease domains, multiple Fibronectin type 2 domains and multiple Hemopexin-like repeats.
  • the Oxford BioMedica clone p2H14 represents Adam 8 precursor.
  • the protein sequence encoded by Adam 8 is represented in the public databases by the accession P78325 and is described in this patent by Seq ID 11.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001109 and is described in this patent by Seq ID 12.
  • Adam 8 is up-regulated by greater than 2-fold by Epas.
  • Adam 8 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Adam 8 contains multiple domains including an ADAM cysteine-rich domain, a reprolysin M12B zinc family metalloproteinase domain and a Snake disintegrin domain.
  • Adrenomedullin precursor The protein sequence encoded by Adrenomedullin is represented in the public databases by the accession BAA07756 and is described in this patent by Seq LD 13.
  • the nucleotide sequence is represented in the public sequence databases by the accession D43639 and is described in this patent by Seq LD 14.
  • Adrenomedullin is a potent hypotensive and vasodilating agent. Adrenomedullin is up-regulated by greater than 2-fold by Epas.
  • Adrenomedullin is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • Adrenomedullin was down regulated 2.7 and 1.3 fold in two of the three diseased patients compared to the control group. Its repression by hypoxia within developing atherosclerotic plaque may exacerbate disease progression, and adrenomedullin levels may be a prognostic marker.
  • the Oxford BioMedica clone plL21 represents AF1Q transmembrane protein.
  • the protein sequence encoded by AF1Q transmembrane protein is represented in the public databases by the accession Q 13015 and is described in this patent by Seq ID 15.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006818 and is described in this patent by Seq ID 16.
  • AF1Q transmembrane protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, AF1Q transmembrane protein is induced in response to TNFalpha, by a factor of 2 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • AF1Q is highly expressed in thymus and all leukaemic cell lines, and is believed to play a role in the pathogenesis of cancers of the myeloid and lymphoid lineages (PMID: 10025907).
  • Our observation of the response of this gene to hypoxia implies its role in the pathogenesis of inflammatory diseases involving cells of these lineages, and this is supported by its induction by TNFalpha.
  • the Oxford BioMedica clone p2C15 represents AMMECRl protein.
  • the protein sequence encoded by AMMECRl protein was previously represented in the public databases by the accession XPJ313145 and is described in this patent by Seq ID 17.
  • the nucleotide sequence was previously represented in the public sequence databases by the accession XM_013145 and is described in this patent by Seq ID 18.
  • the publicly avilable sequence entries referenced in this patent have been removed from the public domain by request from the original author.
  • AMMECRl is now represented in the public sequence databases by the Protein accession NP_056180, and nucleotide accession NM_015365.
  • AMMECRl protein is up-regulated by greater than 2-fold by Epas.
  • AMMECRl protein is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2I10 represents AMP deaminase 2 isoform L.
  • the protein sequence encoded by AMP deaminase 2 isoform L is represented in the public databases by the accession Q01433 and is described in this patent by Seq ID 19.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK025706 and is described in this patent by Seq ED 20.
  • AMP deaminase 2 isoform L is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • AMP deaminase 2 isoform L is induced by a factor of 2.19 in response to IL-13 and 2.11 in response to IL-4, indicating a positive role in Th2 immune responses.
  • AMP deaminase 2 isoform L is suppressed by a factor of 4.76 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors.
  • AMP deaminase 2 isoform L was down-regulated 1.54, 2.5 and 1.04 fold in the three diseased patients compared to the control group. This indicates that AMP deaminase 2 isoform L plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone pi LI 5 represents Angiopoietin-like 4 protein.
  • the protein sequence encoded by Angiopoietin-like 4 protein is represented in the public databases by the accession NP_057193 and is described in this patent by Seq ID 21.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016109 and is described in this patent by Seq ID 22.
  • Angiopoietin-like 4 protein is up-regulated by greater than 2-fold by Epas.
  • Angiopoietin-like 4 protein is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell- hormone interactions at epithelial cell surfaces.
  • Angiopoietin-like 4 protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • COPD chronic obstructive pulmonary disease
  • Angiopoietin-like 4 protein was up- regulated 2.27 fold in one of the patients. This indicates that Angiopoietin-like 4 protein plays a role in the inflammation associated with COPD.
  • Angiopoietin-like 4 protein contains a Fibrinogen-related domain.
  • the Oxford BioMedica clone p2D17 represents Apoptosis-related RNA binding protein.
  • the protein sequence encoded by Apoptosis-related RNA binding protein is represented in the public databases by the accession AAD 13760 and is described in this patent by Seq ID 23.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF090693 and is described in this patent by Seq ID 24.
  • Apoptosis-related RNA binding protein is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone p2E6 represents Ataxin-1 ubiquitin like interacting protein.
  • the protein sequence encoded by Ataxin-1 ubiquitin like interacting protein is represented in the public databases by the accession NP_064516 and is described in this patent by Seq ID 25.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_020131 and is described in this patent by Seq ID 26.
  • Ataxin-1 ubiquitin like interacting protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Ataxin-1 ubiquitin like interacting protein is repressed by a factor of 2.5 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • Ataxin-1 contains multiple Ubiquitin family and Ubiquitin associated domains.
  • the Oxford BioMedica clone p2H20 represents Band 4.1 -like protein 4.
  • the protein sequence encoded by Band 4.1 -like protein 4 is represented in the public databases by the accession Q9HCS5 and is described in this patent by Seq ID 27.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_022140 and is described in this patent by Seq ID 28.
  • Band 4.1-like protein 4 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Band 4.1-like protein 4 is repressed by a factor of 2.17 in response to IL-13 and 1.82 in response to LL-4, indicating a negative role in Th2 immune responses.
  • Band 4.1-like protein 4 contains a FERM domain. The FERM domain is found in a number of cytoskeleton- associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton.
  • Calpactin 1 light chain (P10 protein).
  • the protein sequence encoded by Calpactin 1 light chain is represented in the public databases by the accession P08206 and is described in this patent by Seq ID 29.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002966 and is described in this patent by Seq ID 30.
  • Calpactin 1 light chain induces the dimerization of Annexin ⁇ and may function as a regulator of protein phosphoryaltion. Calpactin 1 light chain is up-regulated by greater than 2-fold by Epas.
  • Calpactin 1 light chain is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Calpactin 1 light chain was down-regulated 1.85, 2.08 and 1.67 fold in the three diseased patients compared to the control group. This indicates that Calpactin 1 light chain plays a role in the process of atherogenesis.
  • Calpactin 1 light chain contains a S 100 Calcium binding domain.
  • the Oxford BioMedica clone p2L3 represents CALU (Calumenin).
  • the protein sequence encoded by Calumenin is represented in the public databases by the accession AAC 17216 and is described in this patent by Seq ID 31.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF013759 and is described in this patent by Seq ID 32.
  • Calumenin is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Calumenin is repressed by a factor of 2.56 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Calumein is repressed by a factor of 1.79 in response to IL-13 and 2.56 in response to IL-4, indicating a negative role in Th2 immune responses.
  • Calumenin is suppressed by a factor of 2.17 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. Calumenin is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ. These data are consistent with the recent observation that calumenin levels correlate inversely with metastatic potential of tumour cells (PMID: 12090472). Our observation of hypoxia induction has very important implications for the in vivo evolution of metastatic potential, because hypoxic conditions often prevail within tumours. This gene is a useful prognostic indicator and functional agonists should be anti-tumourigenic.
  • Calumein In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Calumein was down-regulated 4.76, 1.33 and 2.33 fold in the three diseased patients compared to the control group. This indicates that Calumenin plays a role in the process of atherogenesis.
  • ARPP-19 The Oxford BioMedica clone plK17 represents cAMP-regulated phosphoprotein 19 (ARPP-19).
  • the protein sequence encoded by ARPP-19 is represented in the public databases by the accession P56211 and is described in this patent by Seq ID 33.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF084555 and is described in this patent by Seq LD 34.
  • ARPP-19 which is a substrate for cAMP-dependent protein kinase and may participate in cAMP-mediated signalling, is induced more than 2-fold by both Hif and Epas. Its induction by hypoxia has important implications for the maintenance of normal signalling.
  • the superoxide radical is a potent stimulus frequently associated with ischemic conditions.
  • Gene ID 34 is suppressed by a factor of 1.52 in response to superoxide. This is consistent with the recently proposed role for this gene in neurodegeneration. Decreased ARPP-19 is involved in pathomechanisms of Downs syndrome and Alzheimer's disease (PMID: 11771749). Based on our demonstration of the importance of this gene to ischaemic disease, both diagnostic and therapeutic opportunities have emerged.
  • the Oxford BioMedica clone plM12 represents CBP/P300-interacting transactivator with glu/asp rich carboxy-terminal domain.
  • the protein sequence encoded by seq ID 35 is represented in the public databases by the accession AAF01263 and is described in this patent by Seq ID 35.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF129290 and is described in this patent by Seq ID 36.
  • the sequence encoded by Seq ID 36 interferes with the binding of transcription factors HIF- la and STAT2 to p300/CBP and is induced by hypoxia and deferoxamine.
  • the protein sequence encoded by seq ID 35 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the protein sequence encoded by seq ID 35 is induced by a factor of 1.87 at 6hr and 2.33 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2G20 represents CCR4-NOT transcription complex, subunit 4.
  • the protein sequence encoded by CCR4-NOT is represented in the public databases by the accession NP_037448 and is described in this patent by Seq ID 37.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_013316 and is described in this patent by Seq ID 38.
  • CCR4-NOT is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • CCR4-NOT is suppressed by a factor of 2.04 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • CCR4-NOT contains an RNA recognition motif.
  • the Oxford BioMedica clone pINIO represents Ceruloplasmin precursor (ferroxidase).
  • the protein sequence encoded by Ceruloplasmin is represented in the public databases by the accession P00450 and is described in this patent by Seq ID 39.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000096 and is described in this patent by Seq ID 40. Ceruloplasmin is up-regulated by greater than 2- fold by Epas.
  • Ceruloplasmin is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases.
  • the superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions.
  • Ceruloplasmin is induced by a factor of 2.73 in response to superoxide, which is consistent with its role as an anti-oxidant.
  • Ceruloplasmin is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Ceruloplasmin In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Ceruloplasmin was up-regulated 3.57 fold in one of the patients and was up-regulated 3.59 fold in the other patient. This indicates that Ceruloplasmin plays a role in the inflammation associated with COPD. Ceruloplasmin is a blue, copper-binding glycoprotein found in plasma and may function as a copper transporter. Copper is essential for the process of angiogenesis and therefore inhibition of Ceruloplasmin would be an effective anti- angiogenesis strategy. Elevated ceruloplasmin levels have been shown recently to be associated with rheumatoid arthritis (PMLD: 12175089).
  • Chorein The protein sequence encoded by Chorein is represented in the public databases by the accession BAB59128 and is described in this patent by Seq LD 41.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB023203 and is described in this patent by Seq LD 42.
  • Chorein is up-regulated by greater than 2-fold by Epas. This response to hypoxia has important implications for the pathogenesis of neuro-ischaemia, because chorein is known to be associated with neuro-degeneration (PMID: 11381254).
  • the Oxford BioMedica clone p2C3 represents DEAD-box protein.
  • the protein sequence encoded by DEAD-box protein is represented in the public databases by the accession NP_061135 and is described in this patent by Seq ID 43.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018665 and is described in this patent by Seq ED 44.
  • DEAD-box protein is an ATP-dependent RNA helicase in the DEAD-box family.
  • DEAD-box protein is up-regulated by greater than 2- fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • DEAD-box protein is repressed by a factor of 2.04 in response to LL- Vindicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone p2B24 represents DLAT dihydrolipoamide acetyltransferase E2.
  • the protein sequence encoded by DLAT dihydrolipoamide acetyltransferase E2 is represented in the public databases by the accession CAA68787 and is described in this patent by Seq ID 45.
  • the nucleotide sequence is represented in the public sequence databases by the accession Y00978 and is described in this patent by Seq ID 46.
  • DLAT dihydrolipoamide acetyltransferase E2 is a component of the human pyruvate dehydrogenase complex.
  • DLAT dihydrolipoamide acetyltransferase E2 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • DLAT dihydrolipoamide acetyltransferase E2 is repressed by a factor of 2.13 in response to IL-13 and 1.79 in response to IL-4, indicating a negative role in Th2 immune responses.
  • DLAT dihydrolipoamide acetyltransferase E2 was down-regulated 1.47, 2.27 and 1.39 fold in the three diseased patients compared to the control group. This indicates that DLAT dihydrolipoamide acetyltransferase E2 plays a role in the process of atherogenesis.
  • Dual specificity mitogen-activated protein kinase kinase 7 is represented in the public databases by the accession O14733 and is described in this patent by Seq ID 47.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005043 and is described in this patent by Seq ID 48.
  • MAPKK7 activates the Jun kinases (JNK1 and JNK2).
  • MAPKK7 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2G23 represents Equihbrative nucleoside transporter 1.
  • the protein sequence encoded by Equihbrative nucleoside transporter 1 is represented in the public databases by the accession Q99808 and is described in this patent by Seq ID 49.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004955 and is described in this patent by Seq ID 50.
  • Equihbrative nucleoside transporter 1 mediates both the influx and efflux of nucleosides across the membrane and belongs to the SLC29A family of transporters.
  • Equihbrative nucleoside transporter 1 is up- regulated by greater than 2-fold by Epas.
  • Ets-domain transcription factor ERF The Oxford BioMedica clone plM9 represents Ets-domain transcription factor ERF.
  • the protein sequence encoded by Ets-domain transcription factor ERF is represented in the public databases by the accession P50548 and is described in this patent by Seq ID 51.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006494 and is described in this patent by Seq ID 52.
  • Ets-domain transcription factor ERF is a potent transcriptional repressor that binds to the HI element of the ETS2 promoter. It may regulate other genes involved in cellular proliferation.
  • Ets-domain transcription factor ERF is phosphorylated by multiple kinases including probably ERK2.
  • Ets-domain transcription factor ERF is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Ets-domain transcription factor ERF is repressed by a factor of 2.22 in response to IL-13 and 1.69 in response to IL- 4, indicating a negative role in Th2 immune responses.
  • Eukaryotic translation initiation factor 4E binding protein 1 is represented in the public databases by the accession BAB 18650 and is described in this patent by Seq LD 53.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB044548 and is described in this patent by Seq ID 54.
  • Eukaryotic translation initiation factor 4E binding protein 1 is up-regulated by greater than 2-fold by Hif.
  • EVI2A The Oxford BioMedica clone pi 123 represents EVI2A protein precursor.
  • the protein sequence encoded by EVI2A is represented in the public databases by the accession P22794 and is described in this patent by Seq ID 55 and Seq ID 57.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014210 and is described in this patent by Seq ID 56 and Seq ID 58.
  • EVI2A is a membrane protein that may possibly complex with itself or other proteins to form a cell-surface receptor. EVI2A is up-regulated by greater than 2-fold by Epas.
  • FC-gamma RII-B Fc fragment of IgG low affinity 2b
  • FC-gamma RII-B The protein sequence encoded by FC-gamma RII-B is represented in the public databases by the accession P31994 and is described in this patent by Seq ID 59.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004001 and is described in this patent by Seq ID 60.
  • FC-gamma RII-B is involved in a variety of effector and regulatory functions such as phagocytosis of immune compexes and modulation of antibody production by B-cells.
  • FC-gamma RII-B is up-regulated by greater than 2-fold by Epas.
  • FC-gamma RII-B is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • FC- gamma RII-B is induced by a factor of 1.84 at 6hr and 1.99 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • FC-gamma RII-B is induced by a factor of 4.67 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • FC-gamma RII-B is induced by a factor of 5.29 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • FC-gamma RII-B is induced by a factor of 2.46 in response to EL- 10, indicating a positive role in the response to IL-10.
  • the Oxford BioMedica clone plK20 represents FOS-like antigen 2 (FRA2).
  • FRA2 The protein sequence encoded by FRA2 is represented in the public databases by the accession PI 5408 and is described in this patent by Seq ID 61 and Seq ID 63.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005253 and is described in this patent by Seq ID 62 and Seq ID 64.
  • FRA2 is up-regulated by greater than 2-fold by Epas.
  • FRA2 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • FRA2 forms part of a heterodimeric transcription factor activator protein 1 (API), and thus plays a crucial role in transcriptional regulation.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • FRA2 is induced by a factor of 1.75 in response to IL-13 and 2.11 in response to IL-4, indicating a positive role in Th2 immune responses.
  • FRA2 is induced by a factor of 3.81 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • FRA2 is induced by a factor of 2.36 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • FRA2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • FRA2 was down-regulated 2.27 and 2.33 fold in two of the three diseased patients compared to the control group. This indicates that FRA2 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2B23 represents G/T mismatch specific thymine DNA glycosylase.
  • the protein sequence encoded by G/T mismatch specific thymine DNA glycosylase is represented in the public databases by the accession Q 13569 and is described in this patent by Seq ID 65.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003211 and is described in this patent by Seq ID 66.
  • G/T mismatch specific thymine DNA glycosylase functions to correct G/T mispairs to G/C pairs. It is capable of hydrolyzing the Carbon-Nitrogen bond between the sugar- phosphate backbone of the DNA and a mispaired Thymine.
  • G/T mismatch specific thymine DNA glycosylase belongs to the MUG/TDG family of DNA glycosylases.
  • G/T mismatch specific thymine DNA glycosylase is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2G15 represents Glutamate cysteine ligase, (gamma-ECS).
  • the protein sequence encoded by gamma-ECS is represented in the public databases by the accession P48506 and is described in this patent by Seq ID 67.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001498 and is described in this patent by Seq ID 68.
  • Glutamate cysteine ligase is the first and rate limiting step in de novo Glutathione biosynthesis.
  • gamma-ECS is up-regulated by greater than 2-fold by Epas.
  • gamma-ECS is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • gamma-ECS was up-regulated 7.58 and 3.95 fold in two of the three diseased patients compared to the control group. This indicates that gamma-ECS plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2C5 represents Glutamine synthetase.
  • the protein sequence encoded by Glutamine synthetase is represented in the public databases by the accession P15104 and is described in this patent by Seq ID 69.
  • the nucleotide sequence is represented in the public sequence databases by the accession AL161952 and is described in this patent by Seq ID 70.
  • Glutamine synthetase is up-regulated by greater than 2-fold by Epas.
  • Glutamine synthetase is induced by a factor of 3.09 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • Glutamine synthetase is induced by a factor of 3.51 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • Glutamine synthetase is induced by a factor of 2.36 in response to IL-10, indicating a positive role in the response to IL-10.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone p2H15 represents Glutamate receptor 2 precursor.
  • the protein sequence encoded by Glutmate receptor 2 is represented in the public databases by the accession P44262 and is described in this patent by Seq ID 71.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000826 and is described in this patent by Seq ID 72.
  • Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel.
  • Glutamate receptor 2 is up- regulated by greater than 2-fold by both Hif and Epas.
  • Glutamate receptor 2 was down-regulated 2.7 and 5.56 fold in two of the three diseased patients compared to the control group. This indicates that Glutmate receptor 2 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plMlO represents Glycine amidinotransferase, mitochondrial precursor.
  • the protein sequence encoded by Glycine amidinotransferase is represented in the public databases by the accession P50440 and is described in this patent by Seq ID 73.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001482 and is described in this patent by Seq ID 74.
  • Glycine amidinotransferase is the first and rate limiting step in the biosynthesis of Creatine.
  • Glycine amidinotransferase is up-regulated by greater than 2-fold by Epas.
  • Glycine amidinotransferase is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Glycine amidinotransferase is induced by a factor of 2 in response to IL-13 and 1.69 in response to EL-4, indicating a positive role in Th2 immune responses.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Glycine amidinotransferase As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Glycine amidinotransferase is repressed in response to TNFalpha, by a factor of 2.5 fold, indicating a negative role in pro-inflammatory responses involving this factor. Glycine amidinotransferase is suppressed by a factor of 3.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone plL19 represents Growth factor receptor GRB2 adapter protein.
  • the protein sequence encoded by Growth factor receptor GRB2 adapter protein is represented in the public databases by the accession P29354 and is described in this patent by Seq ID 75.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002086 and is described in this patent by Seq ID 76.
  • Growth factor receptor GRB2 adapter protein associates with activated Tyrosine-phosphorylated EGF receptors and PDGF receptors via its SH2 domain.
  • Growth factor receptor GRB2 adapter protein also assocaites with other cellular Tyrosine-phosphorylated proteins such as IRS-1, SHC and LNK.
  • Growth factor receptor GRB2 adapter protein is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Growth factor receptor GRB2 adapter protein was up-regulated 3.53, 2.65 and 1.13 fold in the three diseased patients compared to the control group. This indicates that Growth factor receptor GRB2 adapter protein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone pi LI 6 represents GTF2I repeat domain containing 1, isoform 1.
  • the protein sequence encoded by GTF2I repeat domain containing 1, isoform 1 is represented in the public databases by the accession NP_057412 and is described in this patent by Seq ID 77.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016328 and is described in this patent by Seq ID 78.
  • the sequence encoded by Seq ID 77 contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif.
  • HLH-proteins may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein.
  • This gene is deleted in Williams- Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7ql l.23.
  • GTF2I repeat domain containing 1, isoform 1 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • GTF2I repeat domain containing 1, isoform 1 is induced by a factor of 2.32 at 6hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • GTF2I repeat domain containing 1, isoform 1 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • GTF2I repeat domain containing 1, isoform 1 was down-regulated 1.61, 1.37 and 2.08 fold in the three diseased patients compared to the control group. This indicates that GTF2I repeat domain containing 1, isoform 1 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL2 represents Heat shock 40KDA protein 1.
  • the protein sequence encoded by Heat shock 40KDA protein 1 is represented in the public databases by the accession NP_006136 and is described in this patent by Seq ID 79.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006145 and is described in this patent by Seq ID 80.
  • Heat shock 40KDA protein 1 is up-regulated by greater than 2-fold by Hif.
  • Heat shock 40KDA protein 1 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases.
  • Heat shock 40KDA protein 1 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • Heat shock 40KDA protein 1 was up- regulated 5.32 fold in one of the patientsHeat shock 40KDA protein 1 plays a role in the inflammation associated with COPD.
  • Heat shock 40KDA protein 1 was down-regulated 6.67, 4.76 and 2.94 fold in the three diseased patients compared to the control group. This indicates that Heat shock 40KDA protein 1 plays a role in the process of atherogenesis.
  • HSP70B Heat shock 70KDA protein 6
  • the protein sequence encoded by HSP70B is represented in the public databases by the accession PI 7066 and is described in this patent by Seq ID 81.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002155 and is described in this patent by Seq ID 82.
  • HSP70B is up-regulated by greater than 2-fold by Hif. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, HSP70B was up-regulated 5.72 fold in one of the patients. HSP70B plays a role in the inflammation associated with COPD.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone plN3 represents Heat shock protein 70KD protein 1-HOM.
  • the protein sequence encoded by Heat shock protein 70KD protein 1-HOM is represented in the public databases by the accession P34931 and is described in this patent by Seq ID 83.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005527 and is described in this patent by Seq ID 84.
  • Heat shock protein 70KD protein 1-HOM belongs to the heat shock protein 70 family but is not regulated by heat shock. Heat shock protein 70KD protein 1-HOM is up-regulated by greater than 2- fold by Hif.
  • Heat shock protein 70KD protein 1-HOM is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Heat shock protein 70KD protein 1-HOM is induced in response to TNFalpha, by a factor of 2.72 fold, indicating a positive role in pro- inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions. Heat shock protein 70KD protein 1-HOM is repressed by a factor of 2.38 in response to IL-10, indicating a negative role in the response to IL-10.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Heat shock protein 70KD protein 1-HOM is repressed in response to Interleukin- 1, by a factor of 2.78 fold at 6hr and 5.56 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • Heat shock protein 70KD protein 1-HOM is suppressed by a factor of 4 at 6hr and 1.72 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • Heat shock protein 70KD protein 1-HOM is repressed by a factor of 3.7 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro- inflammatory responses involving this factor.
  • Heat shock protein 70KD protein 1-HOM is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Heat shock protein 70KD protein 1-HOM was up-regulated 17.95 fold in one of the patients and was up-regulated 1.62 fold in the other patient. This indicates that Heat shock protein 70KD protein 1-HOM plays a role in the inflammation associated with COPD.
  • Heat shock protein 70KD protein 1-HOM was changed in expression - 2.63, -1.72 and -2.13 fold in the three diseased patients compared to the control group. This indicates that Heat shock protein 70KD protein 1-HOM plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I17 represents Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein.
  • the protein sequence encoded by p2I17 is represented in the public databases by the accession Q15011 and is described in this patent by Seq ID 85.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014685 and is described in this patent by Seq ID 86.
  • p2I17 is up-regulated by greater than 2-fold by Hif.
  • the sequence encoded by Seq ID 85 is suppressed by a factor of 2.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the sequence encoded by Seq ID 85 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2El l represents Huntingtin associated protein interacting protein.
  • the protein sequence encoded by Huntingtin associated protein interacting protein is represented in the public databases by the accession O60229 and is described in this patent by Seq ID 87.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003947 and is described in this patent by Seq ID 88.
  • Huntingtin associated protein interacting protein is up-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Huntingtin associated protein interacting protein is induced in response to TNFalpha, by a factor of 6.34 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • Huntingtin associated protein interacting protein is induced by a factor of 2.08 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro- inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions.
  • Huntingtin associated protein interacting protein is repressed by a factor of 2.33 in response to IL-10, indicating a negative role in the response to IL-10.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis.
  • Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Huntingtin associated protein interacting protein is repressed in response to Interleukin- 1, by a factor of 6.25 fold at 6hr and 7.69 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor.
  • Huntingtin associated protein interacting protein is suppressed by a factor of 8.33 at 6hr and 4.35 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • Huntingtin associated protein interacting protein is repressed by a factor of 3.13 in response to EL-13 and 1.52 in response to IL-4, indicating a negative role in Th2 immune responses.
  • Huntingtin associated protein interacting protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • COPD chronic obstructive pulmonary disease
  • Huntingtin associated protein interacting protein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL20 represents the Interleukin- 16 precursor.
  • the protein sequence encoded by IL-16 is represented in the public databases by the accession Q 14005 and is described in this patent by Seq ID 89.
  • the nucleotide sequence is represented in the public sequence databases by the accession M90391 and is described in this patent by Seq ID 90.
  • IL-16 stimulates a migratory response in CD4+ lymphocytes, monocytes and eosinophils. It also induces T-cell expression of Interleukin 2 receptor.
  • IL-16 is up- regulated by greater than 2-fold by Epas.
  • IL-16 is suppressed by a factor of 2.44 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone plPl represents Interleukin- 1 beta precursor.
  • the protein sequence encoded by Interleukin- 1 beta is represented in the public databases by the accession P01584 and is described in this patent by Seq ID 91.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000576 and is described in this patent by Seq ID 92.
  • Interleukin- 1 beta is produced by activated Macrophages and stimulates thymocyte proliferation by inducing IL-2 release, B-cell maturation and proliferation, and Fibroblast growth factor activity.
  • Interleukin- 1 proteins are involved in the inflammatory response and stimulate the release of Postaglandin and Collagenase from synovial cells.
  • Interleukin- 1 beta is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 beta is induced by a factor of 2.09 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. Interleukin- 1 beta is induced by a factor of 75.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • Interleukin- 1 beta is induced by a factor of 27.58 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • Interleukin- 1 beta is repressed by a factor of 2.33 in response to IL-13 and 2.44 in response to IL-4, indicating a negative role in Th2 immune responses.
  • COPD chronic obstructive pulmonary disease
  • MMP7 The Oxford BioMedica clone plL17 represents MMP7.
  • the protein sequence encoded by MMP7 is represented in the public databases by the accession P09237 and is described in this patent by Seq ID 93.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002423 and is described in this patent by Seq ID 94.
  • MMP7 functions to degrade Casein, Gelatins and Fibronectin.
  • MMP7 is up-regulated by greater than 2-fold by both Hif and Epas.
  • MMP7 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • MMP7 is induced in response to TNFalpha, by a factor of 2.84 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • MMP7 was changed in expression 6.37, 4.43 and -1.37 fold in the three diseased patients compared to the control group. This indicates that MMP7 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL3 represents Inter-alpha-trypsin inhibitor heavy chain H- 2 precursor.
  • Inter-alpha-trypsin inhibitor heavy chain H- 2 The protein sequence encoded by Inter-alpha-trypsin inhibitor heavy chain H- 2 is represented in the public databases by the accession PI 9823 and is described in this patent by Seq ID 95.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002216 and is described in this patent by Seq ED 96.
  • Inter- alpha-trypsin inhibitor heavy chain H-2 may act as a carrier of Hyaluron in serum.
  • Inter- alpha-trypsin inhibitor heavy chain H-2 is up-regulated by greater than 2-fold by Epas.
  • Inter-alpha-trypsin inhibitor heavy chain H-2 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone p2H6 represents Interleukin 18 binding protein (IL18BP).
  • IL18BP Interleukin 18 binding protein
  • the protein sequence encoded by IL18BP is represented in the public databases by the accession NP_005690 and is described in this patent by Seq ID 97.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005699 and is described in this patent by Seq ID 98.
  • IL18BP is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • IL18BP is repressed by a factor of 2.08 in response to IL-13 and 1.61 in response to IL-4, indicating a negative role in Th2 immune responses.
  • IL18BP is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • IL18BP In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, IL18BP was changed in expression 3.61, 1.46 and 1.04 fold in the three diseased patients compared to the control group. This indicates that IL18BP plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plN6 represents Kell blood group gylcoprotein.
  • the protein sequence encoded by Kell blood group gylcoprotein is represented in the public databases by the accession P23276 and is described in this patent by Seq ID 99.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000420 and is described in this patent by Seq ED 100.
  • Kell blood group gylcoprotein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Kell blood group gylcoprotein is repressed in response to Interleukin- 1, by a factor of 3.23 fold at 6hr and 2.94 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor.
  • Kell blood group gylcoprotein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Kell blood group gylcoprotein was changed in expression -1.41, -2.38 and -1.37 fold in the three diseased patients compared to the control group. This indicates that Kell blood group gylcoprotein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plM23 represents LEVI domain only 7.
  • the protein sequence encoded by LEVI domain only 7 is represented in the public databases by the accession NP_005349 and is described in this patent by Seq ID 101.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005358 and is described in this patent by Seq ID 102.
  • the LEVI domain is a cysteine-rich sequence motif that binds zinc atoms to form a specific protein-binding interface for protein-protein interactions.
  • LEVI domain only 7 is up-regulated by greater than 2-fold by Epas.
  • LIM domain only 7 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis ⁇
  • the Oxford BioMedica clone p2L12 represents 19A24 protein.
  • the protein sequence encoded by 19A24 protein is represented in the public databases by the accession CAB81950 and is described in this patent by Seq ID 103.
  • the nucleotide sequence is represented in the public sequence databases by the accession AJ276429 and is described in this patent by Seq ID 104.
  • 19A24 protein is a member of the immunoglobulin superfamily receptors and is expressed on activated lymphocytes and promotes homotypic B-cell adhesion. 19A24 protein is up-regulated by greater than 2-fold by both Hif and Epas.
  • 19A24 protein is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • 19A24 protein is induced by a factor of 3.94 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • 19A24 protein is suppressed by a factor of 3.45 at 6hr and 1.89 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • 19A24 protein was changed in expression -2.04, -1.96 and -1.3 fold in the three diseased patients compared to the control group. This indicates that 19A24 protein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2D20 represents LOC92097 similar to phenylalanine 4 hydroxlase (PAH).
  • LOC92097 The protein sequence encoded by LOC92097 is represented in the public databases by the accession XP_012169 and is described in this patent by Seq ID 105.
  • the nucleotide sequence was previously represented in the public sequence databases by the accession XM_012169 and is described in this patent by Seq ID 106.
  • the nucleotide and protein accessions described above have been removed from the public databases and therefore LOC92097 is now represented by the nucleotide accession NM_000277 and the protein accession NP_000268. LOC92097 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2I3 represents LOC92660 sulphotransferase, cytosohc.
  • the protein sequence encoded by LOC92660 was represented in the public databases by the accession XP_016802 and is described in this patent by Seq ID 107.
  • the nucleotide sequence was represented in the public sequence databases by the accession XM_016802 and is described in this patent by Seq ID 108.
  • the nucleotide and protein accessions described above have been removed from the public databases and therefore LOC92660 sulphotransferase, cytosohc is now represented by the nucleotide accession NM_003166 and the protein accession NPJ303157.
  • LOC92660 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • LOC92660 is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • LOC92660 is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • LOC92660 is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor.
  • LOC92660 was changed in expression - 1.72, -2.17 and -1.3 fold in the three diseased patients compared to the control group. This indicates that LOC92660 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2D22 represents LOC92879 sodium and chlorine dependent creatine transporter 2.
  • the protein sequence encoded by LOC92879 was represented in the public databases by the accession XP_047748 and is described in this patent by Seq ID 109.
  • LOC92879 is now represented by the nucleotide accession NM_003166 and the protein accession NP_003157.
  • LOC92879 is up-regulated by greater than 2-fold by Epas.
  • LOC92879 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • LOC92879 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC92879 was changed in expression 2.52, 2.44 and 1.24 fold in the three diseased patients compared to the control group. This indicates that LOC92879 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I3 represents LOC93383 sulphotransferase, cytosohc.
  • the protein sequence encoded by LOC93383 was represented in the public databases by the accession XP_051071 and is described in this patent by Seq ID 111.
  • the nucleotide sequence was represented in the public sequence databases by the accession XM_051071 and is described in this patent by Seq ID 112.
  • the nucleotide and protein accessions described above have been removed from the public databases and therefore LOC93383 sulphotransferase, cytosohc is now represented by the nucleotide accession NM_003166 and the protein accession NP_003157.
  • LOC93383 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • LOC93383 is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • LOC93383 is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • LOC93383 is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor.
  • LOC93383 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC93383 was changed in expression - 1.72, -2.17 and -1.3 fold in the three diseased patients compared to the control group. This indicates that LOC93383 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plKlO represents TIS11A protein TS11 (ZFP-36) and is located on chromosome 19q 13.
  • the protein sequence encoded by ZFP-36 is represented in the public databases by the accession P26651 and is described in this patent by Seq LD 113.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003407 and is described in this patent by Seq ID 114.
  • ZFP-36 is up-regulated by greater than 2-fold by Epas.
  • ZFP-36 is induced by a factor of 2.59 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • ZFP-36 negatively regulates TNF- ⁇ synthesis (Taylor et al, Immunity 1996 May;4(5):445- 54).
  • TNF- ⁇ is an important pro-inflammatory cytokine which contributes to the pathology of a number of diseases including rheumatoid arthritis.
  • ZFP-36 is induced by the hypoxic response enables the use of this gene for diagnosis and intervention in diseases which involve the hypoxic response.
  • COPD chronic obstructive pulmonary disease
  • ZFP-36 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, ZFP-36 was changed in expression -1.16, 2.21 and 3.49 fold in the three diseased patients compared to the control group. Thus in at least some patients ZFP-36 plays a role in the process of atherogenesis.
  • Lysyl oxidase is represented in the public databases by the accession AAB21243 and is described in this patent by Seq ID 115.
  • the nucleotide sequence is represented in the public sequence databases by the accession S78694 and is described in this patent by Seq ID 116.
  • Lysyl oxidase is an extracellular enzyme that is responsible for the posttranslational oxidative deamination of peptidyl Lysine residues in precursors to fibrous Collagen and Elastin. Lysyl oxidase is up-regulated by greater than 2-fold by both Hif and Epas.
  • MMP-12 The Oxford BioMedica clone plLlO represents MMP-12.
  • the protein sequence encoded by MMP-12 is represented in the public databases by the accession P39900 and is described in this patent by Seq ID 117.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002426 and is described in this patent by Seq ID 118.
  • MMP-12 is involved in tissue injury and remodelling. MMP-12 is up- regulated by greater than 2-fold by Epas.
  • MMP-12 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • MMP-12 is induced by a factor of 5.64 in response to EL-13 and 4.07 in response to LL-4, indicating a positive role in Th2 immune responses.
  • the cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • MMP-12 is induced by a factor of 3.81 in response to IL- 10, indicating a positive role in the response to IL-10.
  • MMP-12 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2Cl l represents MEGFIO protein.
  • the protein sequence encoded by MEGFIO protein is represented in the public databases by the accession NP_115822 and is described in this patent by Seq ID 119.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_032446 and is described in this patent by Seq ID 120.
  • MEGFIO protein is up-regulated by greater than 2- fold by Hif.
  • the Oxford BioMedica clone plM4 represents Metastasis suppressor protein.
  • the protein sequence encoded by Metastasis suppressor protein is represented in the public databases by the accession NP_055566 and is described in this patent by Seq ID 121.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014751 and is described in this patent by Seq ID 122.
  • Metastasis suppressor protein is up-regulated by greater than 2-fold by Epas.
  • the cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • Metastasis suppressor protein is induced by a factor of 2.72 in response to IL-10, indicating a positive role in the cellular response to IL-10.
  • the Oxford BioMedica clone plM20 represents MHC class-I chain-related protein A.
  • the protein sequence encoded by MHC class-I chain-related protein A is represented in the public databases by the accession NP_000238 and is described in this patent by Seq ID 123.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000247 and is described in this patent by Seq ID 124.
  • MHC class-I chain- related protein A functions as a stress-induced antigen that is broadly recognized by intestinal epithelial gamma delta T cells.
  • MHC class-I chain-related protein A is up- regulated by greater than 2-fold by Epas.
  • MHC class-I chain-related protein A In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, MHC class-I chain-related protein A was changed in expression -2.5, -2.86 and 1.13 fold in the three diseased patients compared to the control group. This indicates that MHC class-I chain-related protein A plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plN14 represents Mitochondrial uncoupling protein 1.
  • the protein sequence encoded by Mitochondrial uncoupling protein 1 is represented in the public databases by the accession NP_068380 and is described in this patent by Seq ID 125.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021734 and is described in this patent by Seq ID 126.
  • Mitochondrial uncoupling protein 1 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Mitochondrial uncoupling protein 1 is repressed by a factor of 2.13 in response to IL-13 and 1.92 in response to IL-4, indicating a negative role in Th2 immune responses.
  • Mitochondrial uncoupling protein 1 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plN9 represents Monocyte differentiation antigen CD 14 precursor.
  • the protein sequence encoded by CD 14 is represented in the public databases by the accession P08571 and is described in this patent by Seq ID 127.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000591 and is described in this patent by Seq ID 128.
  • CD 14 is up-regulated by greater than 2-fold by Epas.
  • CD14 co-operates with MD-2 and TLR4 to mediate the innate immune response to bacterial lipopolysaccharide.
  • CD 14 is induced by a factor of 2.14 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections.
  • CD 14 acts via MyD88, TIRAP and TRAF6, leading to NF-Kappa-B activation, cytokine secretion and the inflammatory response.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • CD14 is repressed in response to Interleukin- 1, by a factor of 16.67 fold at 6hr and 8.33 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • CD14 is suppressed by a factor of 10 at 6hr and 8.33 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • CD14 is repressed by a factor of 2.5 in response to IL-13 and 2.7 in response to IL-4, indicating a negative role in Th2 immune responses.
  • CD 14 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Myo-inositol monophosphatase A3 is represented in the public databases by the accession AAK52336 and is described in this patent by Seq ID 129 and Seq ID 131.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_017813 and is described in this patent by Seq ID 130 and Seq ID 132.
  • Myo-inositol monophosphatase A3 is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone plM8 represents Myosin IXB (unconventional myosin-9B).
  • the protein sequence encoded by Myosin LXB is represented in the public databases by the accession Q 13459 and is described in this patent by Seq ID 133.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004145 and is described in this patent by Seq LD 134.
  • Myosin IXB is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis.
  • Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Myosin XB is repressed in response to Interleukin- 1, by a factor of 4.35 fold at 6hr and 4.17 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • Myosin LXB is suppressed by a factor of 2.56 at 6hr and 2.63 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2H16 represents a NK inhibitory receptor (IRCl).
  • the protein sequence encoded by NK inhibitory receptor (IRCl) is represented in the public databases by the accession CAB66145 and is described in this patent by Seq ID 135.
  • the nucleotide sequence is represented in the public sequence databases by the accession AJ224864 and is described in this patent by Seq ID 136.
  • NK inhibitory receptor (IRCl) is up-regulated by greater than 2-fold by Epas.
  • NK inhibitory receptor is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • NK inhibitory receptor (IRCl) is induced by a factor of 2.14 in response to IL-13 and 2.38 in response to IL-4, indicating a positive role in Th2 immune responses.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • NK inhibitory receptor (IRCl) is repressed in response to Interleukin- 1, by a factor of 3.85 fold at 6hr and 2.94 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor.
  • the superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions.
  • NK inhibitory receptor (IRCl) is suppressed by a factor of 2.17 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion.
  • NK inhibitory receptor EPCl
  • pro-inflammatory cytokines Down-regulation of NK inhibitory receptor (ERCl) by pro-inflammatory cytokines is consistent with the role of these cytokines, but our observation of its hypoxia-induction is a surprising finding which implies the utility of this important molecule in the control of the response to ischaemic insult.
  • the Oxford BioMedica clone p2C9 represents C-type lectin, superfamily member 2 (CLECSF2).
  • the protein sequence encoded by CLECSF2 is represented in the public databases by the accession CAA65480 and is described in this patent by Seq ID 137.
  • the nucleotide sequence is represented in the public sequence databases by the accession X96719 and is described in this patent by Seq ID 138.
  • CLECSF2 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • CLECSF2 is induced by a factor of 2 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • CLECSF2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plL7 represents Ovarian carcinoma immunoreactive antigen.
  • the protein sequence encoded by Ovarian carcinoma immunoreactive antigen is represented in the public databases by the accession NP_060300 and is described in this patent by Seq ID 139.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_017830 and is described in this patent by Seq ID 140.
  • Ovarian carcinoma immunoreactive antigen is up-regulated by greater than 2-fold by Epas.
  • Ovarian carcinoma immunoreactive antigen is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Ovarian carcinoma immunoreactive antigen is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Ovarian carcinoma immunoreactive antigen is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Ovarian carcinoma immunoreactive antigen was changed in expression -1.64, -2.38 and - 2.17 fold in the three diseased patients compared to the control group. This indicates that Ovarian carcinoma immunoreactive antigen plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2D21 represents P1CDC21 protein, member of the MCM family of chromatin binding proteins.
  • the protein sequence encoded by P1CDC21 protein is represented in the public databases by the accession CAA52801 and is described in this patent by Seq ID 141.
  • the nucleotide sequence is represented in the public sequence databases by the accession X74792 and is described in this patent by Seq ID 142.
  • P1CDC21 protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • P1CDC21 protein is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2E7 represents PD2 protein.
  • the protein sequence encoded by PD2 protein is represented in the public databases by the accession CAC20564 and is described in this patent by Seq ID 143.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_019088 and is described in this patent by Seq ID 144.
  • PD2 protein is up-regulated by greater than 2-fold by Epas.
  • PD2 protein In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, PD2 protein was changed in expression -2.5, -2.5 and -1.15 fold in the three diseased patients compared to the control group. This indicates that PD2 protein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL14 represents Peanut like-2 (PNUTL2).
  • the protein sequence encoded by PNUTL2 is represented in the public databases by the accession AAG45673 and is described in this patent by Seq ID 145.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF176379 and is described in this patent by Seq ID 146.
  • PNUTL2 acts to enhance cell death induced by TGF-beta.
  • PNUTL2 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • PNUTL2 is induced by a factor of 2.7 at 6hr and 1.62 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • PNUTL2 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • PNUTL2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • PNUTL2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • PNUTL2 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, PNUTL2 was changed in expression -3.45, -2.17 and -2.5 fold in the three diseased patients compared to the control group. This indicates that PNUTL2 plays a role in the process of atherogenesis. PNUTL2 is induced specifically by P53 (PMID: 10962554), and in accordance with this induction it has been shown to play a role in the induction of apoptosis (PMID: 11146656). Its suppression in atherosclerotic aorta may contribute to the hyperplasia associated with this disease.
  • PAH phenylalanine hydroxlase
  • the Oxford BioMedica clone p2C16 represents Phospholipid transfer protein.
  • the protein sequence encoded by Phospholipid transfer protein is represented in the public databases by the accession P55058 and is described in this patent by Seq ID 149.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_006227 and is described in this patent by Seq ID 150.
  • Phospholipid transfer protein is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone p2L10 represents Pituitary homebox 1.
  • the protein sequence encoded by Pituitary homebox 1 is represented in the public databases by the accession P78337 and is described in this patent by Seq ID 151.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002653 and is described in this patent by Seq ID 152.
  • Pituitary homebox 1 is up-regulated by greater than 2-fold by both Hif and Epas.
  • the Oxford BioMedica clone plN8 represents Pituitary tumour-transforming protein.
  • the protein sequence encoded by plN8 is represented in the public databases by the accession NP_004210 and is described in this patent by Seq ID 153.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004219 and is described in this patent by Seq ID 154.
  • Pituitary tumour-transforming protein is up- regulated by greater than 2-fold by Epas. Pituitary tumour-transforming protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Pituitary tumour-transforming protein contains two PXXP motifs which are known to be required for its transforming and tumourigenic activities.
  • the Oxford BioMedica clone p2L9 represents Plasma protease Cl inhibitor precursor.
  • the protein sequence encoded by p2L9 is represented in the public databases by the accession P05155 and is described in this patent by Seq ID 155.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000062 and is described in this patent by Seq ID 156.
  • Plasma protease Cl inhibitor is up-regulated by greater than 2-fold by Epas.
  • Plasma protease Cl inhibitor is induced by a factor of 8.15 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • Plasma protease Cl inhibitor precursor is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plM16 represents Plasminogen activator inhibitor-2 precursor (PAI-2).
  • the protein sequence encoded by plM16 is represented in the public databases by the accession P05120 and is described in this patent by Seq ID 157.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002575 and is described in this patent by Seq ID 158.
  • PAI-2 is known to inhibit Urokinase-type plasminogen activator. PAI-2 is up-regulated by greater than 2-fold by Epas.
  • PAI-2 is induced by a factor of 2.42 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • PAI-2 is induced by a factor of 3 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the Oxford BioMedica clone plM15 represents Pleckstrin homology-like domain, family A, member 1.
  • the protein sequence encoded by plM15 is represented in the public databases by the accession S58222 and is described in this patent by Seq ID 159.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF220656 and is described in this patent by Seq ID 160.
  • plM15 is up-regulated by greater than 2-fold by Epas.
  • the sequence encoded by Seq ID 159 is suppressed by a factor of 7.69 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • the sequence encoded by Seq ID 159 is suppressed by a factor of 2.56 in response to superoxide, indicating an anti- inflammatory function in ischaemia/reperfusion.
  • the sequence encoded by Seq ID 159 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plK12 represents Polyamine oxidase isoform- 1.
  • the protein sequence encoded by Polyamine oxidase isoform- 1 is represented in the public databases by the accession AAK55763 and is described in this patent by Seq ID 161.
  • the nucleotide sequence is represented in the public sequence databases by the accession AY033889 and is described in this patent by Seq ED 162.
  • Polyamine oxidase isoform- 1 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Polyamine oxidase isoform- 1 is induced by a factor of 2.34 in response to IL-13 and 4.14 in response to IL-4, indicating a positive role in Th2 immune responses.
  • Polyamine oxidase isoform- 1 is repressed by a factor of 2.27 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • Polyamine oxidase isoform- 1 catabolizes polyamines to produce 3-Aminopropanal. Often the substrates are toxic xenobiotics, but 3- Aminopropanal is a reactive aldehyde that mediates cell death in a number of cell types, including neuronal necrosis and glial apoptosis. (PMID: 11943872).
  • the Oxford BioMedica clone plM22 represents a potential splice variant of Lysyl oxidase.
  • the protein sequence encoded by plM22 is represented in the public databases by the accession P28300 and is described in this patent by Seq ID 163.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002317 and is described in this patent by Seq ID 164.
  • the sequence encoded by Seq ID 164 is up- regulated by greater than 2-fold by Epas.
  • the sequence encoded by Seq ID 164 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the sequence encoded by Seq ID 164 was up-regulated 2.7 fold in one of the patients. This indicates that the sequence encoded by Seq ID 164 plays a role in the inflammation associated with COPD, and is consistent with the known role of lysyl oxidase in collagen and elastin cross-linking and tissue re-modelling.
  • Our observation of the hypoxia induction of this molecule raises the important use of antagonists for the treatment of ischaemic disease.
  • the Oxford BioMedica clone plM6 represents Procollagen lysine, 2-oxoglutarate 5- dioxygenase 2 precursor (LH2).
  • the protein sequence encoded by plM6 is represented in the public databases by the accession O00469 and is described in this patent by Seq ID 165 and 167.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000935 and is described in this patent by Seq ID 166 and Seq ID 168.
  • LH2 is up-regulated by greater than 2-fold by both Hif and Epas.
  • plM6 is preferentially induced by hypoxia in myocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for cardiac ischaemia and ischemic limbs.
  • COPD chronic obstructive pulmonary disease
  • LH2 was changed in expression -1.27, - 3.57 and 1.28 fold in the three diseased patients compared to the control group. This indicates that LH2 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL23 represents Protein kinase Njmu-Rl.
  • the protein sequence encoded by Protein kinase Njmu-Rl is represented in the public databases by the accession Q9HAS0 and is described in this patent by Seq ID 169.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_022344 and is described in this patent by Seq ID 170.
  • Protein kinase Njmu-Rl is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Protein kinase Njmu-Rl is induced by a factor of 2.78 at 6hr and 2.07 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • Protein kinase Njmu-Rl is repressed by a factor of 2.5 in response to IL-10, indicating a negative role in the response to IL-10.
  • Protein kinase Njmu-Rl is suppressed by a factor of 2.5 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. Protein kinase Njmu-Rl is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone pi LI represents Protein tyrosine phosphatase receptor type, f polypeptide.
  • the protein sequence encoded by plLl is represented in the public databases by the accession P10586 and is described in this patent by Seq ID 171.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002840 and is described in this patent by Seq ID 172.
  • Protein tyrosine phosphatase receptor type, f polypeptide is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Protein tyrosine phosphatase receptor type, f polypeptide is repressed by a factor of 2.08 at 24hr in response to the pro-inflammatory cytokine Interleukin-17, indicating a negative role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2D16 represents Protein tyrosine phosphatase receptor type, sigma.
  • the protein sequence encoded by p2D16 is represented in the public databases by the accession NP_002841 and is described in this patent by Seq ID 173.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002850 and is described in this patent by Seq ID 174.
  • Protein tyrosine phosphatase receptor type sigma is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Protein tyrosine phosphatase receptor type, sigma is induced by a factor of 2.04 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone plM3 represents Protein tyrosine phosphatase, non-receptor type 1.
  • the protein sequence encoded by plM3 is represented in the public databases by the accession PI 8031 and is described in this patent by Seq ID 175.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_002827 and is described in this patent by Seq ID 176.
  • Protein tyrosine phosphatase, non-receptor type 1 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plM18 represents nuclear receptor subfamily 5, group A, member 2 (NR5A2).
  • the protein sequence encoded by NR5A2 is represented in the public databases by the accession O00482 and is described in this patent by Seq ID 177.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF146343 and is described in this patent by Seq ID 178.
  • NR5A2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • NR5A2 is induced by a factor of 1.72 at 6hr and 2.18 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2C6 represents Pyrroline-5-carboxylate synthetase.
  • the protein sequence encoded by p2C6 is represented in the public databases by the accession
  • XP_005713 and is described in this patent by Seq ID 179.
  • the nucleotide sequence is represented in the public sequence databases by the accession XM_005713 and is described in this patent by Seq ID 180.
  • Pyrroline-5-carboxylate synthetase is up-regulated by greater than 2-fold by Hif.
  • Pyrroline-5-carboxylate synthetase was changed in expression -2.04, -2.44 and -1.12 fold in the three diseased patients compared to the control group. This indicates that Pyrroline- 5-carboxylate synthetase plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plLl l represents RAS-related protein RAB-l lB.
  • the protein sequence encoded by RAS-related protein RAB-l lB is represented in the public databases by the accession Q 15907 and is described in this patent by Seq ID 181.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_004218 and is described in this patent by Seq ID 182.
  • RAS-related protein RAB-l lB is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, RAS-related protein RAB-l lB is repressed in response to Interleukin- 1, by a factor of 3.85 fold at 6hr and 2.86 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • RAS-related protein RAB-l lB is suppressed by a factor of 2.22 at 6hr and 1.96 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • RAS-related protein RAB-l lB is repressed by a factor of 1.92 in response to IL-13 and 2.33 in response to IL-4, indicating a negative role in Th2 immune responses.
  • COPD chronic obstructive pulmonary disease
  • RAS-related protein RAB-l lB plays a role in the inflammation associated with COPD.
  • RAS-related protein RAB-1 IB was changed in expression -1.56, -2.38 and -1.75 fold in the three diseased patients compared to the control group. This indicates that RAS-related protein RAB-1 IB plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plL4 represents SCA2.
  • the protein sequence encoded by SCA2 is represented in the public databases by the accession AAB 19200 and is described in this patent by Seq ID 183.
  • the nucleotide sequence is represented in the public sequence databases by the accession U70323 and is described in this patent by Seq TD 184.
  • SCA2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, SCA2 is induced in response to TNFalpha, by a factor of 2.19 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2I2 represents a SEC7 homolog.
  • the protein sequence encoded by p2I2 is represented in the public databases by the accession NP_036587 and is described in this patent by Seq ID 185.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_012455 and is described in this patent by Seq ID 186.
  • the SEC7 homolog is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2M5 represents Serine threonine protein kinase.
  • the protein sequence encoded by Serine threonine protein kinase is represented in the public databases by the accession NP_009202 and is described in this patent by Seq ID 187.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB023182 and is described in this patent by Seq ID 188.
  • Serine threonine protein kinase is up-regulated by greater than 2-fold by Epas.
  • Serine threonine protein kinase is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2I18 represents Sialic acid binding Ig-like lectin 7.
  • the protein sequence encoded by p2I18 is represented in the public databases by the accession NP_055200 and is described in this patent by Seq ID 189.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014385 and is described in this patent by Seq ID 190.
  • Sialic acid binding Ig-like lectin 7 is up-regulated by greater than 2-fold by both Hif and Epas.
  • the Oxford BioMedica clone p2H13 represents a gene that is similar to Upregulated by 1,25-dihydroxyvitamin D-3.
  • the protein sequence encoded by p2H13 is represented in the public databases by the accession XP_041721 and is described in this patent by Seq ID 191.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK026436 and is described in this patent by Seq ID 192.
  • the sequence encoded by SEQ ID 192 is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone plK24 represents Solute carrier family 22 (extraneuronal monoamine transporter).
  • Solute carrier family 22 The protein sequence encoded by Solute carrier family 22 is represented in the public databases by the accession NP_068812 and is described in this patent by Seq ID 193.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021977 and is described in this patent by Seq ID 194.
  • Solute carrier family 22 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Solute carrier family 22 is repressed by a factor of 1.79 in response to IL-13 and 2.27 in response to IL-4, indicating a negative role in Th2 immune responses.
  • Solute carrier family 22 is suppressed by a factor of 2.22 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • Solute carrier family 22 was changed in expression -1.32, -5.56 and 1.06 fold in the three diseased patients compared to the control group. This indicates that Solute carrier family 22 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2C10 represents Solute carrier family 6 (neurotransmitter, creatine) CTl.
  • the protein sequence encoded by p2C10 is represented in the public databases by the accession P48029 and is described in this patent by Seq ID 195.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_005629 and is described in this patent by Seq ID 196.
  • the seqeunce encoded by Seq ID 195 is essential for the uptake of Creatine.
  • CTl is up-regulated by greater than 2-fold by Epas.
  • CTl is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • CTl is suppressed by a factor of 2 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • CTl is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • CTl is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2D22 represents Solute carrier family 6 member 8 which is located on chromosome X.
  • the protein sequence encoded by p2D22 is represented in the public databases by the accession CAA91442 and is described in this patent by Seq ID 197.
  • the nucleotide sequence is represented in the public sequence databases by the accession Z66539 and is described in this patent by Seq ID 198.
  • Solute carrier family 6 member 8 is up-regulated by greater than 2-fold by Epas. Solute carrier family 6 member 8 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Solute carrier family 6 member 8 was changed in expression 2.52, 2.44 and 1.24 fold in the three diseased patients compared to the control group. This indicates that Solute carrier family 6 member 8 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plM5 represents Spermatid perinuclear RNA-binding protein.
  • the protein sequence encoded by plM5 is represented in the public databases by the accession AF333337 and is described in this patent by Seq ID 199.
  • the nucleotide sequence is represented in the public sequence databases by the accession AL136866 and is described in this patent by Seq ID 200.
  • Spermatid perinuclear RNA-binding protein is up-regulated by greater than 2-fold by Hif.
  • Spermatid perinuclear RNA-binding protein is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Spermatid perinuclear RNA-binding protein is repressed by a factor of 2.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor.
  • Spermatid perinuclear RNA-binding protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2L13 represents a splice variant of Fibronectin,.
  • the protein sequence encoded by p2L13 is represented in the public databases by the accession P02751 and is described in this patent by Seq ID 201.
  • the nucleotide sequence is represented in the public sequence databases by the accession X02761 and is described in this patent by Seq ID 202.
  • the sequence encoded by SEQ ID 202 is up-regulated by greater than 2-fold by both Hif and Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • SEQ ID 202 The sequence encoded by SEQ ID 202 is repressed by a factor of 2.22 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • the sequence encoded by SEQ ID 202 is repressed in response to Interleukin- 1, by a factor of 14.29 fold at 6hr and 14.29 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor.
  • the sequence encoded by SEQ ID 202 is suppressed by a factor of 10 at 6hr and 11.11 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • the sequence encoded by SEQ ID 202 is suppressed by a factor of 2.56 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the sequence encoded by SEQ ID 202 was changed in expression -2.44, 1.42 and -2.08 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by SEQ ID 202 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2E9 represents Splice variant of KIAA1536 protein.
  • the protein sequence encoded by p2E9 is represented in the public databases by the accession BAA96060 and is described in this patent by Seq LD 203.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB040969 and is described in this patent by Seq ID 204.
  • the sequence encoded by SEQ ID 204 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2I7 represents STXBP1.
  • the protein sequence encoded by p2I7 is represented in the public databases by the accession AAC39689 and is described in this patent by Seq LD 205.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF004563 and is described in this patent by Seq ID 206.
  • STXBP1 is implicated in vesicle trafficking and neurotransmitter release. STXBP1 is up- regulated by greater than 2-fold by Epas.
  • STXBP1 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, STXBP1 was changed in expression 1.78, 11.31 and 1.77 fold in the three diseased patients compared to the control group. This indicates that STXBP1 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I3 represents SULTIAI sulphotransferase, cytosohc.
  • the protein sequence encoded by SULTIAI is represented in the public databases by the accession AAC51816 and is described in this patent by Seq ID 207.
  • the nucleotide sequence is represented in the public sequence databases by the accession U52852 and is described in this patent by Seq ID 208.
  • SULTIAI is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • SULTIAI is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • SULTIAI is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • SULTIAI is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor.
  • SULTIAI plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2H17 represents Tensin.
  • the protein sequence encoded by Tensin is represented in the public databases by the accession NP_072174 and is described in this patent by Seq ID 209.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_022648 and is described in this patent by Seq ID 210.
  • Tensin is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • Tensin is repressed by a factor of 2.04 in response to IL-13 and 1.64 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone p2G16 represents TNF 4- IBB ligand.
  • the protein sequence encoded by p2G16 is represented in the public databases by the accession P41273 and is described in this patent by Seq ID 211.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003811 and is described in this patent by Seq ID 212.
  • TNF 4- IBB ligand may have a role in activation-induced cell death.
  • TNF 4- 1BB ligand is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNF 4- IBB ligand is induced by a factor of 2.43 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
  • the Oxford BioMedica clone plN15 represents the Tyrosine kinase, Syk.
  • the protein sequence encoded by Syk is represented in the public databases by the accession P43405 and is described in this patent by Seq ID 213.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_003177 and is described in this patent by Seq ED 214.
  • Syk is up-regulated by greater than 2-fold by both Hif and Epas.
  • Syk is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • Syk is repressed in response to Interleukin- 1, by a factor of 3.7 fold at 6hr and 3.23 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor.
  • Syk is suppressed by a factor of 2.17 at 6hr and 1.61 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • Syk is suppressed by a factor of 2.04 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors.
  • Syk is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2A22 represents Ubiquitin associated protein.
  • the protein sequence encoded by Ubiquitin associated protein is represented in the public databases by the accession NPJ357609 and is described in this patent by Seq ID 215.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016525 and is described in this patent by Seq ID 216.
  • Ubiquitin associated protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Ubiquitin associated protein is repressed by a factor of 2.86 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • COPD chronic obstructive pulmonary disease
  • Ubiquitin associated protein In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Ubiquitin associated protein was changed in expression 3.7, 2.8 and -1.09 fold in the three diseased patients compared to the control group. This indicates that Ubiquitin associated protein plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I5 represents an unnamed protein product.
  • the protein sequence encoded by p2I5 is represented in the public databases by the accession BAB55306 and is described in this patent by Seq ID 217.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK027699 and is described in this patent by Seq ID 218.
  • the sequence encoded by SEQ ID 218 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoded by SEQ ID 218 is induced by a factor of 2.65 at 6hr and 1.71 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
  • the sequence encoded by SEQ ID 218 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the sequence encoded by SEQ ID 218 was changed in expression -2, -2.38 and -2.56 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by SEQ ID 218 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2Il represents Villin 1.
  • Villin 1 is up-regulated by greater than 2-fold by Epas. Villin 1 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Yes-associated protein homolog DKFZp596I1419 is represented in the public databases by the accession CAB43275 and is described in this patent by Seq ID 221.
  • the nucleotide sequence is represented in the public sequence databases by the accession AL050107 and is described in this patent by Seq ID 222.
  • the seqeunce encoded by SEQ ID 222 is up- regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plN7 represents YYl and E4TF1 associated factor apoptin associated protein APAP1.
  • the protein sequence encoded by plN7 is represented in the public databases by the accession BAA89486 and is described in this patent by Seq ID 223 and SEQ ID 225.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB029551 and is described in this patent by Seq ID 224 and Seq ID 226.
  • YYl and E4TF1 associated factor apoptin associated protein APAP1 is up-regulated by greater than 2-fold by Epas.
  • YYl and E4TF1 associated factor apoptin associated protein APAP1 In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, YYl and E4TF1 associated factor apoptin associated protein APAP1 was up-regulated 2.07 fold in one of the patientsand was up-regulated 1.63 fold in the other patient. This indicates that YYl and E4TF1 associated factor apoptin associated protein APAP1 plays a role in the inflammation associated with COPD.
  • COPD chronic obstructive pulmonary disease
  • YYl and E4TF1 associated factor apoptin associated protein APAP1 were changed in expression -1.35, -2.33 and 1.52 fold in the three diseased patients compared to the control group. This indicates that YYl and E4TF1 associated factor apoptin associated protein APAP1 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2Ll l represents Acinus L.
  • the protein sequence encoded by Acinus L is represented in the public databases by the accession AAD56724 and is described in this patent by Seq ID 227.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF 12476 and is described in this patent by Seq ED 228.
  • Acinus L is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Acinus L is induced in response to TNFalpha, by a factor of 3.11 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Acinus L is repressed in response to Interleukin- 1, by a factor of 2.63 fold at 6hr and 3.23 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • Acinus L is suppressed by a factor of 4.17 at 6hr and 2.38 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • Acinus L is repressed by a factor of 2.17 in response to EL- Vindicating a negative role in Th2 immune responses.
  • Acinus L is suppressed by a factor of 2.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone p2H5 represents the hypothetical protein KIAA0742 .
  • the protein sequence encoded by p2H5 is represented in the public databases by the accession BAA34462 and is described in this patent by Seq ID 229.
  • the nucleotide sequence is represented in the public sequence databases by the accession ABO 18285 and is described in this patent by Seq ID 230.
  • KIAA0742 is up-regulated by greater than 2-fold by both Hif and Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, KIAA0742 was up-regulated 19.8 fold in one of the patientsand was up-regulated 7.4 fold in the other patient. This indicates that KIAA0742 plays a role in the inflammation associated with COPD.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone plN12 represents the hypothetical protein KLAA1147 .
  • the protein sequence encoded by p IN 12 is represented in the public databases by the accession BAA86461 and is described in this patent by Seq ID 231.
  • the nucleotide sequence is represented in the public sequence databases by the accession AB032973 and is described in this patent by Seq LD 232.
  • KIAA1147 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, KIAA1147 is induced in response to TNFalpha, by a factor of 2.39 fold, indicating a positive role in pro-inflammatory responses involving this factor. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions.
  • KIAA1147 is induced by a factor of 2.93 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • KIAA1147 was changed in expression -1.69, -2.56 and -1.61 fold in the three diseased patients compared to the control group. This indicates that KIAA1147 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone plN5 represents the hypothetical protein DKFZP564B167.
  • the protein sequence encoded by plN5 is represented in the public databases by the accession NP_056230 and is described in this patent by Seq ID 233.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_015415 and is described in this patent by Seq ID 234.
  • DKFZP564B167 is up-regulated by greater than 2-fold by Epas.
  • DKFZP564B167 is suppressed by a factor of 3.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone p2H2 represents the hypothetical protein FLJ22704.
  • the protein sequence encoded by p2H2 is represented in the public databases by the accession XP_051421 and is described in this patent by Seq ID 235.
  • the nucleotide sequence is represented in the public sequence databases by the accession XM_051421 and is described in this patent by Seq ID 236.
  • FLJ22704 is up-regulated by greater than 2-fold by Epas.
  • FLJ22704 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • FLJ22704 is induced in response to TNFalpha, by a factor of 2.02 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • FLJ22704 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • COPD chronic obstructive pulmonary disease
  • FLJ22704 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ22704 was changed in expression 1.09, -2.08 and -1.14 fold in the three diseased patients compared to the control group. This indicates that FLJ22704 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone pi LI 2 represents the hypothetical protein PRO0195 .
  • the protein sequence encoded by plL12 is represented in the public databases by the accession NP_054838 and is described in this patent by Seq ID 237.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014119 and is described in this patent by Seq ID 238.
  • the sequence encoded by Seq ID 238 is up- regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2C17 represents the hypothetical protein DKFZp434I225.
  • the protein sequence encoded by p2C17 is represented in the public databases by the accession CAB56026 and is described in this patent by Seq ID 239.
  • the nucleotide sequence is represented in the public sequence databases by the accession ALl 17637 and is described in this patent by Seq ED 240.
  • the sequence encoded by Seq ID 240 is up- regulated by greater than 2-fold by Hif.
  • the sequence encoded by Seq ID 240 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2Hl l represents the hypothetical protein Estradiol induced.
  • the protein sequence encoded by p2Hl l is represented in the public databases by the accession NP_055182 and is described in this patent by Seq ID 241 and Seq ID 243.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_014367 and is described in this patent by Seq ID 242 and Seq ID 244.
  • the sequence encoded by Seq ID 242 is up-regulated by greater than 2-fold by Hif.
  • Seq ID 242 The sequence encoded by Seq ID 242 is suppressed by a factor of 2.86 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone p2H4 represents the hypothetical protein FLJ 10199.
  • the protein sequence encoded by p2H4 is represented in the public databases by the accession NP_060492 and is described in this patent by Seq ID 245.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018022 and is described in this patent by Seq ID 246.
  • FLJ10199 is up-regulated by greater than 2-fold by both Hif and Epas.
  • FLJ 10199 was changed in expression 2.44, 2.03 and 1.1 fold in the three diseased patients compared to the control group. This indicates that FLJ 10199 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2H7 represents the hypothetical protein FLJ 10276.
  • the protein sequence encoded by p2H7 is represented in the public databases by the accession NP_060515 and is described in this patent by Seq ID 247.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_018045 and is described in this patent by Seq ID 248.
  • FLJ 10276 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2L7 represents the hypothetical protein FLJ 13758 which is a putative tumour suppressor.
  • the protein sequence encoded by p2L7 is represented in the public databases by the accession NP_115761 and is described in this patent by Seq ID 249.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_032385 and is described in this patent by Seq ID 250.
  • FLJ 13758 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • FLJ13758 is repressed by a factor of 2.7 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • FLJ 13758 is suppressed by a factor of 2.04 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • FLJ13758 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2C13 represents the hypothetical protein FLJ20315.
  • FLJ20315 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ20315 was changed in expression -1.72, -2.04 and -1.67 fold in the three diseased patients compared to the control group. This indicates that FLJ20315 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2D24 represents the hypothetical protein FLJ20628.
  • the protein sequence encoded by p2D24 is represented in the public databases by the accession NP_060380 and is described in this patent by Seq ID 253.
  • the nucleotide sequence is represented in the public sequence databases by the accession BC010365 and is described in this patent by Seq TD 254.
  • FLJ20628 is up-regulated by greater than 2-fold by Hif.
  • FLJ20628 is induced by a factor of 61.96 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • FLJ20628 is induced by a factor of 10.81 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the Oxford BioMedica clone plK21 represents the hypothetical protein, FLJ23306.
  • the protein sequence encoded by plK21 is represented in the public databases by the accession BAB 15603 and is described in this patent by Seq ID 255.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK026959 and is described in this patent by Seq ID 256.
  • FLJ23306 is up-regulated by greater than 2-fold by Epas.
  • FLJ23306 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • FLJ23306 is induced in response to TNFalpha, by a factor of 2.01 fold, indicating a positive role in pro-inflammatory responses involving this factor.
  • FLJ23306 is induced by a factor of 2.55 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • FLJ23306 is induced by a factor of 2.06 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • FLJ23306 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • FLJ23306 was changed in expression -2.27, -1.96 and 1.5 fold in the three diseased patients compared to the control group. This indicates that FLJ23306 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2G14 represents the hypothetical protein, FLJ23312.
  • the protein sequence encoded by p2G14 is represented in the public databases by the accession NP_079028 and is described in this patent by Seq ID 257.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_024752 and is described in this patent by Seq ID 258.
  • FLJ23312 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plM7 represents the hypothetical protein, MGC4595.
  • the protein sequence encoded by plM7 is represented in the public databases by the accession NP_116127 and is described in this patent by Seq ID 259.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_032738 and is described in this patent by Seq ED 260.
  • MGC4595 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • MGC4595 is repressed by a factor of 1.67 in response to IL-13 and 2.27 in response to IL- 4, indicating a negative role in Th2 immune responses.
  • MGC4595 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • MGC4595 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, MGC4595 was changed in expression -1.56, -2.04 and -1.47 fold in the three diseased patients compared to the control group. This indicates that MGC4595 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2G22 represents the hypothetical protein, PP5395.
  • the protein sequence encoded by p2G22 is represented in the public databases by the accession NP_068378 and is described in this patent by Seq ID 261.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_021732 and is described in this patent by Seq ID 262.
  • PP5395 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plM19 represents a hypothetical protein similar to CGI-78.
  • the protein sequence encoded by plM19 is represented in the public databases by the accession NP_057106 and is described in this patent by Seq ID 263.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_031301 and is described in this patent by Seq ID 264.
  • the sequence encoded by Seq ID 264 is up- regulated by greater than 2-fold by Epas.
  • the sequence encoded by Seq ID 264 is induced by a factor of 2.18 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors.
  • the superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions, the sequence encoded by Seq ID 264 is induced by a factor of 2.19 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the Oxford BioMedica clone p2Hl represents the hypothetical protein, XP_038788.
  • the protein sequence encoded by p2Hl is represented in the public databases by the accession XP_038788 and is described in this patent by Seq ID 265.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK002171 and is described in this patent by Seq ID 266.
  • XP_038788 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • XP_038788 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to EL- 10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • XP_038788 is repressed by a factor of 1.96 in response to IL-13 and 2.33 in response to IL-4, indicating a negative role in Th2 immune responses.
  • XP_038788 is suppressed by a factor of 3.57 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • XP_038788 was changed in expression 1.08, -3.03 and 1.24 fold in the three diseased patients compared to the control group. This indicates that XP_038788 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2H3 represents the hypothetical protein, XP_047730.
  • the protein sequence encoded by p2H3 is represented in the public databases by the accession XP_047730 and is described in this patent by Seq ID 267.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK023833 and is described in this patent by Seq ID 268.
  • XP_047730 is up-regulated by greater than 2-fold by both Hif and Epas.
  • XP_047730 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • XP_047730 is induced by a factor of 2.05 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • XP_047730 is suppressed by a factor of 2.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors.
  • XP_047730 In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, XP_047730 was changed in expression -1.19, -2.86 and -1.22 fold in the three diseased patients compared to the control group. This indicates that XP_047730 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I13 represents the cDNA FLJ14112 fis clone, MAMMA 1001683.
  • the protein sequence encoded by p2I13 is described in this patent by Seq ID 269.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK024174 and is described in this patent by Seq ID 270.
  • p2I13 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoded by Seq ID 270 is induced by a factor of 2.51 at 6hr and 1.66 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the sequence encoded by Seq ID 270 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2G24 represents the cDNA clone, YR92D05.
  • the protein sequence encoded by p2G24 is described in this patent by Seq ID 271.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF085961 and is described in this patent by Seq ID 272.
  • YR92D05 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • YR92D05 is induced by a factor of 2.55 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • YR92D05 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2D18 represents the cDNA clone, IMAGE:4588421.
  • the protein sequence encoded by p2D18 is described in this patent by Seq LD 273.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG422848 and is described in this patent by Seq LD 274.
  • the sequence encoded by Seq ID 274 is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone p2C18 represents the cDNA FLJ23111 fis clone, LNG07835.
  • the protein sequence encoded by p2C18 is described in this patent by Seq ED 275.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK026764 and is described in this patent by Seq ID 276.
  • the sequence encoded by Seq ID 276 is up-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoded by Seq ID 276 is induced by a factor of 2.19 at 6hr and 1.56 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the sequence encoded by Seq ID 276 was changed in expression -2.86, -2.86 and -2 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 276 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2G13 represents an EST.
  • the protein sequence encoded by p2G13 is described in this patent by Seq ID 277.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG774858 and is described in this patent by Seq ID 278.
  • the sequence encoeded by Seq ID 278 is up-regulated by greater than 2- fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the sequence encoeded by Seq ID 278 is repressed by a factor of 1.92 in response to IL-13 and 2 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the nucleotide sequence is represented in the public sequence databases by the accession T66907 and is described in this patent by Seq ID 280.
  • the seqeunce encoded by Seq ID 279 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plL9 represents an EST.
  • the protein sequence encoded by plL9 is described in this patent by Seq ID 281.
  • the nucleotide sequence is represented in the public sequence databases by the accession R84242 and is described in this patent by Seq ID 282.
  • the sequence encoeded by Seq ID 282 is up-regulated by greater than 2-fold by Epas.
  • the sequence encoeded by Seq ID 282 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plL22 represents an EST.
  • the protein sequence encoded by plL22 is described in this patent by Seq ID 283.
  • the nucleotide sequence is represented in the public sequence databases by the accession T83864 and is described in this patent by Seq ID 284.
  • the sequence encoeded by Seq ID 284 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoeded by Seq ID 284 is induced by a factor of 2.87 at 6hr and 2.17 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the sequence encoeded by Seq ID 284 is repressed by a factor of 2.27 in response to IL-10, indicating a negative role in the response to IL-10.
  • plL22 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2E4 represents an EST.
  • the protein sequence encoded by p2E4 is described in this patent by Seq ID 285.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA704858 and is described in this patent by Seq ED 286.
  • the sequence encoeded by Seq ID 286 is up-regulated by greater than 2- fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoeded by Seq ID 286 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • the sequence encoeded by Seq ID 286 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2C14 represents an EST.
  • the protein sequence encoded by p2C14 is described in this patent by Seq ID 287.
  • the nucleotide sequence is represented in the public sequence databases by the accession T64894 and is described in this patent by Seq ID 288.
  • p2C14 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 288 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the seqeunce encoded by Seq ID 288 is repressed by a factor of 3.85 in response to IL-13 and 2.5 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone p2I8 represents an EST.
  • the protein sequence encoded by p2I8 is described in this patent by Seq ID 289.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI032477 and is described in this patent by Seq ID 290.
  • the seqeunce encoded by Seq ID 290 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 290 is induced by a factor of 2.09 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 290 is repressed by a factor of 2.17 in response to IL-10, indicating a negative role in the response to IL-10.
  • the seqeunce encoded by Seq ID 290 was changed in expression -2.13, 1.65 and -1.67 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 290 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I9 represents an EST.
  • the protein sequence encoded by p2I9 is described in this patent by Seq ID 291.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI056809 and is described in this patent by Seq ID 292.
  • the seqeunce encoded by Seq ID 292 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 292 is induced by a factor of 3.35 at 6hr and 1.57 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 292 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 292 was changed in expression -3.85, -3.23 and -2.27 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 292 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2Il 1 represents an EST.
  • the protein sequence encoded by p2Il l is described in this patent by Seq ID 293.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI032945 and is described in this patent by Seq ID 294.
  • the seqeunce encoded by Seq ID 294 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 294 is induced by a factor of 2.31 at 6hr and 1.87 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 294 is repressed by a factor of 3.03 in response to IL-10, indicating a negative role in the response to IL-10.
  • Seq ID 294 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2I19 represents an EST.
  • the protein sequence encoded by p2I19 is described in this patent by Seq ID 295.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI189495 and is described in this patent by Seq ID 296.
  • the seqeunce encoded by Seq ID 296 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ED 296 is induced by a factor of 2.69 at 6hr and 1.5 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 296 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 296 was changed in expression -2.94, -4.17 and -2.63 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 296 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2El represents an EST.
  • the protein sequence encoded by p2El is described in this patent by Seq ID 297.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA679426 and is described in this patent by Seq ID 298.
  • the seqeunce encoded by Seq ID 298 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plMl represents an EST.
  • the protein sequence encoded by plMl is described in this patent by Seq ID 299.
  • the nucleotide sequence is represented in the public sequence databases by the accession T98458 and is described in this patent by Seq ID 300.
  • the seqeunce encoded by Seq ID 300 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 300 is induced by a factor of 2.97 at 6hr and 1.63 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 300 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 300 was changed in expression -3.13, -2.5 and -2.08 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 300 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2B2 represents an EST.
  • the protein sequence encoded by p2B2 is described in this patent by Seq ED 301.
  • the nucleotide sequence is represented in the public sequence databases by the accession T83558 and is described in this patent by Seq ID 302.
  • the seqeunce encoded by Seq ID 302 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 302 is induced by a factor of 2.51 at 6hr and 1.75 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 302 is repressed by a factor of 2.22 in response to IL-10, indicating a negative role in the response to IL-10.
  • the seqeunce encoded by Seq ID 302 was changed in expression -2.86, 1.03 and - 1.64 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 302 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2A13 represents an EST.
  • the protein sequence encoded by p2A13 is described in this patent by Seq ID 303.
  • the nucleotide sequence is represented in the public sequence databases by the accession BE219865 and is described in this patent by Seq ID 304.
  • the seqeunce encoded by Seq ID 304 is up-regulated by greater than 2-fold by Epas.
  • the seqeunce encoded by Seq ID 304 was changed in expression 3.35, 2.64 and 1.09 fold in the three diseased patients compared to the control group.
  • Seq ID 304 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2E3 represents an EST.
  • the protein sequence encoded by p2E3 is described in this patent by Seq ID 305.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA701314 and is described in this patent by Seq ID 306.
  • the seqeunce encoded by Seq ED 306 is up-regulated by greater than 2-fold by Epas.
  • Seq ID 306 The seqeunce encoded by Seq ID 306 is suppressed by a factor of 2 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone p2E2 represents an EST.
  • the protein sequence encoded by p2E2 is described in this patent by Seq ID 307.
  • the nucleotide sequence is represented in the public sequence databases by the accession AW161661 and is described in this patent by Seq ID 308.
  • the seqeunce encoded by Seq ID 308 is up-regulated by greater than 2-fold by Epas.
  • the seqeunce encoded by Seq ID 308 is suppressed by a factor of 2.94 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • the seqeunce encoded by Seq ID 308 is suppressed by a factor of 2.17 in response to superoxide, indicating an anti- inflammatory function in ischaemia/reperfusion.
  • the seqeunce encoded by Seq ID 308 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2E10 represents an EST.
  • the protein sequence encoded by p2E10 is described in this patent by Seq ID 309.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA626254 and is described in this patent by Seq ID 310.
  • the seqeunce encoded by Seq ID 310 is up-regulated by greater than 2-fold by Hif.
  • the seqeunce encoded by Seq ID 310 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 310 was changed in expression -1.08, -2.17 and - 1.54 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 310 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2C8 represents an EST.
  • the protein sequence encoded by p2C8 is described in this patent by Seq ID 311.
  • the nucleotide sequence is represented in the public sequence databases by the accession BF971135 and is described in this patent by Seq ID 312.
  • the seqeunce encoded by Seq ID 312 is up-regulated by greater than 2-fold by Hif.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • the seqeunce encoded by Seq ID 312 is induced by a factor of 2.09 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the seqeunce encoded by Seq ID 312 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 312 was changed in expression -1.61, -2.13 and 1.12 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 310 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2Gl l represents an EST.
  • the protein sequence encoded by p2Gl 1 is described in this patent by Seq ID 313.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK027199 and is described in this patent by Seq ID 314.
  • the seqeunce encoded by Seq ID 314 is up-regulated by greater than 2-fold by Epas.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • the seqeunce encoded by Seq ID 314 is induced by a factor of 2.09 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
  • the Oxford BioMedica clone p2G19 represents an EST.
  • the protein sequence encoded by p2G19 is described in this patent by Seq ID 315.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA700141 and is described in this patent by Seq ID 316.
  • the seqeunce encoded by Seq ID 316 is up-regulated by greater than 2-fold by Epas.
  • p2G19 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2H18 represents an EST.
  • the protein sequence encoded by p2H18 is described in this patent by Seq ID 317.
  • the nucleotide sequence is represented in the public sequence databases by the accession AW968530 and is described in this patent by Seq ID 318.
  • the seqeunce encoded by Seq ID 318 is up-regulated by greater than 2-fold by Hif.
  • the seqeunce encoded by Seq ID 318 was changed in expression -1.47, -2.27 and -1.2 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 318 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2H24 represents an EST.
  • the protein sequence encoded by p2H24 is described in this patent by Seq ID 319.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI032695 and is described in this patent by Seq ID 320.
  • the seqeunce encoded by Seq ID 320 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2I4 represents an EST.
  • the protein sequence encoded by p2I4 is described in this patent by Seq ID 321.
  • the nucleotide sequence is represented in the public sequence databases by the accession AV705233 and is described in this patent by Seq ID 322.
  • the seqeunce encoded by Seq ID 322 is up-regulated by greater than 2-fold by Epas.
  • COPD chronic obstructive pulmonary disease
  • Seq ID 322 plays a role in the inflammation associated with COPD.
  • the seqeunce encoded by Seq ID 322 was changed in expression 1.28, -2.78 and -1.22 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 322 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I14 represents an EST.
  • the protein sequence encoded by p2I14 is described in this patent by Seq ID 323.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG423026 and is described in this patent by Seq ED 324.
  • the seqeunce encoded by Seq ID 324 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 324 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 324 is repressed by a factor of 2.44 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ED 324 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2I15 represents an EST.
  • the protein sequence encoded by p2I15 is described in this patent by Seq ID 325.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI032956 and is described in this patent by Seq ID 326.
  • the seqeunce encoded by Seq ID 326 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 326 is induced by a factor of 2.17 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 326 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 326 was changed in expression -1.96, - 3.85 and -2.27 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 326 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2L4 represents an EST.
  • the protein sequence encoded by p2L4 is described in this patent by Seq ID 327.
  • the nucleotide sequence is represented in the public sequence databases by the accession AK025119 and is described in this patent by Seq ID 328.
  • the seqeunce encoded by Seq ID 328 is up-regulated by greater than 2-fold by Hif.
  • the Oxford BioMedica clone p2L5 represents an EST.
  • the protein sequence encoded by p2L5 is described in this patent by Seq ID 329.
  • the nucleotide sequence is represented in the public sequence databases by the accession HI 1671 and is described in this patent by Seq ED 330.
  • the seqeunce encoded by Seq ID 330 is up-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the seqeunce encoded by Seq LD 330 is repressed by a factor of 2 in response to IL- Vindicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone p2L6 represents an EST.
  • the protein sequence encoded by p2L6 is described in this patent by Seq ID 331.
  • the nucleotide sequence is represented in the public sequence databases by the accession AW581935 and is described in this patent by Seq ID 332.
  • the seqeunce encoded by Seq ED 332 is up-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, the seqeunce encoded by Seq ID 332 is repressed in response to Interleukin- 1, by a factor of 2.94 fold at 6hr and 2.63 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • Seq ID 333 An EST (In Intron for cypl9) is described in this patent by Seq ID 333.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG005535 and is described in this patent by Seq ID 334.
  • the sequence encoded by Seq ID 334 is up- regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plL24 represents an EST (In Intron for cypl9).
  • the protein sequence encoded by plL24 is described in this patent by Seq ID 335.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG005535 and is described in this patent by Seq ID 336.
  • plL24 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the seqeunce encoded by Seq ID 336 is repressed by a factor of 1.56 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the seqeunce encoded by Seq ID 336 is repressed by a factor of 2.08 in response to IL-13 and 1.69 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the seqeunce encoded by Seq ID 336 was changed in expression -2.17, -1.89 and -1.12 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 336 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2H8 represents an EST (In Intron for DD96).
  • the protein sequence encoded by p2H8 is described in this patent by Seq ID 337.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA699567 and is described in this patent by Seq ED 338.
  • the seqeunce encoded by Seq ID 338 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 338 is repressed by a factor of 2.7 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor.
  • the Oxford BioMedica clone p2H19 represents an EST (In intron for LOC87246).
  • the protein sequence encoded by p2H19 is described in this patent by Seq ID 339.
  • the nucleotide sequence is represented in the public sequence databases by the accession T83663 and is described in this patent by Seq ID 340.
  • the seqeunce encoded by Seq ID 340 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2H22 represents an EST (In intron of UBP1).
  • the protein sequence encoded by p2H22 is described in this patent by Seq ID 341.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI023339 and is described in this patent by Seq ID 342.
  • the seqeunce encoded by Seq ID 342 is up- regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2H21 represents an EST (In intron of ZMPSTE24).
  • the protein sequence encoded by p2H21 is described in this patent by Seq ID 343.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI032679 and is described in this patent by Seq ID 344.
  • the seqeunce encoded by Seq ID 344 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 344 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor.
  • Seq ID 345 An EST (within an intron to ABLEVI) is described in this patent by Seq ID 345.
  • the nucleotide sequence is represented in the public sequence databases by the accession W92780 and is described in this patent by Seq ID 346.
  • the sequence encoded by Seq ID 346 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2I20 represents an EST (In intron to CTSB).
  • the protein sequence encoded by p2I20 is described in this patent by Seq LD 347.
  • the nucleotide sequence is represented in the public sequence databases by the accession BF828079 and is described " in this patent by Seq ID 348.
  • the seqeunce encoded by Seq ID 348 is up- regulated by greater than 2-fold by both Hif and Epas.
  • the seqeunce encoded by Seq ED 348 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 348 was changed in expression -1.2, -2 and -1.79 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 348 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2G10 represents an EST (In Intron to ELL2).
  • the protein sequence encoded by p2G10 is described in this patent by Seq ID 349.
  • the nucleotide sequence is represented in the public sequence databases by the accession BG928580 and is described in this patent by Seq ED 350.
  • the seqeunce encoded by Seq ID 350 is up- regulated by greater than 2-fold by Epas.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone p2L2 represents an EST (In Intron to FIJI 1577).
  • the protein sequence encoded by p2L2 is described in this patent by Seq ID 351.
  • the nucleotide sequence is represented in the public sequence databases by the accession T83845 and is described in this patent by Seq ID 352.
  • the seqeunce encoded by Seq ID 352 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the seqeunce encoded by Seq ID 352 is repressed by a factor of 1.69 in response to IL-13 and 2.04 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone p2Cl represents an EST (In intron to HAL).
  • the protein sequence encoded by p2Cl is described in this patent by Seq ID 353.
  • the nucleotide sequence is represented in the public sequence databases by the accession BF902949 and is described in this patent by Seq ID 354.
  • the seqeunce encoded by Seq ID 354 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 354 is induced by a factor of 2.15 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 354 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 354 was changed in expression -3.23, -2.33 and -1.96 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 354 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I16 represents an EST (In Intron to HDAC8).
  • the protein sequence encoded by p2I16 is described in this patent by Seq ID 355.
  • the nucleotide sequence is represented in the public sequence databases by the accession All 24813 and is described in this patent by Seq ID 356.
  • the seqeunce encoded by Seq ID 356 is up- regulated by greater than 2-fold by both Hif and Epas.
  • the seqeunce encoded by Seq ID 356 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the seqeunce encoded by Seq ID 356 was changed in expression -5.88, 2.01 and -2.44 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 356 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2G17 represents an EST (In Intron to SLC21A11).
  • the protein sequence encoded by p2G17 is described in this patent by Seq ID 357.
  • the nucleotide sequence is represented in the public sequence databases by the accession AW976431 and is described in this patent by Seq ID 358.
  • the seqeunce encoded by Seq ID 358 is up-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone p2H23 represents an EST (In intron).
  • the protein sequence encoded by p2H23 is described in this patent by Seq ID 359.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI022630 and is described in this patent by Seq ID 360.
  • the seqeunce encoded by Seq ID 360 is up-regulated by greater than 2-fold by Epas.
  • the seqeunce encoded by Seq ID 360 was changed in expression 2.12, 1.46 and -1.04 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 360 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2I6 represents an EST 2q37.1.
  • the protein sequence encoded by p2I6 is described in this patent by Seq ID 361.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA281534 and is described in this patent by Seq ID 362.
  • p2I6 is up-regulated by greater than 2-fold by Epas.
  • p2I6 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone plMl 1 represents an EST located on chromosome lpl2.
  • the protein sequence encoded by plMl l is described in this patent by Seq ID 363.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA007687 and is described in this patent by Seq ID 364.
  • the seqeunce encoded by Seq ED 364 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions, the seqeunce encoded by Seq ID 364 is repressed by a factor of 2.63 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease, the seqeunce encoded by Seq ID 364 is repressed by a factor of 2.04 in response to IL-13 and 2.13 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the seqeunce encoded by Seq ID 364 is suppressed by a factor of 2.38 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the seqeunce encoded by Seq ID 364 was changed in expression -1.64, -3.23 and -1.43 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 364 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2C4 represents an EST located on chromosome lp32.
  • the protein sequence encoded by p2C4 is described in this patent by Seq ID 365.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA977628 and is described in this patent by Seq ID 366.
  • the seqeunce encoded by Seq ID 366 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the seqeunce encoded by Seq ID 366 is repressed by a factor of 2.08 in response to IL-13 and 1.92 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the seqeunce encoded by Seq ID 366 is suppressed by a factor of 2.13 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • the Oxford BioMedica clone p2D23 represents an EST located on chromosome lp34.
  • the protein sequence encoded by p2D23 is described in this patent by Seq ID 367.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA883805 and is described in this patent by Seq ID 368.
  • the seqeunce encoded by Seq ID 368 is up-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the seqeunce encoded by Seq ID 368 is induced by a factor of 2.52 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
  • the seqeunce encoded by Seq ID 368 was up-regulated 2.11, 2.11 and 1.02 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 368 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2L8 represents an EST located on chromosome 20ql 1. The protein sequence encoded by p2L8 is described in this patent by Seq ID 369.
  • the nucleotide sequence is represented in the public sequence databases by the accession H79736 and is described in this patent by Seq ID 370.
  • the sequence encoded by Seq ID 370 is up-regulated by greater than 2-fold by Epas.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the sequence encoded by Seq ID 370 is repressed by a factor of 1.56 in response to IL-10, indicating a negative role in the response to IL-10.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • the sequence encoded by Seq ID 370 is repressed by a factor of 2.63 in response to EL-13 and 1.82 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the Oxford BioMedica clone plL8 represents an EST located on chromosome 2ql3.
  • the protein sequence encoded by plL8 is described in this patent by Seq ID 371.
  • the nucleotide sequence is represented in the public sequence databases by the accession R84375 and is described in this patent by Seq ID 372.
  • the sequence encoded by Seq ID 372 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the sequence encoded by Seq ID 372 is induced by a factor of 2.68 at 6hr and 1.67 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions.
  • the sequence encoded by Seq ID 372 is repressed by a factor of 2.38 in response to IL-10, indicating a negative role in the response to IL-10.
  • the sequence encoded by Seq ID 372 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the sequence encoded by Seq ID 372 was changed in expression -3.85, -1.69 and -2 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 372 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2E5 represents an EST located on chromosome 8pl2. The protein sequence encoded by p2E5 is described in this patent by Seq ID 373.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA704849 and is described in this patent by Seq ID 374.
  • the sequence encoded by Seq ID 374 is up-regulated by greater than 2-fold by Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis.
  • Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions.
  • the sequence encoded by Seq ID 374 is repressed in response to Interleukin- 1, by a factor of 3.57 fold at 6hr and 2.5 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
  • the sequence encoded by Seq ID 374 is suppressed by a factor of 2.27 at 6hr and 1.96 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor.
  • the sequence encoded by Seq ID 374 is repressed by a factor of 2.38 in response to IL-13 and 2.56 in response to IL-4, indicating a negative role in Th2 immune responses.
  • the sequence encoded by Seq ID 374 is suppressed by a factor of 2.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
  • plN13 represents an EST located on chromosome 12pl3.
  • the protein sequence encoded by plN13 is described in this patent by Seq ID 375.
  • the nucleotide sequence is represented in the public sequence databases by the accession W86870 and is described in this patent by Seq ID 376.
  • plN13 is up-regulated by greater than 2-fold by both Hif and Epas. plN13 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • plN13 was changed in expression -2.38, -2 and -1.82 fold in the three diseased patients compared to the control group. This indicates that plN13 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2C2 represents an EST located on chromosome 3p22.3.
  • the protein sequence encoded by p2C2 is described in this patent by Seq ED 377.
  • the nucleotide sequence is represented in the public sequence databases by the accession AA878193 and is described in this patent by Seq ID 378.
  • the nucleotide sequence encoded by Seq ID 377 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the nucleotide sequence encoded by Seq ID 377 is induced by a factor of 2.29 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 377 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the nucleotide sequence encoded by Seq ID 377 was changed in expression -1.33, -3.7 and -2.78 fold in the three diseased patients compared to the control group. This indicates that the nucleotide sequence encoded by Seq ID 377 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2D19 represents an EST located on chromosome 6q27.
  • the protein sequence encoded by p2D19 is described in this patent by Seq ID 379.
  • the nucleotide sequence is represented in the public sequence databases by the accession T95117 and is described in this patent by Seq ID 380.
  • the nucleotide sequence encoded by Seq ED 380 is up-regulated by greater than 2-fold by Epas.
  • COPD chronic obstructive pulmonary disease
  • the Oxford BioMedica clone p2I12 represents an EST upstream to D?LA2 gamma ( ⁇ 500bp).
  • the protein sequence encoded by p2I12 is described in this patent by Seq ID 381.
  • the nucleotide sequence is represented in the public sequence databases by the accession AI168105 and is described in this patent by Seq ID 382.
  • the nucleotide sequence encoded by Seq ID 382 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the nucleotide sequence encoded by Seq ID 382 is induced by a factor of 3.57 at 6hr and 2.08 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 382 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the nucleotide sequence encoded by Seq ID 382 was changed in expression -2.7, -1.69 and -1.27 fold in the three diseased patients compared to the control group. This indicates that the nucleotide sequence encoded by Seq ID 382 plays a role in the process of atherogenesis.
  • the Oxford BioMedica clone p2K24 represents phorbolin-1 -related protein.
  • the protein sequence encoded by p2K24 is represented in the public databases by the accession AAD00090 and is described in this patent by Seq ID 383.
  • the nucleotide sequence is represented in the public sequence databases by the accession U61084 and is described in this patent by Seq ID 384.
  • the nucleotide sequence encoded by Seq ID 384 is down- regulated by greater than 2-fold by Epas.
  • p2K24 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the nucleotide sequence encoded by Seq ID 384 is induced by a factor of 2.9 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro- inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 384 is induced by a factor of 27.74 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the nucleotide sequence encoded by Seq ID 384 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • the Oxford BioMedica clone p2K2 represents a putative breast epithelial stromal interaction protein .
  • the protein sequence encoded by p2K2 is represented in the public databases by the accession AAK73753 and is described in this patent by Seq ID 385.
  • the nucleotide sequence is represented in the public sequence databases by the accession AF396928 and is described in this patent by Seq ED 386.
  • the nucleotide sequence encoded by Seq ID 386 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • the nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.05 at 6hr and 5.3 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 386 is induced by a factor of 12.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.17 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor.
  • the nucleotide sequence encoded by Seq ID 386 is induced by a factor of 24.61 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • the superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions.
  • the nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.96 in response to superoxide, indicating a pro- inflammatory function in ischaemia/reperfusion.
  • the Oxford BioMedica clone p2J7 represents 71 kDa 2'5' oligoadenylate synthetase.
  • the protein sequence encoded by p2J7 is represented in the public databases by the accession AAA60607 and is described in this patent by Seq ID 387.
  • the nucleotide sequence is represented in the public sequence databases by the accession M87434 and is described in this patent by Seq ID 388.
  • 71 kDa 2'5' oligoadenylate synthetase is down-regulated by greater than 2-fold by Hif.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. 71 kDa 2' 5' oligoadenylate synthetase is induced by a factor of 2.07 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
  • 71 kDa 2'5' oligoadenylate synthetase is induced by a factor of 5.97 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor.
  • 71 kDa 2' 5' oligoadenylate synthetase is induced by a factor of 2.04 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor.
  • 71 kDa 2'5' oligoadenylate synthetase is induced by a factor of 12.32 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
  • 71 kDa 2'5' oligoadenylate synthetase is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
  • Oligoadenylate synthetase 2 is represented in the public databases by the accession P29728 and is described in this patent by Seq ID 389.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_016817 and is described in this patent by Seq ID 390.
  • the sequence encoded by Seq ID 390 is down- regulated by greater than 2-fold by Hif.
  • 60S ribosomal protein is represented in the public databases by the accession P38663 and is described in this patent by Seq ID 391.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_000986 and is described in this patent by Seq ID 392.
  • the sequence encoded by Seq ID 392 is down-regulated by greater than 2-fold by Epas.
  • the Oxford BioMedica clone plP18 represents ADP-ribosyl cyclase 1 (CD38).
  • the protein sequence encoded by plP18 is represented in the public databases by the accession P28907 and is described in this patent by Seq ID 393.
  • the nucleotide sequence is represented in the public sequence databases by the accession NM_001775 and is described in this patent by Seq ID 394.
  • CD38 synthesizes cyclic ADP-ribose, a second messenger for glucose-induced insulin secretion.
  • plP18 is down-regulated by greater than 2-fold by both Hif and Epas.
  • Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer.
  • Th2 cytokines typified by Interleukin-4 and Interleukin- 13 are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease.
  • plP18 is repressed by a factor of 2.08 in response to IL- Vindicating a negative role in Th2 immune responses.

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Abstract

This invention relates to novel genes and gene products that are implicated in certain disease states. According to the invention, a novel gene and its encoded protein are provided, that have been identified and functionally annotated for the first time. Some of these sequences are only identified as "hypothetical proteins" in the public databases.

Description

Genes
This invention relates to novel genes and gene products that are implicated in certain disease states.
All publications, patents and patent applications cited herein are incorporated in full by reference.
Over recent years, the so-called "genomics revolution" has allowed access to large portions of whole genomes, including the human genome. The amount of sequence information now available considerably facilitates the analysis of the results of experiments that aim to elucidate the functions of proteins that are expressed in the body. As this information increases in scope and becomes more readily available, the study of the molecular mechanism of disease, and the elucidation of techniques for combating these diseases will be considerably facilitated.
One particular physiological condition that has considerable relevance to human and other animal disease is the cellular response to hypoxia. The term "hypoxia" is intended to refer to an environment of reduced oxygen tension, as compared to the normal physiological environment for a particular organism, which is termed "normoxia".
In a variety of human diseases, cells are exposed to conditions of low oxygen tension, usually as a result of poor oxygen supply to the diseased area. For instance, tissue oxygenation plays a significant regulatory role in both apoptosis and in angiogenesis (Bouck et al, 1996, Adv. Cancer Res. 69:135-174; Bunn et al, 1996, Physiol. Rev. 76:839-885; Dor et al, 1997, Trends Cardiovasc. Med., 7:289-294; Carmeliet et al, 1998, Nature 394:485-490). Apoptosis (see Duke et al, 1996, Sci. American, 80-87 for review) and growth arrest occur when cell growth and viability are reduced due to oxygen deprivation. Angiogenesis (i.e. blood vessel growth, vascularization), is stimulated when hypooxygenated cells secrete factors that stimulate proliferation and migration of endothelial cells in an attempt to restore oxygen homeostasis (for review see Hanahan et al, 1996, Cell, 86:353-364).
Ischaemic disease pathologies involve a decrease in the blood supply to a bodily organ, tissue or body part generally caused by constriction or obstruction of the blood vessels. For example, solid tumours typically have a disorganised blood supply, leading to hypoxic regions. One particular example of an ischaemic disease pathology is myocardial ischaemia, which encompasses several chronic and acute cardiac pathologies that involve the deprivation of the myocardium of its blood supply, usually through coronary artery occlusion. A key component of ischaemia is hypoxia. Following transient ischaemia, the affected tissue may be subjected to reperfusion and re-oxygenation, and this is of significance in its own right.
Ischaemia/reperfusion is well known to induce cell death in myocardial tissue by apoptosis, leading to impaired function of the myocardium and infarction. Many of the specific molecules required to execute the process of apoptosis are known, but not all of these molecules have been characterised in detail. Cell death may also proceed by a distinct process called necrosis, which unlike apoptosis, is not initiated and controlled by specific and dedicated cellular and biochemical mechanisms (see Nicotera et al, Biochem Soc Symp. 1999; 66:69-73). There is substantial evidence that apoptotic cell death occurs either during or after myocardial ischaemia (Kajstura et al, Lab Invest. 1996; 74(1):86-107; Cheng et al, Exp Cell Res. 1996; 226(2):316-27; Hiss and Gattinger, Circ Res. 1996; 79(5):949-56; Veinot et al, Hum Pathol. 1997; 28(4):485-92; Bialik et al, J Clin Invest. 1997; 100(6): 1363-72; Gottlieb et al, J Clin Invest. 1994; 94(4): 1621 -8; Gottlieb and Engler, Ann N Y Acad Sci. 1999; 874:412-26). In the laboratory, apoptosis is also induced by subjecting cardiac myocytes to hypoxia (Tanaka et al, Circ Res. 1994 Sep;75(3):426-33; Long et al, J Clin Invest. 1997 99(11): 2635-43).
Clearly, there is a significant clinical application were a successful method to inhibit apoptosis in ischaemic myocardial tissue to be devised. A specific and effective treatment requires identifying biochemical target(s), which are responsible for mediating apoptosis, specifically in ischaemic myocardial cells. One target which plays a common role in mediating apoptosis in many cell types, namely p53, is not involved in apoptosis resulting from myocardial ischaemia (Bialik et al, J Clin Invest. 1997; 100(6): 1363-72). Others have shown that inhibiting key mediators of apoptosis, caspases, provides protection against lethal reperfusion injury, following myocardial ischaemia in rat models (Mocanu et al, Br J Pharmacol. 2000; 130(2): 197-200; Yaoita et al, Circulation. 1998 97(3): 276-81 ; Holly et al, J Mol Cell Cardiol. 1999 31(9): 1709-15). However, this approach lacks specificity, since the caspases play a key role in mediating apoptosis in the majority of mammalian cell types, where it is usually beneficial. An approach that involves modulating the activity of molecules shown specifically to mediate apoptosis in ischaemic cardiac cells, would present a distinct advantage in both specificity and efficacy.
Other disease conditions involving hypoxia include stroke, atherosclerosis, retinopathy, acute renal failure, myocardial infarction and diseases involving infection of the airways (such as cystic fibrosis). Therefore, apoptosis and angiogenesis as induced by the ischaemic condition are also considered to be involved in these disease states. It is generally considered that understanding the mechanism by which cells respond to these diseases may be the key to the disease pathology and thus relevant to disease treatment. In a different but related approach, it is now recognised that angiogenesis is necessary for tumour growth and that retardation of this process provide a useful tool in controlling malignancy and retinopathies. For example, neoangiogenesis is seen in many forms of retinopathy and in tumour growth. The ability to be able to induce tumourigenic cells to undergo apoptosis is an extremely desirable goal; particularly in the cancer field, it has been observed that apoptosis and angiogenesis-related genes provide potent therapeutic targets. It has also been observed that hypoxia plays a critical role in the selection of mutations that contribute to more severe tumourigenic phenotypes (Graeber et al, 1996 Nature, 379(6560):88-91).
The macrophage is a key cell type of the immune system, which has been shown to play a central role in the pathology of diseases which currently lack suitable treatments. In many of these diseases macrophages are known or suspected to be under the influence of hypoxia. These diseases include solid tumours (including ovarian and breast), dermal wounds, atherosclerosis, rheumatoid arthritis, proliferative retinopathy, cerebral malaria, peripheral arterial disease, chronic occlusive pulmonary disease (Lewis JS et al, 1999 J.Leukocyte Biol. 66: 889-900). In particular, it has been directly demonstrated that hypoxia inducible factor lα (HIF-lα or HIF-1 alpha) becomes activated in macrophages from the joint synovia of rheumatoid arthritis patients, consistent with previous reports of the rheumatoid synovium being hypoxic (Hollander AP et al, 2001 Arthritis and
Rheumatism 44: 1540-1544). Because the macrophage is accepted as being a key cell type in the pathophysiology and treatment of rheumatoid arthritis (Kinne RW et al, 2000
Arthritis Research, 2:189-202), this confirms that the aberrant functions of macrophages in
RA are at least partly attributable to its exposure to hypoxia.
Of the genes known in the art to be activated by hypoxia in macrophages, many are involved in inflammation, including cytokines, chemokines, and enzymes involved in prostaglandin E2 synthesis (Lewis JS et al, 1999 J.Leukocyte Biol. 66: 889-900). The macrophage is also a key cell type in promoting angiogenesis in response to hypoxia (Knighton DR et al, Science. 1983 221:1283-5), and tumour-infiltrated macrophages are key to the promotion of angiogenesis in cancer, and determining prognosis (Leek RD et al. 1997, 56:4625-4629). For the above reasons, a complete understanding of the transcriptional response of primary human macrophages, would therefore be of great utility in identifying novel therapeutic strategies for the aforementioned diseases. Strategies to improve the efficiency of this by viral-based overexpression of key transcription factors which mediate the hypoxic response are also required.
A number of genes have been identified that are implicated in the physiological response to hypoxia. Early in the history of this field it was discovered that a transcription factor, HIF- 1 α, is ubiquitously present in cells and is responsible for the induction of a number of genes in response to hypoxia. This protein is considered a master regulator of oxygen homeostasis (see, for example, Semenza, (1998) Curr. Op. Genetics and Dev. 8:588-594). Where HIF1 alpha is genetically knocked out, the hypoxia-inducible transcription of virtually all glycolytic enzymes has been shown to be inhibited. Glycolysis is an essential process which goes on in all mammalian cells. This finding is therefore consistent with previous work showing that when cells are exposed to conditions of hypoxia, they up-regulate glycolytic enzymes to enable ATP production, since oxidative phosphorylation is no longer feasible under conditions of low oxygen (Webster (1987) Mol. Cell. Biochem, 77: 19-28). Further support for a critical and general role of HIF1 alpha in the hypoxic response is demonstrated by the knockout mouse, which dies at day 10.5 of gestation. The same is true of the knockout of the ARNT protein, the dimerisation partner of HIF1 alpha.
Although HIF-1 α is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPAS1) or HIF-2α, which shares 48% sequence identity with HIF-1 α ("Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells." Tian H, McKnight SL, Russell DW. Genes Dev. 1997 Jan l;l l(l):72-82.). Evidence suggests that EPAS1 is especially important in mediating the hypoxia-response in certain cell types, and it is clearly detectable in human macrophages, suggesting a role in this cell type (Griffiths et al, 2000, Gene Ther., 7(3):255-62). However, there remains a great need for the identification of other genes that are implicated in this condition, in order to develop a spectrum of diagnostic and therapeutic agents for use as tools in combating diseases in which hypoxia plays a role. Such genes and the proteins that they encode are candidate targets for antagonist or agonist agents that modulate human disease states. Furthermore, the identified genes are associated with regulatory elements that provide alternative and additional candidate targets for exploitation for the delivery of gene products in a cell-specific fashion. Any genes and regulatory elements identified as having a role in hypoxia may be used directly in therapeutic applications via gene therapy, via recombinant protein methods or via chemical mimetics or as targets for the development of agonists and antagonists such as antibodies, small chemical molecules, peptides, regulatory nucleic acids.
According to the invention, a novel gene and its encoded protein are provided, that have been identified and functionally annotated for the first time. Some of these sequences are only identified as "hypothetical proteins" in the public databases. Each and every one of these sequences forms an embodiment of this aspect of the invention. The invention also includes proteins whose amino acid sequences are encoded by a nucleic acid sequence recited in various ESTs deposited in the public databases or encoded by a gene identified from such an EST. At present, all of these EST sequences are functionally unannotated in the public databases. Each and every one of these sequences forms an embodiment of this aspect of the invention.
One embodiment of the invention thus provides a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261,
263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356,
358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
The polypeptide sequences recited in SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 and 531 were, prior to the present disclosure, unannotated in the literature and public sequence databases. Accordingly, until now, no biological function has been attributed to these polypeptide sequences; each of these sequences is generally labelled in the databases as a "hypothetical protein". The novel Smartomics method, described below, has now elucidated a biological function for these polypeptides, in that they have been found to be differentially regulated under physiological conditions of hypoxia as mimicked by viral overexpression of HIF-1 α or EPAS1.
These discoveries allow the development of regulators, such as small drug molecules, that affect the activity of these polypeptides, so allowing diseases and physiological conditions that are caused by hypoxia, or in which hypoxia or the transcription factors HIF-1 α or EPAS 1 have been implicated, to be treated. These discoveries also allow the development of diagnostic agents that are suitable for the detection of hypoxia in biological tissues and, through the identification of mutations and polymorphisms (such as SNPs) within genes coding for the proteins implicated herein, allows the assessment of an individual's risk of being susceptible to diseases and physiological conditions in which hypoxia is implicated.
The method used herein for the identification of hypoxia-induced and hypoxia repressed genes and proteins utilised an approach herein termed "Smartomics". This method is a differential expression screening method for identifying genetic elements that are involved in a particular cellular process and is described in detail in co-pending, co-owned International patent application PCT/GBO 1/00758 entitled "Differential Expression Screening Method". Simplistically put, the method involves comparing:
(a) gene expression in a first cell of interest; and
(b) gene expression in a second cell of interest, which cell comprises altered levels, relative to physiological levels, of a biological molecule implicated in the cellular process, due to the introduction into the second cell of a heterologous nucleic acid directing expression of a polypeptide; and identifying a genetic element whose expression differs, wherein gene expression in said first and/or second cell of interest is compared under at least two different environmental conditions relevant to the cellular process. Gene expression is compared in both the first and the second cell of interest under at least two different environmental conditions relevant to the cellular process.
By altering the levels of particular endogenous biological molecules in a cell, the levels of gene products that are responsive to cellular perturbations such as signalling events and which are affected by the biological molecule(s) become more readily detectable. In other words, the object of the Smartomics methodology is to amplify and/or increase the signal to noise ratio of the differential response normally obtained so as to increase the likelihood of detecting gene products whose levels in a cell are low and/or whose expression normally changes by only a small amount.
The Smartomics method has been utilised herein to improve the discovery of genes activated or repressed in response to hypoxia in primary human macrophages. This involves augmenting the natural response to hypoxia, by experimentally introducing key regulators of the hypoxia response, namely HIF-1 α or EPAS1, into a population of primary human macrophages and comparing gene expression in these cells with that in control cells.
The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia, as mimicked by adenoviral overexpression of HIF-1 α or EPAS1. By "hypoxia-induced" is meant that the polypeptide is expressed at a higher level when a cell overexpresses HIF-1 α or EPAS1 as compared to its expression level in normoxia, in the absence of overexpression. The following polypeptides have been found to be hypoxia- induced: those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265 and 267; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ ID Nos.: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380 and 382, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos. The expression of certain of the polypeptides referred to above has been found to be repressed under conditions of hypoxia, as mimicked by adenoviral overexpression of HIF- lα or EPAS1. The term "hypoxia-repressed" as used herein is intended to mean that the polypeptide is expressed at a lower level when a cell is exposed to hypoxia conditions as mimicked by adenoviral overexpression of HIF-1 or EPAS1, as compared to its expression level under normoxia conditions: those polypeptides whose amino acid sequence is recited in SEQ ID Nos.: 515, 517, 519, 521, 523, 525, 527, 529 and 531; and those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ LD Nos.: 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or encoded by a gene identified from an EST recited in any one of these SEQ LD Nos.
For the purposes of this document, the term "hypoxia" should be taken to mean an environment of oxygen tension such that the oxygen content is between about 5% and 0.1% (v/v). In most cases, hypoxic tissue will have an oxygen content that is less than or equal to about 2%. The term "normoxia" should be taken to mean conditions comprising a normal level of oxygen for the environment concerned. Normoxic tissue typically has an oxygen content above about 5%.
The polypeptide sequences whose amino acid sequence is encoded by a nucleic acid sequence recited in SEQ LD Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or whose amino acid sequence is encoded by a gene identified from an EST recited in any one of these SEQ LD Nos., were also, prior to the present disclosure, unannotated in the literature and public sequence databases, meaning that until now, no biological function has been attributed to these polypeptide sequences.
The sequences in this group fall into a number of different categories. The first of these are cDNA clones, for which a protein sequence has not been predicted by the depositor. A second category is expressed sequence tag (EST) sequences that are represented in the UniGene database (http://www.ncbi.nlm.nih.gov/UniGene/), which contain modest or weak homology to known proteins when translated. ESTs are single-pass sequence files of the 5' or 3' region of an organism's expressed genome as accessed via a force cloned cDNA library. EST sequences tend to be short and as a general rule are error-prone. UniGene (see http://www.ncbi.nlm.nih.gov/Web/Newsltr/aug96.html for review) is an experimental system for automatically partitioning these EST sequences into a non-redundant set of gene-oriented clusters. Each UniGene cluster contains sequences that represent a unique gene, as well as related information such as the tissue types in which the gene has been expressed and map location. A third category of hits identified by the methods described herein is EST sequences that are contained in Unigene clusters, but which are not annotated and exhibit no homologies to proteins contained in the public databases. The fourth and final category encompasses singleton EST sequence entries that are not incorporated as entries in the Unigene database and that only appear as single entries in the public databases.
A biological function has now been attributed to the polypeptides that are encoded by genes incorporating cDNA and EST sequences that fall into the four categories set out above, in that these sequences have been found to be differentially regulated under physiological conditions of hypoxia as mimicked by adenoviral overexpression of HIF-1 α or EPAS1. Such polypeptides may have an amino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566. However, the EST sequences in particular may not be part of the actual coding sequence for a gene, often representing regulatory regions of the gene, or regions that are transcribed, but not translated into polypeptide. Accordingly, this aspect of the invention also includes polypeptides that are encoded by a gene identified from an EST recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566.
Polypeptides of this aspect of the invention are intended to include fragments of polypeptides according to i) or ii) as defined above, provided that the fragment retains a biological activity that is possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii). As used herein, the term "fragment" refers to a polypeptide having an amino acid sequence that is the same as part, but not all, of an amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 and 531, an amino acid sequence that is encoded by a nucleic acid sequence recited in any one of SEQ ID Nos. 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or an amino acid sequence that is encoded by a gene that is linked to a nucleic acid sequence recited in any one of these SEQ ID Nos. The fragments should comprise at least n consecutive amino acids from the sequence and, depending on the particular sequence, n preferably is 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more). Small fragments may form an antigenic determinant.
Such fragments may be isolated fragments, that are not part of or fused to other amino acids or polypeptides, or they may be comprised within a larger polypeptide, of which they form a part or region. When comprised within a larger polypeptide, a fragment of the invention most preferably forms a single continuous region. For instance, certain preferred embodiments relate to a fragment having a pre - and/or pro- polypeptide region fused to the amino terminus of the fragment and/or an additional region fused to the carboxyl terminus of the fragment. However, several fragments may be comprised within a single larger polypeptide. The polypeptides of the present invention or their immunogenic fragments (comprising at least one antigenic determinant) can be used to generate ligands, such as polyclonal or monoclonal antibodies, that are immunospecific for the polypeptides. Such antibodies may be employed to isolate or to identify clones that express a polypeptide according to the invention or, for example, to purify the polypeptide by affinity chromatography. Such antibodies may also be employed as diagnostic or therapeutic aids, amongst other applications, as will be apparent to the skilled reader. The term "immunospecific" means that an antibody has substantially greater affinity for a polypeptide according to the invention than their affinity for related polypeptides. As used herein, the term "antibody" is intended to include intact molecules as well as fragments thereof, such as Fab, F(ab')2 and scFv, which are capable of binding to the antigenic determinant in question.
The invention also includes functional equivalents of a polypeptide of i), ii) or (iii) as recited above. A functionally-equivalent polypeptide according to this aspect of the invention may be a polypeptides that is homologous to a polypeptide whose sequence is explicitly recited herein. Two polypeptides are said to be "homologous" if the sequence of one of the polypeptides has a high enough degree of identity or similarity to the sequence of the other polypeptide. "Identity" indicates that at any particular position in the aligned sequences, the amino acid residue is identical between the sequences. "Similarity" indicates that, at any particular position in the aligned sequences, the amino acid residue is of a similar type between the sequences. Degrees of identity and similarity can be readily calculated according to methods known in the art (see, for example, Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993). Percentage identity, as referred to herein, is as determined using BLAST version 2.1.3 using the default parameters specified by the NCBI (the National Center for Biotechnology Information; http://www.ncbi.nlm.nih.gov/).
Typically, greater than 50% identity between two polypeptides is considered to be an indication of functional equivalence, provided that either the biological activity of the polypeptide is retained or the polypeptides possess an antigenic determinant in common. Preferably, a functionally equivalent polypeptide according to this aspect of the invention exhibits a degree of sequence identity with a polypeptide sequence explicitly identified herein, or with a fragment thereof, of greater than 50%. More preferred polypeptides have degrees of identity of greater than 60%, 70%, 80%, 90%, 95%, 98% or 99%, respectively.
Functionally-equivalent polypeptides according to the invention are therefore intended to include natural biological variants (for example, allelic variants or geographical variations within the species from which the polypeptides are derived) and mutants (such as mutants containing amino acid substitutions, insertions or deletions) of the polypeptides whose sequences are explicitly recited herein. Such mutants may include polypeptides in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code. Typical such substitutions are among Ala, Val, Leu and lie; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gin; among the basic residues Lys and Arg; or among the aromatic residues Phe and Tyr.
Particularly preferred are variants in which several, i.e. between 5 and 10, 1 and 5, 1 and 3, 1 and 2 or just 1 amino acids are substituted, deleted or added in any combination. Especially preferred are silent substitutions, additions and deletions, which do not alter the properties and activities of the protein. Also especially preferred in this regard are conservative substitutions. "Mutant" polypeptides also include polypeptides in which one or more of the amino acid residues include a substituent group.
According to a further aspect of the invention, there is provided a purified and isolated nucleic acid molecule that encodes a polypeptide according to any one of the aspects of the invention discussed above. Such a nucleic acid molecule may consist of the nucleic acid sequence as recited in any one of SEQ LD Nos. 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or may form a redundant equivalent or fragment thereof. This aspect of the invention also includes a purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule as described above.
According to a further aspect of the invention, there is provided an expression vector that contains a purified and isolated nucleic acid molecule according to the aspects of the invention described above. The invention also incorporates a delivery vehicle, such as a liposome, comprising a nucleic acid according to the above-described aspects of the invention.
In a further aspect, the invention provides a host cell transformed with a vector of the above-described aspect of the invention.
In a still further aspect, the invention provides a ligand that binds specifically to a polypeptide according to the above-described aspects of the invention. The ligand may be an antagonist ligand that inhibits the biological activity of the polypeptide, or may be an agonist ligand that activates the hypoxia-induced activity of the polypeptide to augment or potentiate a hypoxia-induced activity.
In a still further aspect of the invention, there is provided a ligand which binds specifically to, and which preferably inhibits the hypoxia-induced activity of, a polypeptide according to any one of the above-described aspects of the invention. Such a ligand may, for example, be an antibody that is immunospecific for the polypeptide in question.
According to a further aspect, the invention provides a polypeptide, a nucleic acid molecule, vector or ligand as described above, for use in therapy or diagnosis of a disease or abnormal physiological condition. Preferably, the disease or abnormal physiological condition that is affected by hypoxia; examples of such diseases include cancer, ischaemic conditions (such as stroke, coronary arterial disease, peripheral arterial disease), reperfusion injury, retinopathy, neonatal stress, preeclampsia, atherosclerosis, inflammatory conditions (including rheumatoid arthritis) and wound healing. The undesired cellular process involved in said diseases might include, but is not restricted to; tumorigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis. The undesired biochemical processes involved in said cellular processes might include, but is not restricted to, glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport or nitric oxide synthesis. According to a further aspect of the invention, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1,
3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117,
119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267,
383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529 or 531; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288,
290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii); for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
Included in this list of polypeptides and nucleic acids are those polypeptide and nucleic acid sequences that are of known function, but which have not until now been implicated in the hypoxia response.
DIFFERENT CELL TYPES
Macrophages and monocytes
It has been found that certain genes respond to hypoxia differently, depending on the particular cell type. This is contrary to the prevailing prejudice in the art that the response to hypoxia is largely generic, occurring equally in different cell types. In one aspect of this invention, it has been found that the expression of certain of the polypeptides is induced under conditions of hypoxia in primary monocytes and/or primary macrophages. The polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 59, 267, 213, 73, 135, 103, 117, 443, 401 and 93. According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
59, 267, 213, 73, 135, 103, 117, 443, 401 and 93; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in monocytes or macrophages. Such pathologies include rheumatoid arthritis and other inflammatory conditions, atherosclerotic plaques and chronic occlusive pulmonary disease.
More preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 59 and 135; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with the response of a macrophage cell type to hypoxia conditions, including rheumatoid arthritis and other inflammatory conditions.
Endothelial cells
The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary endothelial cells. The polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 529 and 525. According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in either one of SEQ ID Nos:
529 and 525; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in endothelial cells, such as the process of angiogenesis.
Hepatocytes
The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary hepatocytes. The polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 395, 235, 39, 95, 83 and 79.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
395, 235, 39, 95, 83 and 79; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in hepatocytes. In particular, such pathologies include ischaemia and other hepatic disorders. Myocytes
The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary myocytes. The polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 5 and 167. In particular, the expression of these polypeptides were found to be induced under conditions of hypoxia in skeletal muscle myocytes and cardiomyocytes.
According to a further aspect of the invention, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in either one of SEQ ID Nos: 5 and 167; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in myocytes. Such pathologies include peripheral arterial disease.
Preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos: 5 and 167; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cardiomyocyte cell type's response to hypoxia conditions including, but not limited to cardiac ischaemia.
Epithelial cells The expression of certain of the polypeptides has been found to be induced under conditions of hypoxia in primary epithelial cells. The polypeptides found to be so induced are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 61, 63, 195, 79, 475, 13, 383, 21 and 199. In particular, the expression of these polypeptides were found to be induced under conditions of hypoxia in primary epithelial cells derived from mammary or renal tissues.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 61, 63, 195, 79, 475, 13, 383, 21 and 199; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology in epithelial cells. Such pathologies include neoplasia, tumorigenesis and disruption of normal tissue homeostasis.
More preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos:
61, 63, 195, 79, 475, 13, 383, 21 and 199; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a mammary or a renal cell type's response to hypoxia conditions including, but not limited to neoplasia and tumorigenesis and disruption of normal tissue homeostasis.
CYTOKLNES AND OTHER MOLECULES The expression of certain hypoxic regulated genes has been found to be responsive to cytokines and/or other molecules.
TNFalpha Polypeptides found to be responsive to TNF alpha are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 87, 227, 93, 83, 107, 111, 207, 231, 09, 01, 183, 483, 409, 395, 467, 235, 63, 255, 15, 39, 103, 121, 31, 153, 283, 169, 353, 201, 253, 239, 357, 243, 335, 249, 371, 293, 411, 351, 61, 181, 297, 485, 495, 507, 13, 59, 89, 385, 539, 519, 547, 135, 73, 533 and 451. According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
87, 227, 93, 83, 107, 111, 207, 231, 09, 01, 183, 483, 409, 395, 467, 235,
63, 255, 15, 39, 103, 121, 31, 153, 283, 169, 353, 201, 253, 239, 357, 243, 335, 249, 371, 293, 411, 351, 61, 181, 297, 485, 495, 507, 13, 59, 89, 385,
539, 519, 547, 135, 73, 533 and 451; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to TNFalpha including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic- associated pathology. Such conditions and pathologies may in particular be infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, severe bacterial infection, septic shock, cerebral malaria, transplant rejection, allergic encephalomyelitis, cancer, gestational diabetes (GDM), insulin resistance syndrome, adult-onset diabetic patients, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, hyperandrogenism, alopecia areata, Japanese Guillain-Barre syndrome, mucocutaneous leishmaniasis, meningococcal disease, lepromatous leprosy, scarring trachoma and asthma. Interleukin I beta (ILI)
Polypeptides found to be responsive to Interleukin 1 beta (LL1) are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 91, 429, 505, 253, 533, 519, 503, 493, 411, 469, 535, 481, 409, 211, 59, 517, 563, 291, 479, 381, 525, 229, 225, 153, 325, 423, 217, 401, 353, 443, 331, 227, 475, 467, 373, 99, 483, 181, 135, 213, 83, 133, 87, 127 and 201.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 91,
429, 505, 253, 533, 519, 503, 493, 411, 469, 535, 481, 409, 211, 59, 517, 563, 291, 479, 381, 525, 229, 225, 153, 325, 423, 217, 401, 353, 443, 331, 227, 475, 467, 373, 99, 483, 181, 135, 213, 83, 133, 87, 127 and 201; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to ILI including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be conditions associated with an acute phase response, infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, cancer, high bone turnover, osteoporosis, cardiovascular disease, Alzheimer's disease, ulcerative colitis and Crohn's disease, lupus erythematosus, cerebral ischaemia, diabetes mellitus.
Lipopolysaccharide and gamma interferon
Polypeptides found to be responsive to a combination of lipopolysaccharide and gamma interferon are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 495, 91, 253, 455, 507, 453, 499, 91, 429, 493, 451, 383, 385, 547, 539, 481, 387, 155, 397, 59, 529, 409, 103, 503, 61, 427, 475, 69, 113, 63, 255, 55, 401, 157, 515, 505, 263, 127, 441, 485, 521, 83, 123, 367, 523, 215, 29, 525, 543, 447, 399, 491, 369, 141, 231, 413, 179, 405, 125, 135, 337, 27, 177, 335, 283, 257, 105, 147, 421, 237, 243, 375, 473, 545, 95, 173, 181, 133, 327, 419, 323, 273, 167, 553, 469, 139, 509, 297, 317, 87, 163, 25,287, 305, 195, 249, 213, 373, 293, 227, 365, 31, 193, 85, 363, 517, 89, 169, 407, 201, 267, 241, 307, 519, 233, 265, 73, 549, 443, 483, 533, 19, 425, 423, 559 and 159.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 495, 91, 253, 455, 507, 453, 499, 91, 429, 493, 451, 383, 385, 547, 539,
481, 387, 155, 397, 59, 529, 409, 103, 503, 61, 427, 475, 69, 113, 63, 255, 55, 401, 157, 515, 505, 263, 127, 441, 485, 521, 83, 123, 367, 523, 215, 29, 525, 543, 447, 399, 491, 369, 141, 231, 413, 179, 405, 125, 135, 337, 27, 177, 335, 283, 257, 105, 147, 421, 237, 243, 375, 473, 545, 95, 173, 181, 133, 327, 419, 323, 273, 167, 553, 469, 139, 509, 297, 317, 87, 163, 25,287,
305, 195, 249, 213, 373, 293, 227, 365, 31, 193, 85, 363, 517, 89, 169, 407, 201, 267, 241, 307, 519, 233, 265, 73, 549, 443, 483, 533, 19, 425, 423, 559 and 159; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to a combination of lipopolysaccharide and gamma interferon including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be acute bacterial infection.
IL-12 Polypeptides found to be responsive to IL-12 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 385, 451, 565, 381, 547, 539, 535, 283, 557, 291, 169, 507, 299, 505, 217, 371, 485, 145, 301, 35, 295, 293, 563, 269, 423, 177, 211, 367, 59, 271, 275, 77, 397, 405, 325, 561, 429, 487, 289, 353, 173, 553, 525, 13, 137, 241, 377, 517, 205, 519, 523, 495, 139, 281, 549, 157, 307, 215, 187, 237, 521, 411, 131, 41, 267, 187, 493, 49, 387, 153, 515, 347, 479, 143, 149, 233, 327, 489, 273, 37, 107, 111, 207, 355, 331, 213, 181, 373, 467, 475, 83, 103, 133, 227, 87, 127 and 201.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ED Nos:
385, 451, 565, 381, 547, 539, 535, 283, 557, 291, 169, 507, 299, 505, 217, 371, 485, 145, 301, 35, 295, 293, 563, 269, 423, 177, 211, 367, 59, 271,
275, 77, 397, 405, 325, 561, 429, 487, 289, 353, 173, 553, 525, 13, 137, 241, 377, 517, 205, 519, 523, 495, 139, 281, 549, 157, 307, 215, 187, 237, 521, 411, 131, 41, 267, 187, 493, 49, 387, 153, 515, 347, 479, 143, 149, 233, 327, 489, 273, 37, 107, 111, 207, 355, 331, 213, 181, 373, 467, 475, 83, 103, 133, 227, 87, 127 and 201; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to LL-12 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be rheumatoid arthritis.
IL-15
Polypeptides found to be responsive to IL-15 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 451, 495, 539, 547, 385, 507, 429, 387, 493, 499, 455, 383, 447, 485, 515, 453, 397, 521, 303, 427,529, 491, 203, 481, 363, 167, 285, 401, 257, 421, 231, 187, 267, 213, 317, 113, 25, 241, 229, 153, 127, 85, 119, 177, 89, 87, 225, 251, 307, 227, 437, 183, 545, 467, 199, 107, 111, 207 and 83. According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
451, 495, 539, 547, 385, 507, 429, 387, 493, 499, 455, 383, 447, 485, 515, 453, 397, 521, 303, 427,529, 491, 203, 481, 363, 167, 285, 401, 257, 421,
231, 187, 267, 213, 317, 113, 25, 241, 229, 153, 127, 85, 119, 177, 89, 87,
225, 251, 307, 227, 437, 183, 545, 467, 199, 107, 111, 207 and 83; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-15 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be atherosclerosis, rheumatoid arthritis and other inflammatory conditions.
IL-17
Polypeptides found to be responsive to IL-17 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 385, 495, 539, 429, 451, 91, 87, 387, 547, 201, 287, 493, 203, 355, 533, 503, 183, 251, 351, 491, 177, 137, 77, 03, 95, 377, 303, 431, 367, 359, 563, 155, 297, 439, 113, 229, 453, 175, 261, 81, 109, 197, 545, 521, 141, 343, 285, 171, 541, 09, 513, 161, 417, 323, 25, 249, 337, 215, 15, 413 and 459.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
385, 495, 539, 429, 451, 91, 87, 387, 547, 201, 287, 493, 203, 355, 533,
503, 183, 251, 351, 491, 177, 137, 77, 03, 95, 377, 303, 431, 367, 359, 563,
155, 297, 439, 113, 229, 453, 175, 261, 81, 109, 197, 545, 521, 141, 343, 285, 171, 541, 09, 513, 161, 417, 323, 25, 249, 337, 215, 15, 413 and 459; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-17 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be arthritis or chronic occlusive pulmonary disease..
IL-13
Polypeptides found to be responsive to LL-13 are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125, 365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos:
117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125, 365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-13 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be cancer, rheumatoid arthritis, Crohn's disease and other inflammatory diseases.
IL-4
Polypeptides found to be responsive to IL-4 are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125, 365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
117, 425, 161, 135, 19, 481, 61, 73, 473, 59, 429, 471, 225, 411, 305, 123, 99, 273, 25, 439, 93, 249, 137, 543, 67, 43, 401, 71, 133, 329, 331, 243, 227, 491, 171, 101, 253, 231, 107, 111, 207, 163, 169, 417, 393, 533, 153, 495, 07, 97, 209, 05, 351, 529, 335, 167, 51, 259, 45, 27, 277, 193, 125,
365, 87, 475, 517, 363, 181, 31, 369, 265, 91, 373, 559, 467, 127 and 287; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-4 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be cancer, rheumatoid arthritis, Crohn's disease and other inflammatory diseases. IL-10
Polypeptides found to be responsive to IL-10 are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 441, 117, 481, 121, 09, 59, 69, 403, 29, 529, 189, 519, 503, 505, 93, 347, 149, 137, 401, 427, 187, 11, 61, 81, 533, 335, 07,369, 243, 99, 411, 495, 181, 25, 145, 483, 545, 227, 193, 273, 133, 381, 393, 539, 353, 387, 507, 259, 379, 103, 203, 45, 265, 287, 323, 289, 301, 201, 283, 467, 87, 371, 83, 169, 31, 363 and 293.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos: 441, 117, 481, 121, 09, 59, 69, 403, 29, 529, 189, 519, 503, 505, 93, 347,
149, 137, 401, 427, 187 , 11, 61, 81, 533, 335, 07,369, 243, 99, 411, 495, 181, 25, 145, 483, 545, 227, 193, 273, 133, 381, 393, 539, 353, 387, 507, 259, 379, 103, 203, 45, 265, 287, 323, 289, 301, 201, 283, 467, 87, 371, 83, 169, 31, 363 and 293; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to IL-10 including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic-associated pathology. Such conditions and pathologies may in particular be those conditions associated with a downregulation of macrophage effector functions.
Superoxide
Polypeptides found to be responsive to superoxide are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 91, 253, 59, 481, 05, 503, 429, 385, 69, 493, 441, 507, 157, 231, 39, 409, 427, 61, 62, 475, 263, 529, 455, 453, 505, 311, 313, 401, 63, 255, 397, 143, 235, 167, 93, 103, 539, 547, 383, 451, 387, 433, 09, 523, 561, 33, 19, 85, 227, 297, 203, 549, 73, 509, 273, 339, 45, 361, 267, 513, 537, 395, 559, 307, 135, 489, 413, 159, 443, 423 and 425. According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ LD Nos:
91, 253, 59, 481, 05, 503, 429, 385, 69, 493, 441, 507, 157, 231, 39, 409, 427, 61, 62, 475, 263, 529, 455, 453, 505, 311, 313, 401, 63, 255, 397, 143,
235, 167, 93, 103, 539, 547, 383, 451, 387, 433, 09, 523, 561, 33, 19, 85, 227, 297, 203, 549, 73, 509, 273, 339, 45, 361, 267, 513, 537, 395, 559, 307, 135, 489, 413, 159, 443, 423 and 425; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of conditions associated with a cell's response to superoxide including, but not limited to tumorigenesis, angiogenesis, apoptosis, inflammatory conditions, the biological response to hypoxia conditions, or a hypoxic- associated pathology. Such conditions and pathologies may in particular be ischaemia/reperfusion-associated tissue damage, rheumatoid arthritis and other inflammatory conditions linked to an inflamed rheumatoid synovium and conditions linked to inflammatory macrophage functions.
TUMOURS
The expression of some hypoxic regulated genes has been found to be different in tumours compared to normal tissue from the same patient. This change in expression may be used as an indicator of genes involved in tumorigenesis. Polypeptides found to be expressed higher in tumour compared to normal tissue are those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 100, 316, 126, 250, 164, 72, 388, 426, 128, 236, 260, 12, 546, 214, 254, 520, 90, 40, 154, 84, 118, 188, 406, 540, 490, 532, 188, 496, 362, 452, 168, 414, 384, 324, 472, 424, 308, 202, 244, 60, 534, 376, 470, 456, 412, 562, 158, 196, 408, 434, 508, 22, 410, 198, 208, 500, 476, 504, 200, 348, 162, 172, 74, 272, 356, 16, 454, 88, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94. Polypeptides found to be expressed lower in tumour compared to normal tissue are those polypeptides whose amino acid sequence is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94.
According to a further aspect of the invention, there is thus provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ LD Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296, 218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140,
318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276, 94, 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300,
140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis.
Preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446,
220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296, 218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276, 94, 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286,
172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis including well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated adenocarcinoma, carcinoma endometrioid adenocarcinoma, poorly differentiated adenocarcinoma and invasive ductal carcinoma. More preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 100, 316, 126, 250, 164, 72, 388, 426, 128, 236, 260, 12, 546, 214, 254, 520, 90, 40, 154, 84, 118, 188,
406, 540, 490, 532, 188, 496, 362, 452, 168, 414, 384, 324, 472, 424, 308, 202, 244, 60, 534, 376, 470, 456, 412, 562, 158, 196, 408, 434, 508, 22, 410, 198, 208, 500, 476, 504, 200, 348, 162, 172, 74, 272, 356, 16, 454, 88, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis; wherein said substantially purified polypeptide is more highly expressed in tumour tissue associated with said condition compared to normal tissue, yet more preferably adjacent normal tissue. Most preferably, the condition associated with tumorigenesis includes well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated adenocarcinoma, carcinoma endometrioid adenocarcinoma, poorly differentiated adenocarcinoma or invasive ductal carcinoma. Or more preferably, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence which is encoded by a nucleic acid sequence as recited in any one of SEQ ID Nos: 310, 72, 312, 254, 520, 90, 102, 138, 490, 452, 168, 472, 202, 482, 60, 160, 412, 158, 196, 442, 446, 220, 62, 256, 538, 32, 240, 480, 208, 500, 98, 18, 354, 162, 286, 172, 514, 74, 86, 16, 140, 462, 10, 2, 378, 294, 170, 396, 284, 78, 156, 146, 68, 30, 114, 372, 276, 296,218, 94, 292, 460, 558, 382, 326, 270, 282, 300, 140, 318, 228, 378, 396, 78, 146, 566, 38, 30, 438, 276 and 94. ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of a condition associated with tumorigenesis; wherein said substantially purified polypeptide is less highly expressed in tumour tissue associated with said condition compared to normal tissue, yet more preferably, normal adjacent tissue. Most preferably, the condition associated with tumorigenesis includes well differentiated squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, moderately differentiated adenocarcinoma, carcinoma endometrioid adenocarcinoma, poorly differentiated adenocarcinoma or invasive ductal carcinoma.
COPD Chronic obstructive pulmonary disease (COPD) is an inflammatory process in which hypoxia has been implicated.
Polypeptides found to be expressed at higher levels in COPD lungs compared to a healthy lung are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 167, 229, 133, 369, 181, 235, 349, 379, 321, 163, 91, 441, 83, 95, 39, 495, 87, 21, 225, 81, 69, 79, 227 and 437. Polypeptides found to be expressed at lower levels in COPD lungs as compared to the healthy lung are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 405, 451, 533, 507, 215, 161 and 113.
According to a further aspect of the invention, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
405, 451, 533, 507, 215, 161 and 113; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of chronic obstructive pulmonary disease.
ARTHEROSCLEROSIS Atherosclerosis if the process of thickening of arterial walls, leading to several pathologies including coronary artery disease, peripheral arterial disease, stroke, and a series of other related diseases. Macrophages in atherosclerotic lesions accumulate cholesterol in the form of modified LDLs, acting as a storage reservoir. The environment of the plaque is likely to involve hypoxia, and the response of macrophages to this is likely to contribute to their role in the disease process.
Polypeptides found to be expressed at higher levels in artherosclerotic arteries compared to normal arteries are those polypeptides whose amino acid sequence is recited in SEQ LD Nos: 413, 183, 87, 559, 425, 359, 513, 537, 11, 399, 421, 395, 91, 367, 417, 109, 197, 215, 187, 97. 03, 205, 285, 461, 245, 403, 551, 543, 525, 419, 447, 67, 75, 501, 93, 459, 113, 491, 155, 237 and 303.
Polypeptides found to be expressed at lower levels in artherosclerotic arteries compared to normal arteries are those polypeptides whose amino acid sequence is recited in SEQ ID Nos: 45, 203, 393, 99, 273, 07, 265, 373, 267, 363, 181, 483, 103, 385, 231, 335, 259, 83, 309, 311, 429, 545, 555, 123, 05, 425, 201, 19, 489, 365, 179, 321, 247, 421, 107, 111, 207, 235, 71, 463, 225, 451, 561, 33, 167, 209, 375, 507, 31, 63, 255, 193, 143, 61, 251, 239, 353, 289, 79, 283, 355, 293,13, 169, 301, 347, 01, 139, 453, 377, 371, 317, 77, 145, 437, 565, 29, 275, 295, 557, 381, 217, 291, 299, 325 and 269.
According to a further aspect of the invention, there is provided a substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
45, 203, 393, 99, 273, 07, 265, 373, 267, 363, 181, 483, 103, 385, 231, 335, 259, 83, 309, 311, 429, 545, 555, 123, 05, 425, 201 , 19, 489, 365, 179, 321, 247, 421, 107, 111, 207, 235, 71, 463, 225, 451, 561, 33, 167, 209, 375, 507, 31, 63, 255, 193, 143, 61, 251, 239, 353, 289, 79, 283, 355, 293,13, 169, 301, 347, 01, 139, 453, 377, 371, 317, 77, 145, 437, 565, 29, 275, 295,
557, 381, 217, 291, 299, 325 and 269; ii) is a fragment of a polypeptide according to i) provided that said fragment retains a biological activity possessed by the full length polypeptide of i), or has an antigenic determinant in common with the polypeptide of i); or iii) is a functional equivalent of a polypeptide of i) or ii); for use in the diagnosis or therapy of atherosclerosis, coronary artery disease, peripheral arterial disease, stroke, other diseases associated with atherosclerotic plaques or lesions and other atherosclerosis related diseases.
The invention also provides a purified and isolated nucleic acid molecule that encodes a polypeptide according to this aspect of the invention, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology. The sequences of these molecules are provided in SEQ ID
Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48,
50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132,
134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168,
170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204,
206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240,
242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312,
314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348,
350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, and 566. As described above for the EST nucleic acid sequences annotated herein, this aspect of the invention includes redundant equivalents and fragments of the sequences explicitly recited in these SEQ ID Nos., and purified nucleic acid molecules which hybridize under high stringency conditions with such nucleic acid molecules, and vectors containing such nucleic acid molecules for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
This aspect of the invention also includes ligands which bind specifically to, and which preferably inhibit the hypoxia-induced activity of, a polypeptide listed in SEQ ID Nos.: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531, or to a polypeptide encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology. The invention also provides a pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable camer.
The invention also provides a vaccine composition comprising a polypeptide, or a nucleic acid molecule as described above.
The invention also provides a method of treating a disease in a patient in need of such treatment by administering to a patient a therapeutically effective amount of a polypeptide, a nucleic acid molecule, vector, ligand or pharmaceutical composition as described above. For diseases in which the expression of the natural gene or the activity of the polypeptide is lower in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, ligand, compound or composition administered to the patient should be an agonist. For diseases in which the expression of the natural gene or activity of the polypeptide is higher in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an antagonist. By the term "agonist" is meant herein, any polypeptide, peptide, synthetic molecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity. By the term "antagonist" is meant herein, any polypeptide, peptide, synthetic molecule or organic molecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharmacological receptor. As will be apparent to a skilled artisan, the discoveries described above relating to the different cell types (monocytes, macrophages etc), cytokines and other molecules (lipopolysaccharide, superoxide etc.), different types of tumours (carcinomas, non-Hodgkin's lymphoma etc.), COPD and artheroschlerosis may allow specific diseases to be treated with the polypeptide, nucleic acid molecule, vector, ligand or pharmaceutical composition of the present invention.
The invention also provides a polypeptide, nucleic acid molecule, vector, ligand or pharmaceutical composition according to any one of the above-described aspects of the invention, for use in the manufacture of a medicament for the treatment of a hypoxia- regulated condition. The invention also provides a method of monitoring the therapeutic treatment of disease or physiological condition in a patient, comprising monitoring over a period of time the level of expression or activity of polypeptide, nucleic acid molecule, vector or ligand in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease or physiological condition.
The invention also provides a method of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by administering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or more of the nucleic acid molecules as described above.
The invention also provides a method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of the aspects of the invention described above in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition. Particularly, the invention provides such a method wherein the tissue is lung, ileum, colon, kidney, cervix, ovary or breast tissue and the hypoxia-regulated condition is squamous cell carcinoma, non-Hodgkin's lymphoma, adenocarcinoma, carinoma, endometrioid adenocarcinoma, or invasive ductal carcinoma.
Such a method of diagnosis may be carried out in vitro. One example of a suitable method comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
A further example of a suitable method may comprises the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule whose sequence is recited in any one of SEQ D Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of the hypoxia-related condition.
A still further example of a suitable method may comprise the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid primer under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule whose sequence is recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, and the primer; b) contacting a control sample with said primer under the same conditions used in step a); c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; wherein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the amplified nucleic acid in the control sample is indicative of the hypoxia-related condition.
A still further example of a suitable method may comprised the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of the above-described aspects of the invention from said tissue sample; and c) diagnosing the patient for the hypoxia-related condition by detecting the presence of a mutation which is associated with the hypoxia-related condition in the nucleic acid molecule as an indication of the hypoxia-related condition. This method may comprise the additional step of amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
Particular hypoxia-related conditions that may be diagnosed in this fashion include cancer, ischaemia, reperfusion, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, rheumatoid arthritis, cardiac arrest or stroke, for example, caused by a disorder of the cerebral, coronary or peripheral circulation.
In a further aspect, the invention provides a method for the identification of a compound that is effective in the treatment and/or diagnosis of a hypoxia-regulated condition, comprising contacting a polypeptide, nucleic acid molecule, or ligand according to any one of the above-described aspects of the invention with one or more compounds suspected of possessing binding affinity for said polypeptide, nucleic acid molecule or ligand, and selecting a compound that binds specifically to said nucleic acid molecule, polypeptide or ligand.
According to a still further aspect of the invention, there is provided a kit useful for diagnosing a hypoxia-regulated condition, comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of the aspects of the invention described above; a second container containing primers useful for amplifying said nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of the hypoxia-regulated condition. The kit may additionally comprise a third container holding an agent for digesting unhybridised RNA.
To facilitate in the diagnosis of the hypoxia-regulated condition using one of the methods outlined above, in a further aspect, the invention provides an array of at least two nucleic acid molecules, wherein each of said nucleic acid molecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of the aspects of the invention described above. Such an anay may contain nucleic acid molecules that either correspond to the sequence of, are complementary to the sequence of, or hybridise specifically to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283 or more of the nucleic acid molecules implicated in a hypoxia-regulated condition as recited above. The nucleic acid molecules on the anay may consist of oligonucleotides of between twelve and fifty nucleotides, more preferably, between forty and fifty nucleotides. Alternatively, the nucleic acid molecules on the array may consist of PCR-amplified cDNA inserts where the nucleic acid molecule is between 300-2000 nucleotides. In a related aspect, again useful for diagnosis, the invention provides an array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia-regulated condition as described above. The invention also provides an anay of polypeptides, comprising at least two polypeptide species as recited above, wherein each polypeptide species is implicated in a hypoxia-regulated condition, or is a functional equivalent variant or fragment thereof.
Kits useful in the diagnostic methods of the invention may comprise such nucleic acid, antibody and/or polypeptide arrays.
According to the invention, a kit may also comprise one or more antibodies that bind to a polypeptide as recited above, and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide. According to a still further aspect of the invention, there is provided a genetically-modified non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of the aspects of the invention described above. Preferably, said genetically-modified animal is a transgenic or knockout animal. The invention also provides a method for screening for a compound effective to treat a hypoxia-regulated condition, by contacting a non-human genetically-modified animal as described above with a candidate compound and determining the effect of the compound on the physiological state of the animal.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, recombinant DNA technology and immunology, which are within the skill of those working in the art.
Most general molecular biology, microbiology recombinant DNA technology and immunological techniques can be found in Sambrook et al, Molecular Cloning, A Laboratory Manual (2000) Cold Harbor-Laboratory Press, Cold Spring Harbor, N.Y. or Ausubel et al, Current protocols in molecular biology (1990) John Wiley and Sons, N.Y.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
A. Polypeptides The term "polypeptide" as used herein, refers to a chain (may be branched or unbranched) of two or more amino acids linked to each other by means of a peptide bond or modified peptide bond (isosteres). The term polypeptide encompasses but is not limited to oligopeptides, peptides and proteins. The polypeptide of the invention may additionally be either in a mature protein form or in a pre-, pro- or prepro-protein form that requires subsequent cleavage for formation of the active mature protein. The pre-, pro-, prepro- part of the protein is often a leader or secretory sequence but may also be an additional sequence added to aid protein purification (for example, a His tag) or to conform a higher stability to the protein.
A polypeptide according to the invention may also include modified amino acids, that is, amino acids other than those 20 that are gene-encoded. This modification may be a result of natural processes such as post-translational processing or by chemical modification. Examples of modifications include acetylation, acylation, amidation, ADP-ribosylation, arginylation, attachment of a lipid derivative or phosphatidylinositol, γ-carboxylation, covalent attachment of a flavin or haeme moiety, a nucleotide or nucleotide derivative, cyclisation, demethylation, disulphide bond formation, formation of covalent cross-links, formylation, glycosylation, GPI anchor formation, hydroxylation, iodination, lipid attachment, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemisation, selenoylation, sulphation, and ubiquitination. Modification of the polypeptide can occur anywhere within the molecule including the backbone, the amino acid side-chains or at the N- or C-terminals.
A polypeptide according to the invention may either be isolated from natural sources (for example, purified from cell culture), or be a recombinantly produced polypeptide, or a synthetically produced polypeptide or a combination of all the above.
Antibodies A polypeptide according to the invention, its functional equivalents and/or any immunogenic fragments derived from the polypeptide may be used to generate ligands including immunospecific monoclonal or polyclonal antibodies, or antibody fragments. These antibodies can then be used to isolate or identify clones expressing the polypeptide of the invention or to purify the polypeptide by affinity chromatography. Further uses of these immunospecific antibodies may include, but are not limited to, diagnostic, therapeutic or general assay applications. Examples of assay techniques that employ antibodies are immunoassays, radioimmunoassays (RIA) or enzyme linked immunosorbent assay (ELISA). In these cases, the antibodies may be labelled with an analytically- detectable reagent including radioisotopes, a fluorescent molecule or any reporter molecule.
The term "immunospecific" as used herein refers to antibodies that have a substantially higher affinity for a polypeptide of this invention compared with other polypeptides. The term "antibody" as used herein refers to a molecule that is produced by animals in response to an antigen and has the particular property of interacting specifically with the antigenic determinant that induced its formation. Fragments of the aforementioned molecule such as Fab, F(ab')2 and scFv, which are capable of binding the antigen determinant, are also included in the term "antibody". Antibodies may also be modified to make chimeric antibodies, where non-human variable regions are joined or fused to human constant regions (for example, Liu et al, PNAS, USA, 84, 3439 (1987)). Particularly, antibodies may be modified to make them less immunogenic to an individual in a process such as humanisation (see, for example, Jones et al, Nature, 321, 522 (1986); Verhoeyen et al, Science, 239, 1534 (1988); Kabat et al, J. Immunol., 147, 1709 (1991); Queen et al, PNAS, USA, 86, 10029 (1989); Gorman et al, PNAS, USA, 88, 34181 (1991) and Hodgson et al, Bio/Technology, 9, 421 (1991)). The term "humanised antibody", as used herein, refers to antibody molecules in which the amino acids of the CDR (complementarity-determining region) and selected other regions in the variable domains of the heavy and/or light chains of a non-human donor antibody have been substituted with the equivalent amino acids of a human antibody. The humanised antibody therefore closely resembles a human antibody, but has the binding ability of the donor antibody. Antibodies may also have a "bispecific" nature, that is, the antibody has two different antigen binding domains, each domain being directed against a different epitope. Specific polyclonal antibodies may be made by immuno-challenging an animal with a polypeptide of this invention. Common animals used for the production of antibodies include the mouse, rat, chicken, rabbit, goat and horse. The polypeptide used to immuno- challenge the animal may be derived by recombinant DNA technology or may be chemically-synthesised. In addition, the polypeptide may be conjugated to a earner protein. Commonly used earners to which the polypeptides may be conjugated include, but are not limited to BSA (bovine serum albumin), thyroglobulin and keyhole limpet haemocyanin. Serum from the immuno-challenged animal is collected and treated according to known procedures, for example, by immunoaffinity chromatography.
Specific monoclonal antibodies can generally be made by methods known to one skilled in the art (see for example, Kohler, G. and Milstein, C, Nature 256, 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985) and Roitt, I. et al, Immunology, 25.10, Mosby- Year Book Europe Limited (1993)). Panels of monoclonal antibodies produced against the polypeptides of the invention can be screened for various properties, i.e., for isotype, epitope, affinity, etc. against which they are directed. Alternatively, genes encoding the monoclonal antibodies of interest may be isolated from hybridomas, for instance using PCR techniques known in the art, and cloned and expressed in appropriate vectors. Phage display technology may be utilised to select the genes encoding the antibodies that have exhibited an immunospecific response to the polypeptides of the invention (see McCafferty, J., et al, (1990), Nature 348, 552-554; Marks, J. et al, (1992) Biotechnology 10, 779-783).
Ligands
The polypeptides of the invention may also be used to search for interacting ligands. Methods for doing this include the screening of a library of compounds (see Coligan et al, Cunent Protocols in Immunology 1(2); Chapter 5 (1991), isolating the ligands from cells, isolating the ligands from a cell-free preparation or natural product mixtures. Ligands to the polypeptide may activate (agonise) or inhibit (antagonise) its activity. Alternatively, compounds may affect the levels of the polypeptide present in the cell, including affecting gene expression and/or mRNA stability.
Ligands to the polypeptide form a further aspect of the invention, as discussed in more detail above. Preferced "antagonist" ligands include those that bind to the polypeptide of this invention and strongly inhibit any activity of the polypeptide. Prefened "agonist" ligands include those that bind to the polypeptide and strongly induce activity of the polypeptide of this invention or increases substantially the level of the polypeptide in the cell. As defined above, the term "agonist" is meant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an activator, by increasing the effective biological activity of a polypeptide, for example, by increasing gene expression or enzymatic activity. The term "antagonist" is meant to include any polypeptide, peptide, synthetic molecule or organic molecule that functions as an inhibitor, by decreasing the effective biological activity of the gene product, for example, by inhibiting gene expression of an enzyme or a pharmacological receptor. Ligands to a polypeptide according to the invention may come in various forms, including natural or modified substrates, enzymes, receptors, small organic molecules such as small natural or synthetic organic molecules of up to 2000Da, preferably 800Da or less, peptidomimetics, inorganic molecules, peptides, polypeptides, antibodies, structural or functional mimetics of the aforementioned. B. Nucleic acid molecules Preferred nucleic acid molecules of the invention are those which encode the polypeptide sequences recited in any one of SEQ ID Nos. 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531, or which encode polypeptides encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos. Examples of such nucleic acid molecules include those listed in SEQ ID Nos. 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, homologous nucleic acids and nucleic acids that are complementary to these nucleic acid molecules. Nucleic acid molecules of this aspect of the invention may be used in numerous methods and applications, as described generally herein. A nucleic acid molecule preferably omprises of at least n consecutive nucleotides from any one of the sequences disclosed in SEQ LD Nos: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, where n is 10 or more. A nucleic acid molecule of the invention also includes sequences that are complementary to the nucleic acid molecule described above (for example, for antisense or probing purposes). A nucleic acid molecule according to this aspect of the invention may be in the form of RNA, such as mRNA, DNA, such as cDNA, synthetic DNA or genomic DNA. The nucleic acid molecule may be double-stranded or single-stranded. The single-stranded form may be the coding (sense) strand or the non-coding (antisense) strand. A nucleic acid molecule may also comprise an analogue of DNA or RNA, including, but not limited to modifications made to the backbone of the molecule, such as, for example, a peptide nucleic acid (PNA). The term "PNA" as used herein, refers to an antisense molecule that comprises an oligonucleotide of at least five nucleotides in length linked to a peptide backbone of amino acid residues, preferably ending in lysine. The terminal lysine confers solubility to the composition. PNAs may be pegylated to extend their lifespan in a cell, where they preferentially bind complementary single-stranded DNA and RNA and stop transcript elongation (Nielsen, P.E. et al. (1993) Anticancer Drug Des. 8:53-63).
A nucleic acid molecule according to this aspect of the invention can be isolated by cloning, purification or separation of the molecule directly from a particular organism, or from a library, such as a genomic or cDNA library. The molecule may also be synthesised, for example, using chemical synthetic techniques such as solid phase phosphoramidite chemical synthesis. RNA may be synthesized in vitro or in vivo by transcription of the relevant DNA molecule. Due to the degeneracy of the genetic code, differing nucleic acid sequences may encode the same polypeptide (or mature polypeptide). Thus, nucleic acid molecules included in this aspect of the invention include any molecule comprising a variant of the sequence explicitly recited. Such variants may include variant nucleic acid molecules that code for the same polypeptide (or mature polypeptide) as that explicitly identified, that code for a fragment of the polypeptide, that code for a functional equivalent of the polypeptide or that code for a fragment of the functional equivalent of the polypeptide. Also included in this aspect of the invention, are variant nucleic acid molecules that are derived from nucleotide substitutions, deletions, reanangements or insertions or multiple combinations of the aforementioned. Such molecules may be naturally occuning variants, such as allelic variants, non-naturally occuning variants such as those created by chemical mutagenesis, or variants isolated from a species, cell or organism type other than the type from which the sequence explicitly identified originated. Variant nucleic acid molecules may differ from the nucleic acid molecule explicitly recited in a coding region, non-coding region or both these regions. Nucleic acid molecules may also include additional nucleic acid sequence to that explicitly recited, for example, at the 5' or 3' end of the molecule. Such additional nucleic acids may encode for a polypeptide with added functionality compared with the original polypeptide whose sequence is explicitly identified herein. An example of this would be an addition of a sequence that is heterologous to the original nucleic acid sequence, to encode a fusion protein. Such a fusion protein may be of use in aiding purification procedures or enabling techniques to be canied out where fusion proteins are required (such as in the yeast two hybrid system). Additional sequences may also include leader or secretory sequences such as those coding for pro-, pre- or prepro- polypeptide sequences. These additional sequences may also include non-coding sequences that are transcribed but not translated including ribosome binding sites and termination signals.
A nucleic acid molecule of the invention may include molecules that are at least 70% identical over their entire length to a nucleic acid molecule as explicitly identified herein in SEQ ID Nos.: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566. Preferably, a nucleic acid molecule according to this aspect of the invention comprises a region that is at least 80% identical over its entire length to a nucleic acid molecule as explicitly identified herein in these SEQ ID Nos., preferably at least 90%, more preferably at least 95% and most preferably at least 98% or 99% identical. Further preferred embodiments include nucleic acid molecules that encode polypeptides that retain substantially the same biological function or activity as the polypeptide explicitly identified herein.
The nucleic acid molecules of the invention can also be engineered using methods generally known in the art. These methods include but are not limited to DNA shuffling; random or non-random fragmentation (by restriction enzymes or shearing methods) and reassembly of fragments; insertions, deletions, substitutions and reanangements of sequences by site-directed mutagenesis (for example, by PCR). These alterations may be for a number of reasons including for ease of cloning (such as introduction of new restriction sites), altering of glycosylation patterns, changing of codon preferences, splice variants changing the processing, and/or expression of the gene product (the polypeptide) in general or creating fusion proteins (see above). Hybridisation
Nucleic acid molecules of the invention may also include antisense molecules that are partially complementary to a nucleic acid molecule as explicitly identified herein in SEQ LD Nos.: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566 and which therefore will hybridise to the encoding nucleic acid molecules. These antisense molecules, including oligonucleotides, can be designed to recognise, specifically bind to and prevent transcription of a target nucleic acid encoding a polypeptide of the invention, as will be known by those of ordinary skill in the art (see Cohen, J.S., Trends in Pharm. Sci., 10, 435 (1989), Okano, J. Neurochem. 56, 560 (1991); O'Connor, J. Neurochem 56, 560 (1991); Lee et al, Nucleic Acids Res 6, 3073 (1979); Cooney et al, Science 241, 456 (1988); Dervan et al, Science 251, 1360 (1991).
The term "hybridisation" used herein refers to any process by which a strand of nucleic acid binds with a complementary strand of nucleic acid by hydrogen bonding, typically forming Watson-Crick base pairs. As canied out in vitro, one of the nucleic acid populations is usually immobilised to a surface, whilst the other population is free. The two molecule types are then placed together under conditions conducive to binding.
The phrase "stringency of hybridisation" refers to the percentage of complementarity that is needed for duplex formation. "Stringency" thus refers to the conditions in a hybridization reaction that favour the association of very similar molecules over association of molecules that differ. Conditions can therefore exist that allow not only nucleic acid strands with 99-100% complementarity to hybridise, but sequences with lower complementarity (for example, 50%) to also hybridise. High stringency hybridisation conditions are defined herein as overnight incubation at 42°C in a solution comprising 50% formamide, 5XSSC (150mM NaCI, 15mM trisodium citrate), 50mM sodium phosphate (pH7.6), 5x Denhardts solution, 10% dextran sulphate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1X SSC at approximately 65°C. Low stringency conditions involve the hybridisation reaction being carried out at 35°C (see Sambrook et al [supra]). Preferably, the conditions used for hybridization are those of high stringency.
Some trans- and c/s-acting factors that may affect the binding of two complementary strands include strand length, base composition (GC pairs have an extra hydrogen bond and are thus require more energy to separate than AT pairs) and the chemical environment. The presence of monovalent cations (such as Na+) stabilises duplex formation whereas chemical denaturants such as formamide and urea destabilise the duplex by disruption of the hydrogen bonds. Use of compounds such as polyethylene glycol (PEG) can increase reassociation speeds by increasing overall DNA concentration in aqueous solution by abstracting water molecules. Denhardt's reagent or BLOTTO are chemical agents often added to block non-specific attachment of the liquid phase to the solid support. Increasing the temperature will also increase the stringency of hybridisation, as will increasing the stringency of the washing conditions following hybridisation (Sambrook et al. [supra]).
Numerous techniques exist for effecting hybridisation of nucleic acid molecules. Such techniques usually involve one of the nucleic acid populations being labelled. Labelling methods include, but are not limited to radiolabelling, fluorescence labelling, chemiluminescent or chromogenic labelling or chemically coupling a modified reporter molecule to a nucleotide precursor such as the biotin-streptavidin system. This can be done by oligolabelling, nick-translation, end-labelling or PCR amplification using a labelled polynucleotide. Labelling of RNA molecules can be achieved by cloning the sequences encoding the polypeptide of the invention into a vector specifically for this purpose. Such vectors are known in the art and may be used to synthesise RNA probes in vitro by the addition of an appropriate RNA polymerase such as T7, T3 or SP6 and labelled nucleotides.
Various kits are commercially available that allow the labelling of molecules. Examples include those made by Pharmacia & Upjohn (Kalamazoo, MI); Promega (Madison WI); and the U.S. Biochemical Corp. (Cleveland, OH). Hybridisation assays include, but are not limited to dot-blots, Southern blotting, Northern blotting, chromosome in situ hybridisation (for example, FISH [fluorescence in situ hybridisation]), tissue in situ hybridisation, colony blots, plaque lifts, gridded clone hybridisation assays, DNA microanays and oligonucleotide microanays. These hybridisation methods and others, may be used by a skilled artisan to isolate copies of genomic DNA, cDNA, or RNA encoding homologous or orthologous proteins from other species.
The invention therefore also embodies a process for detecting a nucleic acid molecule according to the invention, comprising the steps of: (a) contacting a nucleic probe with a biological sample under hybridising conditions to form duplexes: and (b) detecting any such duplexes that are formed. The term "probe" as used herein refers to a nucleic acid molecule in a hybridisation reaction whose molecular identity is known and is designed specifically to identify nucleic acids encoding homologous genes in other species. Usually, the probe population is the labelled population, but this is not always the case, as for example, in a reverse hybridisation assay.
One example of a use of a probe is to find nucleic acid molecules with an equivalent function to those that are explicitly identified herein, or to identify additional family members in the same or other species. This can be done by probing libraries, such as genomic or cDNA libraries, derived from a source of interest, such as a human, a non- human animal, other eukaryote species, a plant, a prokaryotic species or a virus. The probe may be natural or artificially designed using methods recognised in the art (for example, Ausubel et al, [supra]). A nucleic acid probe will preferably possess greater than 15, more preferably greater than 30 and most preferably greater than 50 contiguous bases complementary to a nucleic acid molecule explicitly identified herein.
In many cases, isolated DNA from cDNA libraries will be incomplete in the region encoding the polypeptide, normally at the 5' end. Methods available for subsequently obtaining full-length cDNA sequence include RACE (rapid amplification of cDNA ends) as described by Frohman et al, (Proc. Natl. Acad. Sci. USA 85, 8998-9002 (1988)), and restriction-site PCR, which uses universal primers to retrieve unknown nucleic acid sequence adjacent to a known locus (Sarkar, G. (1993) PCR Methods Applic, 2:318-322). "Inverse PCR" may also be used to amplify or to extend sequences using divergent primers based on a known region (Triglia, T. et al, (1988) Nucleic Acids Res. 16:8186). Another method which may be used is "capture PCR", which involves PCR amplification of DNA fragments adjacent to a known sequence in human and yeast artificial chromosome DNA
(Lagerstrom, M. et al, (1991) PCR Methods Applic, 1: 111-119). Another method which may be used to retrieve unknown sequences is that of Parker, J.D. et al, (1991); Nucleic
Acids Res. 19:3055-3060). Additionally, one may use PCR, nested primers, and libraries, such as the PromoterFinder™ library (Clontech, Palo Alto, CA) to walk genomic DNA. This latter process avoids the need to screen libraries and is useful in finding intron/exon junctions.
When screening for full-length cDNAs, it is preferable to use libraries that have been size- selected to include larger cDNAs. Also, random-primed libraries are preferable, in that they will contain more sequences that contain the 5' regions of genes. Use of a randomly primed library may be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.
In one embodiment of the invention, a nucleic acid molecule according to the invention may be used for chromosome localisation. In this technique, a nucleic acid molecule is specifically targeted to, and can hybridise with, a particular location on an individual human chromosome. The mapping of relevant sequences to chromosomes is an important step in the confirmatory conelation of those sequences with the gene-associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be conelated with genetic map data. Such data are found in, for example, McKusick, Mendelian Inheritance in Man (available on-line through Johns Hopkins University Welch Medical Library). The relationships between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes). This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localised by genetic linkage to a particular genomic region, any sequences mapping to that area may represent associated or regulatory genes for further investigation. The nucleic acid molecule may also be used to detect differences in the chromosomal location due to translocation, inversion, etc. among normal, canier, or affected individuals.
Nucleic acid molecules of the present invention are also valuable for tissue localisation. Such techniques facilitate the determination of expression patterns of the polypeptide in tissues by detection of the mRNAs that encode them. These techniques include in situ hybridisation techniques and nucleotide amplification techniques, such as PCR. Results from these studies provide an indication of the normal functions of the polypeptide in the organism, as well as highlighting the involvement of a particular gene in a disease state or abnormal physiological condition. In addition, comparative studies of the normal expression pattern of mRNAs with that of mRNAs encoded by a mutant gene provide valuable insights into the role of mutant polypeptides in disease. Such inappropriate expression may be of a temporal, spatial or quantitative nature. Vectors
The nucleic acid molecules of the present invention may be incorporated into vectors for cloning (for example, pBluescript made by Stratagene) or expression purposes. Vectors containing a nucleic acid molecule explicitly identified herein (or a variant thereof) form another aspect of this invention. The nucleic acid molecule may be inserted into an appropriate vector by any variety of well known techniques such as those described in Sambrook et al. [supra]. Generally, the encoding gene can be placed under the control of a control element such as a promoter, ribosome binding site or operator, so that the DNA sequence encoding the desired polypeptide is transcribed into RNA in the transformed host cell. Vectors may be derived from various sources including, but not limited to bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses for example, baculoviruses and SV40 (simian virus), vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, or combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, including cosmids and phagemids. Human, bacterial and yeast artificial chromosomes (HACs, BACs and YACs respectively) may also be employed to deliver larger fragments of DNA than can be contained and expressed in a plasmid.
Examples of retroviruses include but are not limited to: murine leukaemia virus (MLV), human immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukaemia virus (Mo-MLV), FBR murine osteosarcoma virus (FBR MSV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukaemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29), and Avian erythroblastosis virus (AEV). A detailed list of retroviruses may be found in Coffin et al ("Retroviruses" 1997 Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763).
Lentiviruses can be divided into primate and non-primate groups. Examples of primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto-immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV). The non-primate lentiviral group includes the prototype "slow virus" visna/maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV) and the more recently described feline immunodeficiency virus (FIV) and bovine immunodeficiency virus (BIV).
A distinction between the lentivirus family and other types of retroviruses is that lentiviruses have the capability to infect both dividing and non-dividing cells (Lewis et al 1992 EMBO. J 11: 3053-3058; Lewis and Emerman 1994 J. Virol. 68: 510-516). In contrast, other retroviruses - such as MLV - are unable to infect non-dividing cells such as those that make up, for example, muscle, brain, lung and liver tissue.
A vector may be configured as a split-intron vector. A split intron vector is described in PCT patent applications WO 99/15683 and WO 99/15684.
If the features of adenoviruses are combined with the genetic stability of retroviruses/lentiviruses then essentially the adenovirus can be used to transduce target cells to become transient retroviral producer cells that could stably infect neighbouring cells. Such retroviral producer cells engineered to express an antigen of the present invention can be implanted in organisms such as animals or humans for use in the treatment of angiogenesis and/or cancer.
Poxvirus vectors are also suitable for use in accordance with the present invention. Pox viruses are engineered for recombinant gene expression and for the use as recombinant live vaccines. This entails the use of recombinant techniques to introduce nucleic acids encoding foreign antigens into the genome of the pox virus. If the nucleic acid is integrated at a site in the viral DNA which is non-essential for the life cycle of the virus, it is possible for the newly produced recombinant pox virus to be infectious, that is to say to infect foreign cells and thus to express the integrated DNA sequence. The recombinant pox virus prepared in this way can be used as live vaccines for the prophylaxis and/or treatment of pathologic and infectious disease.
For vaccine delivery, prefened vectors are vaccinia virus vectors such as MVA or NYVAC. Most prefened is the vaccinia strain modified virus ankara (MVA) or a strain derived therefrom. Alternatives to vaccinia vectors include avipox vectors such as fowlpox or canarypox known as ALVAC and strains derived therefrom which can infect and express recombinant proteins in human cells but are unable to replicate. Bacterial vectors may be also used, such as salmonella, listeria and mycobacteria.
Vectors containing the relevant nucleotide sequence may enter the host cell by a variety of methods well known in the art and described in many standard laboratory manuals (such as Sambrook et al, [supra], Ausubel et al, [supra], Davis et al, Basic Methods in Molecular Biology (1986)). Methods include calcium phosphate transfection, cationic lipid-mediated transfection, DEAE-dextran mediated transfection, electroporation, microinjection, scrape loading, transduction, and ballistic introduction or infection.
Host cells
The choice of host cells is often dependent on the vector type used as a carrier for the nucleic acid molecule of the present invention. Bacteria and other microorganisms are particularly suitable hosts for plasmids, cosmids and expression vectors generally (for example, vectors derived from the pBR322 plasmid), yeast are suitable hosts for yeast expression vectors, insect cell systems are suitable host for virus expression vectors (for example, baculovirus) and plant cells are suitable hosts for vectors such as the cauliflower mosaic virus (CaMV) and tobacco mosaic virus (TMV). Other expression systems include using animal cells (for example, with the Lenti Vectors™, Oxford BioMedica) as a host cell or even using cell-free translating systems. Some vectors, such as "shuttle vectors" may be maintained in a variety of host cells. An example of such a vector would be pEG 202 and other yeast two-hybrid vectors which can be maintained in both yeast and bacterial cells (see Ausubel et al, [supra] and Gyuris, J., Cell, 75, 791-803).
Examples of suitable bacterial hosts include Streptococci, Staphylococci, Escherichia coli, Streptomyces and Bacillus subtilis cells. Yeast and fungal hosts include Saccharomyces cerevisiae and Aspergillus cells. Mammalian cell hosts include many immortalised cell lines available from the American Type Culture Collection (ATCC) such as CHO (Chinese Hamster Ovary) cells, HeLa cells, BHK (baby hamster kidney) cells, monkey kidney cells, C127, 3T3, BHK, HEK 293, Bowes melanoma and human hepatocellular carcinoma (for example, Hep G2) cells. Insect host cells that are used for baculovirus expression include Drosophila S2 and Spodoptera Sf9 cells. Plant host cells include most plants from which protoplasts be isolated and cultured to give whole regenerated plants. Practically, all plants can be regenerated from cultured cells or tissues, including but not limited to all major species of sugar cane, sugar beet, cotton, fruit and other trees, legumes and vegetables. Expression systems
Also included in present invention are expression vectors that comprise a nucleic acid molecule as described above. Expression vectors and host cells are preferably chosen to give long term, high yield production and stable expression of the recombinant polypeptide and its variants.
Expression of a polypeptide can be effected by cloning an encoding nucleic acid molecule into a suitable expression vector and inserting this vector into a suitable host cell. The positioning and orientation of the nucleic acid molecule insert with respect to the regulatory sequences of the vector is important to ensure that the coding sequence is properly transcribed and translated. Alternatively, control and other regulatory sequences may be ligated onto the nucleic acid molecule of this invention prior to its insertion into the expression vector. In both cases, the sequence of the nucleic acid molecule may have to be adjusted in order to effect correct transcription and translation (for example, addition of nucleotides may be necessary to obtain the correct reading frame for translation of the polypeptide from its encoding nucleic acid molecule).
A nucleic acid molecule of the invention may comprise control sequences that encode signal peptides or leader sequences. These sequences may be useful in directing the translated polypeptide to a variety of locations within or outside the host cell, such as to the lumen of the endoplasmic reticulum, to the nucleus, to the periplasmic space, or into the extracellular environment. Such signals may be endogenous to the nucleic acid molecules of the invention, or may be a heterologous sequence. These leader or control sequences may be removed by the host during post-translational processing.
A nucleic acid molecule of the present invention may also comprise one or more regulatory sequences that allow for regulation of the expression of polypeptide relative to the growth of the host cell. Alternatively, these regulatory signals may be due to a heterologous sequence from the vector. Stimuli that these sequences respond to include those of a physical or chemical nature such as the presence or absence of regulatory compounds, changing temperatures or metabolic conditions. Regulatory sequences as described herein, are non-translated regions of sequence such as enhancers, promoters and the 5' and 3' untranslated regions of genes. Regulatory sequences interact with host cellular proteins that cany out translation and transcription. These regulatory sequences may vary in strength and specificity. Examples of regulatory sequences include those of constitutive and inducible promoters. In bacterial systems, an example of an inducible promoter is the hybrid lacZ promoter of the Bluescript phagemid (Stratagene, LaJolla, CA) or pSportlTM plasmid (Gibco BRL). The baculovirus polyhedrin promoter may be used in insect cells. An example of a prefened expression system is the lentivirus expression system, for example, as described in International patent application WO98/17815.
Detection of uptake of vectors by the host organism
Various methods are known in the art to detect the uptake of a nucleic acid or vector molecule by a host cell and/or the subsequent successful expression of the encoded polypeptide (see for example Sambrook et al, [supra]).
Vectors frequently have marker genes that can be easily assayed. Thus, vector uptake by a host cell can be readily detected by testing for the relevant phenotype. Markers include, but are not limited to those coding for antibiotic resistance, herbicide resistance or nutritional requirements. The gene encoding dihydrofolate reductase (DHFR) for example, confers resistance to methotrexate (Wigler, M. et al (1980) PNAS 77:3567-70) and the gene npt confers resistance to the aminoglycosides neomycin and G-418 (Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14). Additional selectable genes have been described, examples of which will be clear to those of skill in the art.
Markers however, only indicate that a vector has been taken up by a host cell but does not distinguish between vectors that contain the desired nucleic acid molecule and those that do not. One method of detecting for the said nucleic acid molecule is to insert the relevant sequence at a position that will disrupt the transcription and translation of a marker gene.
These cells can then be identified by the absence of a marker gene phenotype.
Alternatively, a marker gene can be placed in tandem with a sequence encoding a polypeptide of the invention under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
More direct and definitive methods to detect the presence of the nucleic acid molecule of the present invention include DNA-DNA or DNA-RNA hybridisation with a probe comprising the relevant antisense molecule, as described above. More direct methods to detect polypeptide expression include protein bioassays for example, fluorescence activated cell sorting (FACS), immunoassay techniques such as ELISA or radioimmunoassays.
Alternative methods for detecting or quantitating the presence of the nucleic acid molecule or polypeptide of this invention include membrane, solution or chip-based technologies (see Hampton, R. et al, (1990) Serological Methods, a Laboratory Manual, APS Press, St Paul, MN) and Maddox, D.E. et al., (1983) J. Exp. Med, 158, 1211-1216).
Transgenic animals
In another embodiment of this invention, a nucleic acid molecule according to the invention may be used to create a transgenic animal, most commonly a rodent. The modification of the animal's genome may either be done locally, by modification of somatic cells or by germ line therapy to incorporate inheritable modifications. Such transgenic animals may be particularly useful in the generation of animal models for drug molecules effective as modulators of the polypeptides of the present invention.
Polypeptide purification A polypeptide according to the invention may be recovered and purified from recombinant cell cultures by methods including, but not limited to cell lysis techniques, ammonium sulphate precipitation, ethanol precipitation, acid extraction, anion or cation chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography, high performance liquid chromatography (HPLC) or fast performance liquid chromatography (FPLC). The polypeptide may need refolding after purification or isolation and many well known techniques are available that will help regenerate an active polypeptide conformation.
Many expression vectors are commercially available that aid purification of the relevant polypeptide. These include vectors that join the sequence encoding the polypeptide to another expressed sequence creating a fused protein that is easier to purify. Ways in which these fused parts can facilitate purification of the polypeptide of this invention include fusions that can increase the solubility of the polypeptide, joining of metal chelating peptides (for example, histidine-tryptophan modules) that allow for purification with immobilised metals, joining of protein A domains which allow for purification with immobilised immunoglobulins and the joining of the domain that is utilised in the FLAGS extension/affinity purification system (Immunex Corp., Seattle, WA). Fusion of the polypeptide of this present invention with a secretion signal polypeptide may also aid purification. This is because the medium into which the fused polypeptide has been secreted can subsequently be used to recover and purify the expressed polypeptide.
If necessary, these extraneous polypeptides often comprise a cleavable linker sequence which allows the polypeptide to be isolated from the fusion. Cleavable linker sequences between the purification domain and the polypeptide of the invention include those specific for Factor Xa or for enterokinase (Invitrogen, San Diego, CA). One such expression vector provides for expression of a fusion protein containing the polypeptide of the invention fused to several histidine residues preceding a thioredoxin or an enterokinase cleavage site. The histidine residues facilitate purification by IMAC (immobilised metal ion affinity chromatography as described in Porath, J. et al. (1992), Prot. Exp. Purif. 3: 263-281), while the thioredoxin or enterokinase cleavage site provides a means for purifying the polypeptide from the fusion protein. A discussion of vectors that contain fusion proteins is provided in Kroll, D.J. et al (1993; DNA Cell Biol. 12:441-453).
Assays
Another aspect of this invention includes assays that may be canied out using a polypeptide or nucleic acid molecule according to the invention Such assays may be for many uses including the development of drug candidates, for diagnostic purposes or for the gathering of information for therapeutics.
If the polypeptide is to be expressed for use in screening assays, generally it is prefened that it be produced at the surface of the host cell in which it is expressed. In this event, the host cells may be harvested prior to use in the screening assay, for example using techniques such as fluorescence activated cell sorting (FACS) or immunoaffinity techniques. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the expressed polypeptide. If polypeptide is produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
The polypeptide of the invention can be used to screen libraries of compounds in any of a variety of drug screening techniques. Such compounds may activate (agonise) or inhibit
(antagonise) the level of expression of the gene or the activity of the polypeptide of the invention and form a further aspect of the present invention. Examples of suitable compounds are those which are effective to alter the expression of a natural gene which encodes a polypeptide of the invention or to regulate the activity of a polypeptide of the invention.
Agonist or antagonist compounds may be isolated from, for example, cells, cell-free preparations, chemical libraries or natural product mixtures. These agonists or antagonists may be natural or modified substrates, ligands, enzymes, receptors or structural or functional mimetics. For a suitable review of such screening techniques, see Coligan et al., Cunent Protocols in Immunology l(2):Chapter 5 (1991).
Potential agonists or antagonists include small organic molecules, peptides, polypeptides and antibodies that bind to the polypeptide of the invention and thereby modulate its activity. In this fashion, binding of the polypeptide to normal cellular binding molecules may be potentiated or inhibited, such that the normal biological activity of the polypeptide is enhanced or prevented.
The polypeptide of the invention that is employed in such a screening technique may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. In general, such screening procedures may involve using appropriate cells or cell membranes that express the polypeptide that are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response. The functional response of the cells contacted with the test compound is then compared with control cells that were not contacted with the test compound. Such an assay may assess whether the test compound results in a signal generated by activation of the polypeptide, using an appropriate detection system. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist in the presence of the test compound is observed.
Alternatively, simple binding assays may be used, in which the adherence of a test compound to a surface bearing the polypeptide is detected by means of a label directly or indirectly associated with the test compound or in an assay involving competition with a labelled competitor. In another embodiment, competitive drug screening assays may be used, in which neutralising antibodies that are capable of binding the polypeptide specifically compete with a test compound for binding. In this manner, the antibodies can be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide. Assays may also be designed to detect the effect of added test compounds on the production of mRNA encoding the polypeptide in cells. For example, an ELISA may be constructed that measures secreted or cell-associated levels of polypeptide using monoclonal or polyclonal antibodies by standard methods known in the art, and this can be used to search for compounds that may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues. The formation of binding complexes between the polypeptide and the compound being tested may then be measured.
Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the polypeptide of interest (see International patent application WO84/03564). In this method, large numbers of different small test compounds are synthesised on a solid substrate, which may then be reacted with the polypeptide of the invention and washed. One way of immobilising the polypeptide is to use non-neutralising antibodies. Bound polypeptide may then be detected using methods that are well known in the art. Purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques.
A polypeptide according to the invention may be used to identify membrane-bound or soluble receptors, through standard receptor binding techniques that are known in the art, such as ligand binding and crosslinking assays in which the polypeptide is labelled with a radioactive isotope, is chemically modified, or is fused to a peptide sequence that facilitates its detection or purification, and incubated with a source of the putative receptor (for example, a composition of cells, cell membranes, cell supernatants, tissue extracts, or bodily fluids). The efficacy of binding may be measured using biophysical techniques such as surface plasmon resonance and spectroscopy. Binding assays may be used for the purification and cloning of the receptor, but may also identify agonists and antagonists of the polypeptide, that compete with the binding of the polypeptide to its receptor. Standard methods for conducting screening assays are well understood in the art.
A typical polypeptide-based assay might involve contacting the appropriate cell(s) or cell membrane(s) expressing the polypeptide with a test compound. In such assays, a polypeptide according to the invention may be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. Any response to the test compound, for example a binding response, a stimulation or inhibition of a functional response may then be compared with a control where the cell(s) or cell membrane(s) was/were not contacted with the test compound. A binding response could be measured by testing for the adherence of a test compound to a surface bearing a polypeptide according to the invention. The test compound may aid polypeptide detection by being labelled, either directly or indirectly. Alternatively, the polypeptide itself may be labelled, for example, with a radioisotope, by chemical modification or as a fusion with a peptide or polypeptide sequence that will facilitate polypeptide detection. Alternatively, a binding response may be measured, for example, by performing a competition assay with a labelled competitor or vice versa. One example of such a technique is a competitive drug screening assay, where neutralising antibodies that are capable of specifically binding to the polypeptide compete with a test compound for binding. In this manner, the antibodies may be used to detect the presence of any test compound that possesses specific binding affinity for the polypeptide. Alternative binding assay methods are well known in the art and include, but are not limited to, cross-linking assays and filter binding assays. The efficacy of binding may be measured using biophysical techniques including surface plasmon resonance and spectroscopy.
High throughput screening is a type of assay which enables a large number of compounds to be searched for any significant binding activity to the polypeptide of interest (see patent application WO84/03564). This is particularly useful in drug screening. In this scenario, many different small test compounds are synthesised on to a solid substrate. The polypeptide is then introduced to this substrate and the whole apparatus washed. The polypeptide is then immobilised by, for example, using non-neutralising antibodies. Bound polypeptide may then be detected using methods that are well known in the art. Purified polypeptide may also be coated directly onto plates for use in the aforementioned drug screening techniques. Assay methods that are also included within the terms of the present invention are those that involve the use of the genes and polypeptides of the invention in overexpression or ablation assays. Such assays involve the manipulation of levels of these genes/polypeptides in cells and assessment of the impact of this manipulation event on the physiology of the manipulated cells. For example, such experiments reveal details of signaling and metabolic pathways in which the particular genes/polypeptides are implicated, generate information regarding the identities of polypeptides with which the studied polypeptides interact and provide clues as to methods by which related genes and proteins are regulated.
Another aspect of this invention provides for any screening kits that are based or developed from any of the aforementioned assays. C. Pharmaceuticals
A further aspect of the invention provides a pharmaceutical composition suitable for modulating the biological response to hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide, a nucleic acid molecule, vector or ligand as described above, in conjunction with a pharmaceutically-acceptable carrier. A composition containing a polypeptide, nucleic acid molecule, ligand or any other compound of this present invention (herein known as X) is considered to be "substantially free of impurities" (herein known as Y) when X makes up more than 85% mass per mass of the total [X+Y] mass. Preferably X comprises at least 90% of the total X+Y mass. More preferably X comprises at least 95%, 98% and most preferably 99% of the total X+Y mass.
Carriers
Canier molecules may be genes, polypeptides, antibodies, liposomes or indeed any other agent provided that the canier does not itself induce toxicity effects or cause the production of antibodies that are harmful to the individual receiving the pharmaceutical composition. Further examples of known earners include polysaccharides, polylactic acids, polyglycolic acids and inactive virus particles. Caniers may also include pharmaceutically acceptable salts such as mineral acid salts (for example, hydrochlorides, hydrobromides, phosphates, sulphates) or the salts of organic acids (for example, acetates, propionates, malonates, benzoates). Pharmaceutically acceptable carriers may additionally contain liquids such as water, saline, glycerol, ethanol or auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like. Carriers may enable the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slunies, suspensions to aid intake by the patient. A thorough discussion of pharmaceutically acceptable caniers is available in Remington's Pharmaceutical Sciences
(Mack Pub. Co., NJ. 1991).
Dosage
The amount of component X in the composition should also be in therapeutically effective amounts. The phrase "therapeutically effective amounts" used herein refers to the amount of agent needed to treat, ameliorate, or prevent (for example, when used as a vaccine) a targeted disease or condition. An effective initial method to determine a "therapeutically effective amount" may be by canying out cell culture assays (for example, using neoplastic cells) or using animal models (for example, mice, rabbits, dogs or pigs). In addition to determining the appropriate concentration range for X to be therapeutically effective, animal models may also yield other relevant information such as preferable routes of administration that will give maximum effectiveness. Such information may be useful as a basis for patient administration. A "patient" as used in herein refers to the subject who is receiving treatment by administration of X. Preferably, the patient is human, but the term may also include animals.
The therapeutically-effective dosage will generally be dependent on the patient's status at the time of adminstration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug combinations, reaction sensitivities and the patient's tolerance or response to the therapy. The precise amount can be determined by routine experimentation but may ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 mg/kg (mass of drug compared to mass of patient) to 50 mg/kg, preferably 0.05 mg/kg to 10 mg/kg. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
Routes of administration Uptake of a pharmaceutical composition of the invention by a patient may be initiated by a variety of methods including, but not limited to enteral, intra-arterial, intrathecal, intramedullary, intramuscular, intranasal, intraperitoneal, intravaginal, intravenous, intraventricular, oral, rectal (for example, in the form of suppositories), subcutaneous, sublingual, transcutaneous applications (for example, see WO98/20734) or transdermal means.
Gene guns or hyposprays may also be used to administer the pharmaceutical compositions of the invention. Typically, the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. Direct delivery of the compositions can generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue. The compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule.
Inhibition of excessive activity If a particular disease state is partially or completely caused by an inappropriate excess in the activity of a polypeptide according to the invention, several approaches are available for inhibiting this activity. One approach comprises administering to a patient an inhibitor compound (antagonist) along with a pharmaceutically acceptable canier in an amount effective to inhibit the function of the polypeptide, such as by blocking the binding of a ligand, substrate, enzyme, receptor, or by inhibiting a second signal, and thereby alleviating the abnormal condition. Such an antagonist molecule may, for example, be an antibody. Most preferably, such antibodies are chimeric and/or humanised to minimise their immunogenicity, as previously described.
In another approach, soluble forms of the polypeptide that retain binding affinity for the ligand, substrate, enzyme, receptor, in question, may be administered to the patient to compete with the biological activity of the endogenous polypeptide. Typically, the polypeptide may be administered in the form of a fragment that retains a portion that is relevant for the desired biological activity.
In an alternative approach, expression of the gene encoding the polypeptide can be inhibited using expression blocking techniques, such as by using antisense nucleic acid molecules (as described above), either internally generated or separately administered. Modifications of gene expression may be effected by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5' or regulatory regions (signal sequence, promoters, enhancers and introns) of the gene encoding the polypeptide. Similarly, inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J.E. et al. (1994) In: Huber, B.E. and B.I. Can, Molecular and Immunologic Approaches, Futura Publishing Co., Mt. Kisco, NY). The complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes. Such oligonucleotides may be administered or may be generated in situ from expression in vivo.
Gene silencing approaches may also be undertaken to down-regulate endogenous expression of a gene. RNA interference (RNAi) (Elbashir, SM et al., Nature 2001, 41 1, 494-498) is one method of sequence specific post-transcriptional gene silencing that may be employed. Short dsRNA oligonucleotides are synthesised in vitro and introduced into a cell. The sequence specific binding of these dsRNA oligonucleotides triggers the degradation of target mRNA, reducing or ablating target protein expression. In addition, expression of a polypeptide according to the invention may be prevented by using a ribozyme specific to the encoding mRNA sequence for the polypeptide. Ribozymes are catalytically active RNAs that can be natural or synthetic (see for example Usman, N, et al, Cun. Opin. Struct. Biol (1996) 6(4), 527-33). Synthetic ribozymes can be designed to specifically cleave mRNAs at selected positions thereby preventing translation of the mRNAs into functional polypeptide. Ribozymes may be synthesised with a natural ribose phosphate backbone and natural bases, as normally found in RNA molecules. Alternatively the ribozymes may be synthesised with non-natural backbones, for example, 2'-O-methyl RNA, to provide protection from ribonuclease degradation and may contain modified bases.
Efficacy of the gene silencing approaches assessed above may be assessed through the measurement of polypeptide expression (for example, by Western blotting), and at the RNA level using TaqMan-based methodologies.
RNA molecules may be modified to increase their intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of non-traditional bases such as inosine, queosine and butosine, as well as acetyl-, methyl-, thio- and similarly modified forms of adenine, cytidine, guanine, thymine and uridine that are not as easily recognised by endogenous endonucleases.
Activation of a polypeptide activity
If a particular disease state is partially or completely due to a lowered level of biological activity from a polypeptide according to the invention, various methods may be used. An example of such a method includes administering a therapeutically effective amount of compound that can activate (i.e. an agonist) or cause increased expression of the polypeptide concerned. Administration of such a compound may be via any of the methods described previously.
Gene Therapy Another aspect of the present invention provides for gene therapy methods involving nucleic acid molecules identified herein. Gene therapy may be used to affect the endogenous production of the polypeptide of the present invention by relevant cells in a patient. For example, gene therapy can be used permanently to treat the inappropriate production of a polypeptide by replacing a defective gene with the corrected therapeutic gene.
Treatment may be effected either in vivo or ex vivo. Ex vivo gene therapy generally involves the isolation and purification of the patient's cells, introduction of the therapeutic gene into the cells and finally, the introduction of the genetically-altered cells back into the patient. In vivo gene therapy does not require the isolation and purification of patient cells prior to the introduction of the therapeutic gene into the patient. Instead, the therapeutic gene can be packaged for delivery into the host. Gene delivery vehicles for in vivo gene therapy include, but are not limited to, non-viral vehicles such as liposomes, replication- deficient viruses (for example, adenovirus as described by Berkner, K.L., in Cun. Top. Microbiol. Immunol., 158, 39-66 (1992)) or adeno-associated virus (AAV) vectors as described by Muzyczka, N., in Cun. Top. Microbiol. Immunol., 158, 97-129 (1992) and U.S. Patent No. 5,252,479. Alternatively, "naked DNA" may be directly injected into the bloodstream or muscle tissue as a form of in vivo gene therapy.
One example of a strategy for gene therapy including a nucleic acid molecule of this present invention may be as follows. A nucleic acid molecule encoding a polypeptide of the invention is engineered for expression in a replication-defective retroviral vector. This expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding the polypeptide, such that the packaging cell now produces infectious viral particles containing the gene of interest. These producer cells may be administered to a patient for engineering cells in vivo and expression of the polypeptide in vivo (see Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics (1996), T Strachan and A P Read, BIOS Scientific Publishers Ltd).
Genetic delivery of antibodies that bind to polypeptides according to the invention may also be effected, for example, as described in International patent application WO98/55607.
Vaccines
A further embodiment of the present invention provides that the polypeptides or nucleic acid molecules identified may be used in the development of vaccines. Where the aforementioned polypeptide or nucleic acid molecule is a disease-causing agent, vaccine development can involve the raising of antibodies against such agents. Where the aforementioned polypeptide or nucleic acid molecule is one that is up-regulated, vaccine development can involve the raising of antibodies or T cells against such agents (as described in WO00/29428).
Vaccines according to the invention may either be prophylactic (i.e. prevents infection) or therapeutic (i.e. treats disease after infection). Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid, usually in combination with pharmaceutically-acceptable caniers as described above. Additionally, these caniers may function as immunostimulating agents ("adjuvants"). Furthermore, the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H. pylori, and other pathogens.
Vaccination processes may involve the use of heterologous vectors eg: prime with MVA and boost with DNA.
Since polypeptides may be broken down in the stomach, vaccines comprising polypeptides are preferably administered parenterally (for instance, subcutaneous, intramuscular, intravenous, or intradermal injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents. The vaccine formulations of the invention may be presented in unit-dose or multi-dose containers. For example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation. The technology refened to as jet injection (see, for example, www.powderject.com) may also be useful in the formulation of vaccine compositions.
In accordance with this aspect of the present invention, polypeptides can be delivered by viral or non-viral techniques. Non-viral delivery systems include but are not limited to DNA transfection methods. Here, transfection includes a process using a non-viral vector to deliver a antigen gene to a target mammalian cell. Typical transfection methods include electroporation, nucleic acid biolistics, lipid-mediated transfection, compacted nucleic acid- mediated transfection, liposomes, immunoliposomes, lipofectin, cationic agent-mediated, cationic facial amphiphiles (CFAs) (Nature Biotechnology 1996 14; 556), multivalent cations such as spermine, cationic lipids or polylysine, 1, 2,-bis (oleoyloxy)-3-(trirnethylammonio) propane (DOTAP)-cholesterol complexes (Wolff and Trubetskoy 1998 Nature Biotechnology 16: 421) and combinations thereof. Viral delivery systems include but are not limited to adenovirus vectors, adeno-associated viral (AAV) vectors, herpes viral vectors, influenza, retroviral vectors, lentiviral vectors or baculoviral vectors, Venezuelan equine encephalitis virus (VEE), poxviruses such as: canarypox virus (Taylor et al 1995 Vaccine 13:539-549), entomopox virus (Li Y et al 1998 Xllth International Poxvirus Symposium pl44. Abstract), penguine pox (Standard et al. J Gen Virol. 1998 79:1637-46) alphavirus, and alphavirus based DNA vectors.
In addition to the use of polypeptide-based vaccines, this aspect of the invention includes the use of genetically-based vaccines, for example, those vaccines that are effective through eliciting the expression of a particular gene (either endogenous or exogenously derived) in a cell, so targeting this cell for destruction by the immune system of the host organism. A number of suitable methods for vaccination and vaccine delivery systems are described in International patent application WO00/29428.
D. Diagnostics
Another aspect of the present invention provides for the use of a nucleic acid molecule identified herein as a diagnostic reagent. For example, a nucleic acid molecule may be detected or isolated from a patient's tissue and used for diagnostic purposes. "Tissue" as defined herein refers to blood, urine, any matter obtained from a tissue biopsy or any matter obtained from an autopsy. Genomic DNA from the tissue sample may be used directly for detection of a hypoxia-related condition. Alternatively, the DNA may be amplified using methods such as polymerase chain reaction (PCR), the ligase chain reaction (LCR), strand displacement amplification (SDA), or other amplification techniques (see Saiki et al, Nature, 324, 163-166 (1986); Bej, et al, Crit. Rev. Biochem. Molec. Biol., 26, 301-334 (1991); Birkenmeyer et al, J. Virol. Meth., 35, 117-126 (1991) and Brunt, J., Bio/Technology, 8, 291-294 (1990)). Such diagnostics are particularly useful for prenatal and even neonatal testing. A method of diagnosis of disease using a polynucleotide may comprise assessing the level of expression of the natural gene and comparing the level of encoded polypeptide to a control level measured in a normal subject that does not suffer from the disease or physiological condition that is being tested. The diagnosis may comprise the following steps: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule of the invention and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of differing levels of the hybrid complex in the patient sample compared to levels of the hybrid complex in the control sample is indicative of the dysfunction.
A further aspect of the invention comprises a diagnostic method comprising the steps of: a) obtaining a tissue sample from a patient being tested for disease; b) isolating a nucleic acid molecule according to the invention from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation in the nucleic acid molecule which is associated with disease.
To aid the detection of nucleic acid molecules in the above-described methods, an amplification step, such as PCR, may be included. An example of this includes detection of deletions or insertions indicative of the dysfunction by a change in the size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridising amplified DNA to labelled RNA of the invention or alternatively, labelled antisense DNA sequences of the invention. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase digestion or by assessing differences in melting temperatures. The presence or absence of the mutation in the patient may be detected by contacting DNA with a nucleic acid probe that hybridises to the DNA under stringent conditions to form a hybrid double-stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion conesponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation in the corresponding portion of the DNA strand. Point mutations and other sequence differences between the reference gene and "mutant" genes can be identified by other well-known techniques, such as direct DNA sequencing or single-strand conformational polymorphism, (see Orita et al, Genomics, 5, 874-879 (1989)). For example, a sequencing primer may be used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabelled nucleotides or by automatic sequencing procedures with fluorescent-tags. Cloned DNA segments may also be used as probes to detect specific DNA segments. The sensitivity of this method is greatly enhanced when combined with PCR. Further, point mutations and other sequence variations, such as polymorphisms, can be detected as described above, for example, through the use of allele-specific oligonucleotides for PCR amplification of sequences that differ by single nucleotides.
DNA sequence differences may also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (for example, Myers et al, Science (1985) 230:1242). Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and SI protection or the chemical cleavage method (see Cotton et al, PNAS. USA (1985) 85: 4397-4401).
In addition to conventional gel electrophoresis and DNA sequencing, mutations such as microdeletions, aneuploidies, translocations, inversions, can also be detected by in situ analysis (see, for example, Keller et al, DNA Probes, 2nd Ed., Stockton Press, New York, N.Y., USA (1993)), that is, DNA or RNA sequences in cells can be analysed for mutations without need for their isolation and/or immobilisation onto a membrane. FISH is presently the most commonly applied method and numerous reviews of FISH have appeared (see, for example, Trachuck et al, Science, 250, 559-562 (1990), and Trask et al, Trends, Genet., 7, 149-154 (1991)).
Arrays
In another embodiment of the invention, an array of oligonucleotide probes comprising a nucleic acid molecule according to the invention can be constructed to conduct efficient screening of genetic variants, mutations and polymorphisms. Anay technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability (see for example: M.Chee et al, Science (1996), Vol 274, pp 610-613).
In one embodiment, the array is prepared and used according to the methods described in WO95/11995 (Chee et al); Lockhart, D. J. et al. (1996) Nat. Biotech. 14: 1675-1680); and Schena, M. et al (1996) PNAS 93: 10614-10619). Oligonucleotide pairs may range from two to over one million. The oligomers are synthesized at designated areas on a substrate using a light-directed chemical process. The substrate may be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support. In another aspect, an oligonucleotide may be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application W095/251116 (Baldeschweiler et al). In another aspect, a "gridded" anay analogous to a dot (or slot) blot may be used to anange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536 or 6144 oligonucleotides, or any other number between two and over one million which lends itself to the efficient use of commercially-available instrumentation.
Diagnostics using polypeptides or mRNA In addition to the methods discussed above, diseases may be diagnosed by methods comprising determining, from a sample derived from a subject, an abnormally decreased or increased level of polypeptide or mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods.
Assay techniques that can be used to determine levels of a polypeptide of the present invention in a sample derived from a host are well-known to those of skill in the art and are discussed in some detail above (including radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays). One example of this aspect of the invention provides a diagnostic method which comprises the steps of: (a) contacting a ligand as described above with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
Protocols such as ELISA, RIA, and FACS for measuring polypeptide levels may additionally provide a basis for diagnosing altered or abnormal levels of polypeptide expression. Normal or standard values for polypeptide expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably humans, with antibody to the polypeptide under conditions suitable for complex formation The amount of standard complex formation may be quantified by various methods, such as by photometric means. Antibodies which specifically bind to a polypeptide of the invention may be used for the diagnosis of conditions or diseases characterised by expression of the polypeptide, or in assays to monitor patients being treated with the polypeptides, nucleic acid molecules, ligands and other compounds of the invention. Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for the polypeptide include methods that utilise the antibody and a label to detect the polypeptide in human body fluids or extracts of cells or tissues. The antibodies may be used with or without modification, and may be labelled by joining them, either covalently or non-covalently, with a reporter molecule. A wide variety of reporter molecules known in the art may be used, several of which are described above. Quantities of polypeptide expressed in subject, control and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease. Diagnostic assays may be used to distinguish between absence, presence, and excess expression of polypeptide and to monitor regulation of polypeptide levels during therapeutic intervention. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials or in monitoring the treatment of an individual patient.
Diagnostic kits
A diagnostic kit of the present invention may comprise:
(a) a nucleic acid molecule of the present invention; (b) a polypeptide of the present invention; or
(c) a ligand of the present invention. In one aspect of the invention, a diagnostic kit may comprise a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to the invention; a second container containing primers useful for amplifying the nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease. The kit may further comprise a third container holding an agent for digesting unhybridised RNA.
In an alternative aspect of the invention, a diagnostic kit may comprise an anay of nucleic acid molecules, an anay of antibody molecules, and/or an anay of polypeptide molecules, as discussed in more detail above. Such kits will be of use in diagnosing a disease or susceptibility to disease, particularly inflammation, oncology, or cardiovascular disease.
Various aspects and embodiments of the present invention will now be described in more detail by way of example, with particular reference to polypeptides regulated differentially under hypoxic conditions as opposed to normoxic conditions. It will be appreciated that modification of detail may be made without departing from the scope of the invention.
The method used in the following examples for the identification of hypoxia-induced genes and proteins utilised an approach herein termed "Smartomics". This method is a differential expression screening method for identifying genetic elements that are involved in a particular cellular process and is described in detail in co-pending, co-owned International patent application PCT/GBO 1/00758 entitled "Differential Expression Screening Method". Simplistically put, the method involves comparing:
(a) gene expression in a first cell of interest; and
(b) gene expression in a second cell of interest, which cell comprises altered levels, relative to physiological levels, of a biological molecule implicated in the cellular process, due to the introduction into the second cell of a heterologous nucleic acid directing expression of a polypeptide; and identifying a genetic element whose expression differs, wherein gene expression in said first and/or second cell of interest is compared under at least two different environmental conditions relevant to the cellular process. In preferred embodiments of the invention, gene expression is compared in both the first and the second cell of interest under at least two different environmental conditions relevant to the cellular process. By altering the levels of particular endogenous biological molecules in a cell, the levels of gene products that are responsive to cellular perturbations such as signalling events and which are affected by the biological molecule(s) become more readily detectable. In other words, the object of the Smartomics methodology is to amplify and/or increase the signal to noise ratio of the differential response normally obtained so as to increase the likelihood of detecting gene products whose levels in a cell are low and/or whose expression normally changes by only a small amount.
The Smartomics method has been utilised herein to improve the discovery of genes activated or repressed in response to hypoxia in primary human macrophages. This involves augmenting the natural response to hypoxia, by experimentally introducing a key regulator of the hypoxia response, namely hypoxia inducible factor lα (HIF-1 α), into a population of primary human macrophages and comparing gene expression in these cells with that in control cells.
Although HIF-lα is well known to mediate responses to hypoxia, other transcription factors are also known or suspected to be involved. These include a protein called endothelial PAS domain protein 1 (EPASl) or HIF-2α, which shares 48% sequence identity with HIF-1 α ("Endothelial PAS domain protein 1 (EPASl), a transcription factor selectively expressed in endothelial cells." Tian H, McKnight SL, Russell DW. Genes Dev.
1997 Jan l;l l(l):72-82.). Evidence suggests that EPASl is especially important in mediating the hypoxia-response in certain cell types, and it is clearly detectable in human macrophages, suggesting a role in this cell type (Griffiths et al, 2000, Gene Ther. 7(3):
255-62). In the light of this, the cunent example also utilises overexpression of EPASl, as an independent means of improving discovery of hypoxia-responsive genes, to overexpression of HIF-1 α . It also illustrates an embodiment of the Smartomics invention, whereby differences in the response to HIF-lα or EPASl (or other mediators of the hypoxia response) may be identified, with the goal of identifying therapeutic target molecules more suitable for specific and efficient treatment of disease.
Overexpression of HIF-1 α or EPASl was done either in isolation or was done in combination with exposing the cells to hypoxia. This allowed the detection of resulting gene expression changes that would otherwise have not been detectable in response to hypoxia alone. Brief description of the Figures
Figure 1: Northern blots performed to confirm overexpression of HLF-lα and EPASl using adenoviral gene transfer in transduced macrophages. RNA loading was as follows Lanes 1,2: Macrophages transduced with the adenovirus AdApt ires-GFP. Lanes 3,4 Macrophages transduced with the adenovirus AdApt HLF-lα-ires-GFP. Lanes 4,5 Macrophages transduced with the adenovirus AdApt EPASl -ires-GFP. In lanes 1,3,5 the macrophages were maintained in normoxia (20% O ). In lanes 2,4,6 the macrophages were maintained in hypoxia (0.1% O ). Positions of bands from an RNA size ladder are indicated to the right of each blot in kilobases (kb). Hybridisation probes were complimentary to the genes HIF-1 α (A), EPAS 1 (B) and 28s ribosomal RNA (C).
Figure 2: A scatter plot of two representative RNA samples analysed using Research Genetics GeneFilters. RNA from non-transduced macrophages in normoxia (Y-axis) or hypoxia (X-axis) was hybridised to two Research Genetics GeneFilters GF200 anays. Analysis was output as normalised intensity for each gene on the anay, with two values per gene conesponding to the signals from normoxia and hypoxia. These values were plotted as a scatter graph, with each dot representing a gene on the array. Genes expressed at similar levels between the RNA samples are located at the x=y line. In this representation an indication is apparent of the dynamic range of detection.
Figure 3: Analysis of Lactate Dehydrogenase A expression with Smartomics. In section A, thumbnail images of spots conesponding to the lactate dehydrogenase-A (LDH-A) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. Each strip of 6 images corresponds to a discrete anay position or experiment, over the range of RNA samples. Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O2). Anay location: Identity of the spot as defined by Research Genetics. Clone: IMAGE identification. The histogram (section B) shows the average of the figures shown and error bars are standard deviation, gfp: cells transduced with AdApt ires-GFP. Hif-la: Cells transduced with AdApt Hif-lα-ires-GFP. Epasl: Cells transduced with AdApt Epasl -ires-GFP. Figure 4: Analysis of Glyceraldehyde 3-phosphate dehydrogenase expression with Smartomics. In section A, thumbnail images of spots conesponding to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. Each strip of 6 images conesponds to a discrete anay position or experiment, over the range of RNA samples. Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O2). Anay location: Identity of the spot as defined by Research Genetics. Clone: IMAGE identification. The histogram (section B) shows the average of the figures shown and enor bars are standard deviation, gfp: cells transduced with AdApt ires-GFP. Hif-la: Cells transduced with AdApt Hif-lα-ires-GFP. Epasl: Cells transduced with AdApt Epasl -ires- GFP. Figure 5: Analysis of Platelet derived growth factor beta expression with Smartomics. In section A, thumbnail images of spots conesponding to the Platelet derived growth factor beta (PDGF Beta) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. Each strip of 6 images conesponds to a discrete array position or experiment, over the range of RNA samples. Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O2). Anay location: Identity of the spot as defined by Research Genetics. Clone: IMAGE identification. For this gene is noted that different IMAGE clones corresponding to the same gene are present. The histogram (section B) shows the average of the figures shown and enor bars are standard deviation. gfp: cells transduced with AdApt ires-GFP. Hif-la: Cells transduced with AdApt Hif-lα- ires-GFP. Epasl: Cells transduced with AdApt Epasl -ires-GFP.
Figure 6: Analysis of Monocyte Chemotactic Protein- 1 expression with Smartomics. In section A, thumbnail images of spots corresponding to the Monocyte Chemotactic Protein- 1 (MCP-1) gene are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. Each strip of 6 images conesponds to a separate experiment, over the range of RNA samples. Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O2). Anay location: Identity of the spot as defined by Research Genetics. Clone: IMAGE identification. The histogram (section B) shows the average of the figures shown and error bars are standard deviation, gfp: cells transduced with AdApt ires-GFP. Hif-la: Cells transduced with AdApt Hif-lα-ires-GFP. Epasl: Cells transduced with AdApt Epasl -ires-GFP. Figure 7: Discovery of a novel gene (EST acc:N64734 (LMAGE:293336)) using Smartomics. In section A, thumbnail images of spots conesponding to the EST from UniGene cluster EST acc:N64734 (IMAGE:293336) are shown. Contrast levels were set at a level to allow optimal visualisation of this gene, but are at a constant setting throughout this figure. For this gene, contrast levels are at maximum. Each strip of 6 images conesponds to a separate experiment, over the range of RNA samples. Figures beneath individual spot images are ratios of the normalised intensity of that spot compared to the reference condition (gfp; 20%O2). Anay location: Identity of the spot as defined by Research Genetics. Clone: IMAGE identification. The histogram (section B) shows the average of the figures shown and enor bars are standard deviation, gfp: cells transduced with AdApt ires-GFP. Hif-la: Cells transduced with AdApt Hif-lα-ires-GFP. Epasl: Cells transduced with AdApt Epasl -ires-GFP.
Figure 8: Virtual Northern blot hybridisation to validate discovery of EST acc:N64734 (IMAGE:293336) by Smartomics. A) Hybridisation probe = IMAGE clone 1674154 (ace: AI051607) which conesponds to the same gene as EST acc:N64734. B) Hybridisation probe = β actin. Lanes 1-6 are the RNA samples used in Figures 3-7, from cells transduced with adenovirus. Lanes 7-10 are from non-transduced macrophages with (lanes 9,10) or without (lanes 7,8) prior activation. Histograms show relative mRNA expression levels, from phosphorimager analysis, relating to the Northern blots positioned above. Figures are relative expression ratios compared to gfp (20% O2).
EXAMPLES
Example 1: The use of Smartomics for the identification of hypoxia-regulated genes in macrophages
The introduction of foreign gene sequences (i.e. HIF-lα or EPASl) to primary macrophages may be achieved by recombinant adenovirus. A commercially available system was used herein to produce adenoviral particles involving the adenoviral transfer vector AdApt, the adenoviral genome plasmid AdEasy and the packaging cell line Per-c6 (Introgene, Leiden, The Netherlands). The standard manufacturer's instructions were followed.
Three derivatives of the AdApt transfer vector have been prepared, named AdApt ires- GFP, AdApt HLF-lα-ires-GFP and AdApt EPASl -ires-GFP. In these vectors, for convenience, AdApt was modified such that inserted genes (i.e. HIF-1 α or EPASl) expressed from the powerful cytomegalovirus (CMV) promoter were linked to the green fluorescent protein (gfp) marker, by virtue of an internal ribosome entry site (ires). Therefore presence of green fluorescence provides a convenient indicator of viral expression of HIF- 1 α or EPAS 1 in transduced mammalian cells.
Standard molecular biology methods were used to construct the derivatives of AdApt, which included reverse transcriptase PCR (RT-PCR), transfer of DNA fragments between plasmids by restriction digestion, agarose gel DNA fragment separation, "end repairing" double stranded DNA fragments with overhanging ends to produce flush blunt ends, and DNA ligation. Subcloning steps were confirmed by DNA sequencing. These techniques are well known in the art, but reference may be made in particular to Sambrook et al, Molecular Cloning, A Laboratory Manual (2000) and Ausubel et al, Short Protocols in Molecular Biology (1999) 4th Ed, John Wiley & Sons, Inc.
Briefly, AdApt ires-GFP was made by inserting the encephalomyocarditis virus EMCV ires followed by the green fluorescent protein gene (GFP), into the end-repaired Hpal restriction site of AdApt, immediately downstream of and in the same orientation as the CMV promoter. Both EMCV ires and gfp sequences are widely used and can be obtained from commonly available plasmids. SEQ ID NO:A recites the exact nucleotide sequence of the joined ires-GFP which was inserted into the AdApt plasmid.
The plasmid AdApt HIF-1 α-ires-GFP was derived from AdApt ires-GFP by inserting the protein coding sequence of human HIF-lα between the CMV promoter and the ires-GFP elements of AdApt ires-GFP. To do this, human HLF-lα cDNA was cloned by RT-PCR from human mRNA, and the sequence was verified by comparison to the published HIF- lα cDNA nucleotide sequence (Genbank accession U22431). The HEF-lα sequence was ligated as an end-repaired fragment into the end-repaired Agel restriction site of AdApt ires-GFP [this is also the Agel restriction site of the parental vector AdApt immediately downstream of the CMV promoter]. The exact DNA sequence containing HLF-lα that was inserted into AdApt ires-GFP is shown in SEQ ID NO: B.
The plasmid AdApt EPAS 1-ires-GFP was derived from AdApt ires-GFP by inserting the protein coding sequence of human EPAS 1 between the CMV promoter and the ires-GFP elements of AdApt ires-GFP. To do this, human EPASl cDNA was cloned by reverse transcriptase PCR (RT-PCR) from human mRNA, and the sequence was verified by comparison to the published EPASl cDNA nucleotide sequence (GenBank accession U81984). The EPASl sequence was ligated as an end-repaired fragment into the end- repaired Agel restriction site of AdApt ires-GFP [this is also the Agel restriction site of the parental vector AdApt immediately downstream of the CMV promoter]. The exact DNA sequence containing EPAS 1 which was inserted into AdApt ires-GFP is shown in SEQ LD NO:C
The adenoviral transfer vectors AdApt HIF-1 α-ires-GFP and AdApt EPASl -ires-GFP, were verified prior to production of adenoviral particles, for their ability to drive expression of functionally active HIF-1 α or EPASl protein from the CMV promoter in mammalian cells. This was achieved by transient transfection luciferase-reporter assays as described (Boast K, Binley K, Iqball S, Price T, Spearman H, Kingsman S, Kingsman A, Naylor S. Hum Gene Ther. 1999 Sep l;10(13):2197-208. "Characterisation of physiologically regulated vectors for the treatment of ischemic disease.").
Using the aforementioned Introgene adenoviral system, caesium-banded, pure adenoviral particles were produced for each of the vectors AdApt ires-GFP, AdApt HIF-1 α-ires-GFP and AdApt EPASl -ires-GFP. Following the Introgene manual, adenoviral preparations were quantitated by spectrophotometry, yielding values of viral particles (VP) per milliliter.
To isolate human macrophage, monocytes were derived from peripheral blood of healthy human donors. 100ml bags of buffy coat from the Bristol Blood Transfusion Centre (Bristol, UK) were mixed with an equal volume of RPMI1640 medium (Sigma). This was layered on top of 10ml ficol-paque (Pharmacia) in 50ml centrifuge tubes and centrifuged for 25 min at 800 x g. The interphase layer was removed, washed in MACS buffer (phosphate buffered saline pH 7.2, 0.5% bovine serum albumin, 2mM EDTA) and resuspended at 80 microliter per 10n7 cells. To this, 20 microliter CD 14 Microbeads (Miltenyi Biotec) were added, and the tube incubated at 4 degrees for 15 min. Following this, one wash was performed in MACS buffer at 400 x g and the cells were resuspended in 3 ml MACS buffer and separated on an LS+ MACS Separation Column (Miltenyi Biotec) positioned on a midi-MACS magnet (Miltenyi Biotec). The column was washed with 3 x 3ml MACS buffer. The column was removed from the magnet and cells were eluted in 5 ml MACS buffer using a syringe. Cells were washed in culture medium (AIM V (Sigma) supplemented with 2% human AB serum (Sigma), and resuspended at 2 x 10n5 cells per ml in the same medium and placed in large teflon-coated culture bags (Sud-Laborbedarf GmbH, 82131 Gauting, Germany) and transfened to a tissue culture incubator (37 degrees, 5% CO2) for 7-10 days. During this period, monocytes spontaneously differentiate to macrophages. This is confirmed by examining cell morphology using phase contrast microscopy. Cells are removed from the bags by placing at 4 degrees for 30 min and emptying the contents.
The macrophages were washed and resuspended in DMEM (Gibco, Paisley, UK) supplemented with 4% fetal bovine serum (Sigma). 4xl06 cells were plated into individual 10cm Primeria (Falcon) tissue culture dishes in a total volume of 8 ml per plate, with 6x10° adenoviral particles per ml. Following culture for 16 hr, during which the macrophages adhere to the plate and are infected by the adenoviral particles, the medium is removed and replaced by AIM V medium supplemented with 2% human AB serum. A further 24 hr period of culture is allowed prior to experimentation, to allow gene expression from the transduced adenovirus.
The above dosage of adenoviral particles was determined to be the minimum amount required to achieve transduction of the majority (over 80%) of the macrophage population, using green fluorescence as a marker of gene transfer. This was confirmed using a separate adenoviral construct containing the LacZ reporter gene. By selecting the minimum dose of virus, possible non-specific effects of viral transfer are minimised.
For experimentation with hypoxia, identical culture dishes were divided into two separate incubators: One at 37 degrees, 5% CO2, 95% air (=Normoxia) and the other at 37 degrees, 5% CO2, 94.9% Nitrogen, 0.1% Oxygen (=Hypoxia). After 8 hours culture under these conditions, the dishes were removed from the incubator, placed on a chilled platform, washed in cold PBS and total RNA was extracted using RNazol B (Tel-Test, Ine; distributed by Biogenesis Ltd) following the manufacturer's instructions.
The design of this experiment was to obtain six populations of cells (referred to for simplicity as "cell types"), differing only in their treatment with adenovirus and/ or hypoxia, as shown below: 'Cell Type" Adenovirus Expressed gene Oxvεen condition l AdApt ires-GFP none Normoxia (20% Oxygen)
2 AdApt ires-GFP none Hypoxia (0.1% Oxygen) 3 AdApt HIF-1 α-ires-GFP HIF-1 α Normoxia (20% Oxygen) 4 AdApt HIF-1 α-ires-GFP HIF-1 α Hypoxia (0.1% Oxygen) 5 AdApt EPASl -ires-GFP EPAS l Normoxia (20% Oxygen) 6 AdApt EPASl -ires-GFP EPASl Hypoxia (0.1 % Oxygen)
Gene discovery can be implemented by comparing gene expression profiles between these "cell types". According to conventional methods available in the literature, one would make comparisons between cell types 2 and 1. By implementing the Smartomics method, several other possibilities are seen. Firstly, a comparison can be made between cell types 3 or 5 and cell type 1. Here, the stimulus of overexpressing key molecules involved in the hypoxia response may exceed the natural response the hypoxia, as seen for cell type 2. Secondly, in a prefened embodiment of the invention, a comparison can be made between cell types 4 or 6 and cell type 1. In this situation, the natural response to hypoxia is being augmented or boosted by overexpressing key molecules involved in the hypoxia response.
It should be noted that the experimental design illustrated above uses a control adenovirus in place of untreated cells. By doing this, any non-specific effects of viral transduction should occur equally throughout the analysis, and will disappear.
Although efficient adenoviral gene transfer was indicated by green fluorescence in the transduced macrophages, Northern blotting was used to absolutely confirm overexpression of HIF-lα and EPASl. RNA samples extracted from cell types 1-6 as described above were analysed by Northern blotting (Figure 1). The RNA samples (8ug total RNA per lane) were electrophoresed on a formaldehyde denaturing 1% agarose gel, then transferred to a nylon membrane (Hybond-N, Amersham, UK), and sequentially hybridised with 33P- labelled DNA probes complementary in nucleotide sequence to HIF-lα (Figure la), EPASl (Figure lb) or 28S ribosomal RNA (Figure lc). The methodology used for Northern blotting, probe hybridisation under stringent conditions, and removal of probes between hybridisations, is well known in the art. In Figure la, it can be seen that all lanes contain a faint band of approximately 4 kb, conesponding to the endogenous HIF-lα mRNA. In lanes 3,4, which contain RNA from cells transduced with AdApt HIF-1 α-ires-GFP, a much stronger band of a similar size is observed, indicating successful overexpression of HIF-1 α. In Figure lb, it can be seen that all lanes contain a very faint band of approximately 5 kb, conesponding to the endogenous EPASl mRNA. In lanes 5,6, which contain RNA from cells transduced with AdApt EPASl -ires-GFP, a much stronger band at approximately 4 kb is observed, indicating successful overexpression of EPAS 1. The difference in size of the endogenous and overexpressed EPAS 1 is due to the long untranslated region of the endogenous gene, which is of no consequence.
In Figure lc, it can be seen that 28S ribosomal RNA is detected in all lanes, indicating equal loading of RNA on the gel.
By phosphorimager quantitative analysis of Figures la and lb it is apparent that overexpression levels of both HIF-1 α and EPASl are approximately 80-fold over the endogenous levels. Adenoviral-directed mRNA overexpression of these genes is not further augmented by hypoxia. For example, in Figure la, the band intensity for lane 4 does not exceed that for lane 3. However at the protein and functional levels, hypoxia potentiates the action of the proteins encoded by these mRNAs (Semenza GL. Annu Rev Cell Dev Biol. 1999;15:551-78. "Regulation of mammalian O2 homeostasis by hypoxia- inducible factor 1").
Global mRNA expression profiles from the RNA samples isolated from the six "cell types" were obtained using Research Genetics Human GeneFilters Release 1 (GF200) (Research Genetics, Huntsville, AL). This method uses pre-made arrays of DNA complementary to 5,300 genes covering a range of levels of characterisation, including sequences which only match unannotated ESTs or cDNA sequences of unknown function.
The anays are nylon in composition, and are spotted with DNA derived from specific IMAGE consortium cDNA clones (http://image.llnl.gov/image/). The anays are hybridised to RNA samples which have been radioactively labelled with the isotope 33P to measure the abundance of individual genes within the RNA samples. Multiple RNA samples are labelled and hybridised in parallel to separate copies of the anay, and spot hybridisation signals are compared between the RNA samples. Key issues in anay-based mRNA expression analysis are sensitivity and reliability. Cunently two other methods are available; glass microanays and DNA chips, both of which utilise fluorescently labelled RNA (Bowtell DD. Nat Genet. 1999 Jan;21(l Suppl):25-32. "Options available—from start to finish—for obtaining expression data by microanay."). Although these methods are often believed to offer increased sensitivity over Nylon-based methods, this belief lacks definitive proof. To the contrary, a careful comparison of the three approaches shows that for similar amounts of unamplified RNA, the nylon-based radioactive method is superior (Bertucci F, Bernard K, Loriod B, Chang YC, Granjeaud S, Birnbaum D, Nguyen C, Peck K, Jordan BR. Hum Mol Genet. 1999 Sep;8(9): 1715-22. "Sensitivity issues in DNA array-based expression measurements and performance of nylon microanays for small samples."). The microanay and DNA chip methods require much larger amounts of RNA which are often not easily obtained from primary cells, or complicated amplification methods, which are liable to introduce enor.
To demonstrate the sensitivity of the anay-based gene expression method used in the cunent exemplification of Smartomics, a scatter plot of two representative RNA samples analysed in our laboratory using Research Genetics GeneFilters, demonstrates a range of detection approaching 4-logs (Figure 2). By comparison, arguably the most sophisticated anay-based method, the DNA chip, is quoted as having a range of detection of 3-logs (Affymetrix). Therefore, it is reasonable to assume that the improvements afforded by Smartomics regarding sensitivity issues, as illustrated by the cunent exemplification, could not easily be obtained by utilising an alternative array-based method. In any case, any potentially superior anay methodology could be further improved by utilising the Smartomics invention described here. RNA extracted from the 6 "cell types" as described above, was radioactively labelled and hybridised to separate copies of the Research Genetics Human GeneFilter GF200 (experiment #1). Methods provided by the manufacturer were followed (http://www.resgen.com/products/GF200_protocol.php3). Images of hybridised anays were obtained using a Molecular Dynamics Storm phosphorimager. RNA was then stripped from the arrays, following the aforementioned protocol.
To ensure reproducibility, this procedure was repeated with the same RNA samples (experiment #2). The entire data set was then imported and analysed using Research Genetics Pathways 3.0 software, as explained in the Pathways 3.0 manual. Key aspects of the cunent analysis are summarised below:
Project Tree set-up
"Condition Pairs" mode was used to simultaneously analyse multiple experiments. "Condition" means several arrays hybridised to similar RNA samples, derived from the same "cell type".
Condition "Cell Type" Adenovirus Oxygen Experiment #
1 1 AdApt ires-GFP Normoxia 1
1 1 AdApt ires-GFP Normoxia 2
2 2 AdApt ires-GFP Hypoxia 1
2 2 AdApt ires-GFP Hypoxia 2
3 3 AdApt HIF-1 α-ires-GFP Normoxia 1
3 3 AdApt HIF-1 α-ires-GFP Normoxia 2
4 4 AdApt HIF-1 α-ires-GFP Hypoxia 1
4 4 AdApt HIF-1 α-ires-GFP Hypoxia 2
5 5 AdApt EPASl -ires-GFP Normoxia 1
5 5 AdApt EPASl-ires-GFP Normoxia 2
6 6 AdApt EPASl-ires-GFP Hypoxia 1
6 6 AdApt EPASl-ires-GFP Hypoxia 2
Normalisation set-up
The "all data points" option and Y. Chen algorithm with default settings were selected, as explained in the Pathways 3.0 manual. The two experiments were treated as separate normalisation groups, such that global differences between hybridisation signals from different arrays from the same experiment were corrected.
Comparison analysis
Pair-wise comparisons were made between condition 2 and condition 1 condition 3 and condition 1 condition 4 and condition 1 condition 5 and condition 1 condition 6 and condition 1 In other words, pair- wise comparisons were made using condition 1 (i.e. cell type 1) as the reference condition. This conesponds to cells transduced with the control adenovirus AdApt ires-GFP and placed under normal oxygen concentration (normoxia). Comparisons are made in this way for all genes present on the Research Genetics GF200 array. By comparing conditions, the analysis considers data from both experiments #1 and #2.
Filter settings
Filtering was then done to select genes with expression ratios of above 2.0 for at least one of the five pair-wise comparisons detailed above. Genes with low signal intensities for all of the six conditions were automatically eliminated, using an Intensity II filter of min 0.2, max 1000. Genes that did not respond in a reproducible way in experiment #1 and #2, were automatically eliminated using the Students t-test filter (90% confidence level).
Results were output as expression profiles of individual genes, showing normalised signal intensity and expression ratio. A key advantage of analysis in Pathways 3.0 is that high magnification thumbnail images of individual spots are displayed. This allows visual verification that the area being measured truly covers the region containing the hybridised anay spot, and that the spot is real and not a background artefact.
Minor differences between quantitative data and conesponding thumbnail images are sometimes seen even though the sampled area is clearly the bona fide anay spot. For example, by eye there might seem to be a small difference between two spots, though the quantitative analysis might suggest a larger difference. It should be noted that thumbnail images are not normalised to compensate for global differences, and are limited in image quality. Greyscale images are inherently limited in their capacity to depict quantitative differences in intensity. Digital images generated by the Storm phosphorimager cover a linear dynamic range of 100,000 for a single pixel, whereas printed images can only be depicted as 256 shades of grey.
Results for three representative known hypoxia-regulated genes
As demonstration that overexpression of HIF-1 α or EPASl together with hypoxia exposure is superior to using non-transduced hypoxic cells, in terms of discovering bona fide hypoxia-regulated genes, results are shown for genes which are already known in the art to be regulated in hypoxia. Three genes have been selected which are represented as double spots on the Research Genetics GF200 array. Therefore, because the whole experiment was repeated, a total of four repeat comparisons are possible for these genes.
The lactate dehydrogenase A (LDH-A) gene is known in the art to be activated by hypoxia (Webster KA. Mol Cell Biochem. 1987 Sep;77(l): 19-28. "Regulation of glycolytic enzyme RNA transcriptional rates by oxygen availability in skeletal muscle cells."). In Figure 3, it can be seen that in response to hypoxia alone (gfp 0.1% O2) there is on average a 2.24-fold increase in mRNA expression compared to normoxia (gfp 20% O ).
By overexpressing HIF-lα there is on average a 3.39-fold increase in LDH-A expression, providing a significant improvement over the natural response (Figure 3; HIF-lα 20% O2). By utilising a prefened embodiment of the Smartomics method, and simultaneously overexpressing HIF-lα in the presence of hypoxia, the average response of LDH-A is elevated further to 4.50-fold (Figure 3; HIF-lα 0.1% O2).
In the prior art it has been established that HIF-lα is responsible for mediating the hypoxia-induced activation of LDH-A (Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Genes Dev. 1998 Jan 15;12(2): 149-62 "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha."). However it has never been envisaged or demonstrated that overexpression of HIF-lα in a stable manner using viral gene transfer techniques, both with or without simultaneous hypoxia, causes secondary changes in gene expression which are markedly greater than the natural hypoxia response. The response to hypoxia of LDH- A is also improved by overexpressing EPASl (Figure 3; EPASl), though this is less dramatic than overexpressing HIF-1 α .
Like LDH-A, the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene is known in the art to be activated by hypoxia (Webster KA. Mol Cell Biochem. 1987 Sep;77(l): 19-28. "Regulation of glycolytic enzyme RNA transcriptional rates by oxygen availability in skeletal muscle cells."). In Figure 4, it can be seen that in response to hypoxia alone (gfp 0.1% O2) there is on average a 1.52-fold increase in mRNA expression compared to normoxia. By overexpressing HIF-1 α there is on average a 3.33-fold increase in GAPDH expression, providing a significant improvement over the natural response (Figure 4; HLF-lα 20% O2). By utilising the full embodiment of the Smartomics method, and simultaneously overexpressing HIF-lα in the presence of hypoxia, the average response of GAPDH is elevated further to 4.57-fold (Figure 4; HLF-lα 0.1% O2).
In the published literature, it has been established that HIF-lα is responsible for mediating the hypoxia-induced activation of GAPDH (Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Genes Dev. 1998 Jan 15; 12(2): 149-62 "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha."). However in the art, it has never been envisaged or demonstrated that overexpression of HLF-lα in a stable manner using viral gene transfer techniques, both with or without simultaneous hypoxia, causes secondary changes in gene expression which are markedly greater than the natural hypoxia response.
For GAPDH, it can be seen that overexpression of EPASl (Figure 4; EPASl 20% O2 and 0.1% O2), has a significantly smaller effect than overexpressing HIF-1 α. This demonstrates a separate embodiment of the Smartomics method, whereby genes are identified which respond selectively or preferentially to overexpression of EPASl or HIF- lα.
Platelet derived growth factor beta (PDGF β) is also known in the art to be activated by hypoxia (Kourembanas S, Hannan RL, Faller DV. J Clin Invest. 1990 Aug;86(2):670-4 "Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells."). In Figure 5, it can be seen that in response to hypoxia alone (gfp 0.1% O2) there is on average a 2.14-fold increase in mRNA expression compared to normoxia.
By overexpressing EPASl, there is on average a 9.28-fold increase in PDGF β expression (Figure 5; EPASl 20% O2), providing a large improvement over the natural response. In this case, the combination of hypoxia and EPASl overexpression does not exceed the response of EPASl overexpression alone, indicating saturation of the dose-response (Figure 5; EPASl 0.1% O2).
From Figure 5, it is clear that there is a striking specificity in the response of PDGF β to
EPASl and HIF-1 α, in the opposite manner observed for GAPDH. Overexpression of HIF-1 α alone has no significant effect on PDGF β, whereas overexpression of EPASl produces large effects. This demonstrates a separate embodiment of the Smartomics method, whereby genes are identified which respond selectively or preferentially to overexpression of EPAS 1 or HIF-lα.
The gene encoding monocyte chemotactic protein 1 (MCP-1) is known in the art to respond to hypoxia in a negative fashion, by decreasing mRNA expression (Negus RP, Turner L, Burke F, Balkwill FR. J Leukoc Biol 1998 Jun;63(6):758-65. "Hypoxia down- regulates MCP-1 expression: implications for macrophage distribution in tumors"). In Figure 6 it can be seen that in response to hypoxia alone (gfp 0.1% O2) there is on average a 0.407-fold change (i.e. a 2.46 fold decrease) in mRNA expression compared to normoxia.
By overexpressing HIF-lα, there is on average a 0.243-fold change (i.e. a 4.11-fold decrease) in MCP-1 expression, providing a significant improvement over the natural response (Figure 6; HIF-lα 20% O2). By utilising a prefened embodiment of the Smartomics method, and simultaneously overexpressing HIF-lα in the presence of hypoxia, the average response of MCP-1 is further improved to a 0.112-fold change (i.e. an 8.93-fold decrease) (Figure 6; HIF-lα 0.1% O2). Even more pronounced improvements in the hypoxia-induced inhibition of MCP-1 expression are obtained by overexpressing EPASl (Figure 6; EPASl 20% O2 and 0.1% O2). This demonstrates a use of Smartomics to improve the discovery of genes that are inhibited or repressed by disease signals.
The finding that overexpressing HIF-lα or EPASl potentiates hypoxia-induced gene repression, as exemplified by MCP-1, is totally without precedent in this field. The structure of both HIF-1 α and EPASl proteins is that they contain transactivation domains but not known transcriptional repressor domains (Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. J Biol Chem. 1997 Apr 25;272(17): 11205-14. "Activation of hypoxia-inducible factor- 1; definition of regulatory domains within the alpha subunit.").
In the above section, it is shown that by focusing on genes known in the art to be regulated in hypoxia, and showing how the Smartomics method can significantly enhance the response, an argument is provided that Smartomics would provide an improved method for the identification of novel bona fide hypoxia-regulated genes. Figure 7 shows the expression profile of a gene discovered using the described method, conesponding to an EST not previously known to be induced by hypoxia (GenBank accession N64734; IMAGE clone 293336). Thumbnail array spot images are shown at maximal contrast, such that the background signal is apparent. It can be seen that in response to hypoxia alone (gfp 0.1% O2) there is on average a 1.4-fold increase in mRNA expression compared to normoxia. However, this is not significant, because it is derived from widely different ratios from individual experiments (2.41 and 0.46). From the thumbnail images for gfp 20% O and gfp 0.1% O2 it is evident that expression of the genes under these conditions is below the detection threshold of the array-based method. However, when the Smartomics invention is used, and EPAS 1 is overexpressed using viral gene transfer methods, a clearly detectable response in seen, with induction ratios of over 8-fold (Figure 7; EPASl 20% O2 or 0.1% O2). The expression profile in Figure 7 also demonstrates a separate embodiment of Smartomics, for the identification of genes which respond selectively to HIF-lα or EPASl. To confirm the results presented in Figure 7, a more sensitive method was used to study expression of the gene corresponding to EST acc:N64734 (LMAGE:293336), namely virtual Northern blotting. It should be noted that this method would not have been suitable for the original discovery that EST acc:N64734 (LMAGE:293336) is induced by hypoxia, because virtual Northern blotting and similar methods do not allow simultaneous screening of large numbers of genes. The technique is similar to conventional Northern blotting, with the exception that double stranded cDNA conesponding to the mRNA population of expressed genes is resolved by electrophoresis and blotted onto a nylon membrane. It relies on a method of cDNA synthesis which produces full length cDNA molecules, which is commercially available (SMART PCR cDNA Synthesis Kit; Clontech Laboratories Ine, Palo Alto, CA, USA).
The method for virtual Northern blotting was followed as described in the instruction manual for the SMART PCR cDNA Synthesis Kit. Briefly, 600ng cDNA was synthesised from the six RNA samples used for array hybridisation. An additional four RNA samples were also processed, derived from non-transduced macrophages cultured in normoxia and hypoxia (6 hours at 0.1% O2) both with and without pre-treatment for 16 hours with 100 ng/ml Lipopolysaccharide (E.coli 026:B6 Sigma, UK) and 1000 u/ml human gamma interferon (Sigma, UK). This combination of factors causes macrophage activation, a process key to the physiological and pathophysiological actions of the macrophage. All 10 cDNA samples were resolved on an agarose gel, and alkali transfer onto Hybond N+ membrane (AmershamPharmacia, UK) was carried out according to the Hybond N+ instructions. Stringent hybridisations with 33P-labelled cloned cDNA probes were performed as for standard Northern blot hybridisation, which is well known in the art. cDNA probes were radiolabelled using a commercially available kit (Prime-a-Gene, Promega, UK). The virtual Northern blot was hybridised first with the cDNA insert of IMAGE clone 1674154 (ace: AI051607), which corresponds to the same gene as EST acc:N64734 (IMAGE:293336) (Figure 8a). The blot was then stripped, by a high temperature / low salt wash, and was re-probed with the protein coding region of the human β-actin gene (Figure 8b).
From Figure 8a, it can be seen that the mRNA corresponding to EST acc:N64734 (IMAGE:293336) is detected as a doublet band of approximately 4.5 kb. This gene is strongly induced by adenoviral-directed overexpression of EPAS 1 (lanes 5,6), consistent with the anay data from Figure 7. The higher induction ratios in this non-anay analysis are due to increased sensitivity afforded by the virtual Northern technique. Unlike the anay data, expression of EST acc:N64734 (IMAGE:293336) is within the range of detection for all RNA samples. Importantly, hypoxia alone is seen to cause an induction ratio of approximately 60-fold (Figure 8a; lanes 2, 8). Therefore EST acc:N64734 (IMAGE:293336) is identified as a bone fide hypoxia-regulated gene, despite being beneath the detection level of an anay screen in the absence of the Smartomics method used herein.
The results in Figure 8a also demonstrate a separate embodiment of the Smartomics method, whereby genes are identified which respond selectively or preferentially to overexpression of EPASl or HIF-lα. Overexpression of HIF-1 α causes an induction ratio of 18.9-fold (lane 3), whereas overexpression of EPASl causes a much larger induction ratio of 141 -fold (lane 5).
In Figure 8b expression of the human β-actin gene is found to be roughly constant throughout this experiment, consistent with the differences in Figure 8a being due to specific changes in gene expression. The data presented above, elaborates in detail how viral-mediated overexpression of key regulators of the hypoxia response (HIF and EPAS), presents an improvement compared to the conventional strategy, whereby cells are exposed only to the natural environmental stimulus, i.e. hypoxia. This same methodology, using the same adenoviral constructs and anay screening methodology, has been applied to screen the full series of Research Genetics Human GeneFilters (GF200, GF201, GF202, GF203, GF204, GF205, GF206, GF207, GF208). The genes identified in this way are presented in tables 1 and 2. For each case, in previous undisclosed work where comparisons were made between normoxia and hypoxia in cells without viral overexpression of HIF or EPAS, these genes were not clearly defined as being responsive to hypoxia using the described methodology. In some cases, as shown in Figures 7 and 8, this was a sensitivity issue of the array methodology, in that no appreciable signal could be detectable in hypoxic cells unless additional HIF or EPAS were provided by viral transduction.
It is expected that the genes that are identified in Tables 1 and 2 are bona fide hypoxia- responsive genes, and will have utility based on this predicted activity. Using anay-based methods, they would not be detected unless additional HIF or EPAS were to be provided by viral transduction. Additionally, mere viral-mediated overexpression of HIF and EPAS (without exposure to hypoxia) will yield genes that are regulated by these transcription factors which are not part of the natural hypoxia response, but have utility based on other functions of HIF and EPAS. Indeed, in the art it is well established that HIF-lα may be induced by stimuli other than hypoxia, which are pertinent to human disease, including thrombin (Gorlach A. et al; Circ Res. 89:47-54), nitric oxide (Palmer LA. et al; Mol Pharmacol. 58:1197-203), Angiotensin II, platelet-derived growth factor, and other hormones (Richard DE et al; J Biol Chem. 275:26765-71). Additionally HLF-lα is frequently activated in human cancer cells in the absence of hypoxia (Wiesener MS et al; Cancer Res. 61:5215-22). In Tables 1 and 2, expression data is presented for genes identified by the procedure mentioned above. Adenoviral overexpression of HIF-lα was always done in combination with exposing cells with hypoxia to obtain the maximum dose of this transcription factor. For adenoviral overexpression of EPAS, as demonstrated in Figures 3-7, a maximal dose of this transcription factor does not require simultaneous exposure to hypoxia.
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Legend to Table 1
Columnl (IMAGE clone Accession) denotes the GenBank EST accession number of the IMAGE clone represented on the gene array. Column 2 (title) denotes the name commonly associated with the gene. Column 3 (Nucl Seq ID) denotes the patent identification number of the nucleotide sequence. Column 4 (Nucleotide Accession) refers to the longest nucleotide sequence corresponding to the IMAGE clone as determined by standard bioinformatics procedures. Column 5 (Prot Seq ID) denotes the patent identification number of the protein sequence. Column 6 (Protein Accession) refers to the GenBank accession number of the protein sequence as determined by standard bioinformatics procedures. Columns 7-10 describe expression ratios, obtained by comparing mRNA expression levels under the named condition to that where cells were transduced with an equal dose of control adenovirus under normoxia. In columns 7,9 adenoviral overexpression of HIF-1 α and EPASl is further supplemented by exposure to hypoxia. In column 8, adenoviral overexpression of EPAS 1 is not supplemented by hypoxia, which is unnecessary.
Table 2. Genes down-regulated in response to adenoviral expression of HIF-lαor EPASl
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Legend to Table 2
Column 1 (IMAGE clone Accession) denotes the GenBank EST accession number of the IMAGE clone represented on the gene array Column 2 (title) denotes the name commonly associated with the gene Column 3 (Nucl Seq ID) denotes the patent identification number of the nucleotide sequence Column 4 (Nucleotide Accession) refers to the longest nucleotide sequence corresponding to the IMAGE clone as determined by standard bioinformatics procedures Column 5 (Prot Seq ID) denotes the patent identification number of the protein sequence Column 6 (Protein Accession) refers to the GenBank accession number of the protein sequence as determined by standard bioinformatics procedures. Columns 7-10 describe expression ratios, obtained by comparing mRNA expression levels under the named condition to that where cells were transduced with an equal dose of control adenovirus under normoxia. In columns 7,9 adenoviral overexpression of HIF-lα and EPASl is further supplemented by exposure to hypoxia. In column 8, adenoviral overexpression of EPASl is not supplemented by hypoxia, which is unnecessary.
Example 2 Preparation of the custom gene array
To confirm the findings presented in Example 1, and to obtain more accurate and additional were fabricated into an independently produced and verified gene array (referred to herein as the "custom gene array"), composed of PCR-amplified insert DNA. The methods used to produce this array are common in the art, but the key points are summarised below.
IMAGE clones were obtained from the UK MRC HGMP Resource Centre (Hinxton, Cambridge CB10 1SB, UK) and were re-isolated as individual colonies and sequenced to verify the correct identity of the clone. In the majority of cases, the same IMAGE clone identified from the Research Genetics Human GeneFilters was selected, but in some instances these clones were not available and alternatives were selected, corresponding to the same gene.
Additional genes, with well-defined roles in various disease processes relevant to hypoxia, were also represented on the array, as derived from IMAGE clones. It is well established in the literature that genes with similar functions are often co-regulated at the mRNA level, as determined by microarray data clustering methods (Iyer VR et al, Science. 1999 283(5398):83-7; Eisen MB et al Proc Natl Acad Sci U S A. 1998 95(25): 14863-8). This allows associations to be made between genes of unknown function (as present in the current specification) to genes of well defined function, in order to add significance to the former.
Normalisation is a key issue in array analysis. The custom gene array is a single colour type array, and contains a selection of additional IMAGE clones corresponding to genes which were empirically determined not to be affected by hypoxia and which are highly expressed in a wide range of human tissues and cell types. During data analysis, spot intensities were divided by the mean of all the reference genes shown below, each of which was present in quadruplicate on each array.
Figure imgf000101_0001
IMAGE clone plasmid miniprep DNA was prepared and PCR amplified with flanking vector primers of the sequences GTTTTCCCAGTCACGACGTTG and TGAGCGGATAACAATTTCACACAG. This was then purified and concentrated by ethanol precipitation, and the presence of a single band and DNA concentration were determined by agarose gel electrophoresis and by digital imaging methods.
Purified PCR product was normalised to 0.5 mg/ ml by dilution. Arrays were fabricated onto Hybond N+ (Amersham) membranes using a BioRobotics TAS arrayer (Biorobotics, Cambridge CB37LW, UK) with a 500 micron pin tool. Using 384-well source plates and a 2x2 arraying format this array was relatively low density, thereby eliminating problems of spot-to-spot signal bleed. Also the large pin size and high source plate DNA concentration improves the sensitivity of detection. Post-arraying denaturation/ neutralisation was essentially as described by Bertucci F et al., 1999 (Oncogene 18: 3905-3912). Total RNA was extracted from cells using RNeasy® (Qiagen) and 7 micrograms RNA was labelled with 100 microCi 33P dCTP using 2 micrograms poly dT (10-20 mer) as primer in a reverse transcription reaction. First strand RNA was then degraded under alkaline contitions, and this was then neutralised with Tris HC1 pH 8.0, and the labelled cDNA was purified using BioRad BioSpin-6 chromatography columns. Pre-hybridisation was performed in 4 ml Research Genetics MicroHyb solution supplemented with lOmicrograms poly dA (10-20 mer) and 10 micrograms Cot-1 DNA, at 45 degrees for 2-3 hours. The cDNA was then denatured by heating and added to the pre-hybridisation, which was continued for 18-20hr. Washing steps were done as follows: 2xSSC/ 1% SDS 2x20min at 50 degrees and 0.5xSSC/ 1% SDS lOmin at 55 degrees. Arrays were exposed to Amersham Low Energy phosphor screens for 24hr and scanned using a phosphorimager at 50 micron resolution. Image analysis was done using ArrayVision software (Imaging Research Ine). Tab delimited data files were exported and a full analysis performed using GeneSpring software (Silicon Genetics).
Using the described methodology a dynamic range of detection of 4 logs and a sensitivity of at least 1 / 50,000 is obtained, as determined by spike doping titration experiments. Having several technical differences eompared to the Research Genetics Human GeneFilters, as used in Example 1, data from the custom gene array is expected to be quantitatively different. Moreover, the increased sensitivity offered by this optimised array has allowed a proportion of the genes identified as hypoxia regulated by amplifying the response with recombinant adenoviruses, to be validated as hypoxia-induced / repressed genes in the natural state. Other genes, identified in Example 1, still require amplification to detect their hypoxic regulation, showing that a sensitivity exceeding that of both Research Genetics GeneFilters and the custom gene array is required.
Example 3 Tissue-specific hypoxia regulation of gene expression by an analysis of a series of primary human cell cultures
Equivalent cultures of non-immortalised, non-transformed primary human cells of 10 distinct types, were cultured in either normoxia or were exposed to hypoxia for 6 hr and 18 hr, and gene expression changes were determined. Unlike the vast majority of information in the public domain relating to genes responsive to hypoxia, all of these cells were human and were cultured without any modifications following isolation from the human donors. By using primary cells rather than cell lines or immortalised cultures, the findings shown here more accurately represents the situation in the human body.
Most cell types were obtained from Clonetics (distributed by BioWhittaker, Walkersville, MD) and cultured according to the manufacturer's recommendations, unless where otherwise shown. A total of 11 cell types were compared. These were: #l:adipocyte
(Clonetics CC-2568; derived from subcutaneous adult adipose tissue), #2:cardiomyocyte (Clonetics CC-2582; derived from fetal tissue; prior to experimentation cultured in minimal medium: DMEM, 4% Horse serum), #3:endothelial (TCS CellWorks ZHC-2101 human umbilical vein endothelial cells), #4:fibroblast (Clonetics CC-2511 dermal fibroblasts derived from adult tissue), #5:hepatocyte (Clonetics CC-2591, derived from adult tissue), #6:macrophage (derived from human blood as described elsewhere in the specification), #7:mammary epithelial (Clonetics CC-2551 ; derived from adult tissue), #8:monocyte (derived from human blood as described elsewhere in the specification but without the 7 day differentiation culture period), #9: neuroblastoma (neuroblastoma-derived cell line SH-SY5Y), #10:renal epithelial (Clonetics CC-2556; derived from fetal tissue) and #l l:skeletal muscle myocyte (Clonetics CC-2561; derived from adult tissue). A non- primary cell type (#9) was used to represent neurons, since primary human neurons are difficult to source. It should be noted that RNA from hepatocytes at the 16hr timepoint of hypoxia was not available for this work.
Genes which were induced or repressed preferentially in particular cell type(s) were identified by hybridisation of the RNA samples to the custom gene array, as described previously. Each RNA sample was hybridised to duplicate or triplicate arrays, to ensure reproducible data, and was analysed using GeneSpring software. Data from replicate arrays were merged during analysis to generate mean values. Data normalisation was achieved per-array using the aforementioned list of control genes, such that differences in RNA labelling or hybridisation due to experimental variation were corrected by referencing each gene to the mean value of the reference genes on the same array. Also, for each gene, expression values were obtained which represent the value in each experimental condition
(e.g. macrophages 6hr hypoxia) as compared to the median of value of that gene throughout the full range of experimental conditions (i.e. from all cell types). This transformation does not alter the relative values of any gene between the different experimental conditions, and is done since these is no obvious single reference experimental condition to create ratio values. This is common in microarray data analysis.
From this analysis it is apparent that certain genes respond to hypoxia differently, depending on the particular cell type. This is contrary to the prevailing prejudice in the art that the response to hypoxia is largely generic, occurring equally in different cell types. The information obtained is valuable in identifying biological targets for the development of therapeutic and diagnostic products. Not only does it indicate a particularly significant role for these genes in the specific cell type implicated in a disease, but it also identifies that any therapeutic product is less likely to produce problematic toxicological effects. It will be appreciated that the initial discovery of these genes as being responsive to hypoxia was done in macrophages and with an amplified response achieved by adenoviral overexpression of transcription factors HIFl and HLF2 (see Example 1). Here, it is shown that by studying the responses in other primary cell types without adenoviral overexpression to amplify the hypoxia response, that for certain genes significantly greater responses are seen in these other cell types, and this may extend the utility of the original findings in macrophages. Data shown below and are an accurate determination of mRNA expression levels. This may be confirmed by independent means, such as quantitative real time RT-PCR.
Tables are presented below containing quantitative data regarding the expression of certain genes found to be induced in response to hyopxia preferentially in certain cell types. As explained above, the expression values contained in these tables represent the ratio of the expression in cell types compared to the median value of that gene throughout all cell types and oxygen conditions. For instance, in this analysis a normalised expression value of 0.5 therefore represents 2-fold underexpression and a normalised expression value of 0.333 therefore represents 3-fold underexpression compared to the median level.
Genes with a greater response in primary monocytes or macrophages Since monocytes and macrophages are similar cell types, the latter derived from the former, they will be analysed together. The following genes were observed to be induced preferentially in monocytes/ macrophages, illustrating specific utility in the diagnosis and treatment of diseases involving the hypoxic macrophage as detailed in Example 1:
Figure imgf000104_0001
Figure imgf000105_0001
Expression data generated from the custom gene array for these genes in the aforementioned 11 cell types in normoxia or various periods of hypoxia are presented in the following tables. It will be appreciated from this data that the values for normalised expression are highest in hypoxic monocytes and/ or macrophages.
beta-Fc-gamma receptor II. (Sen ID: 59/60) Clone:plN2
Figure imgf000106_0001
FL.T13771 fis. clone PLACE4000270 (Seo ID: 267/268) Clone:p2H3
Figure imgf000107_0001
Spleen tyrosine kinase (Seα ID: 213/214) Clone:plN15
Figure imgf000108_0001
L-arginine:elvcine amidinotransferase (Seo ID: 73/74) Clone:plM10
Figure imgf000109_0001
IRCl (Sea ID: 135/136) Clone:p2H16
Figure imgf000110_0001
NK cell receptor CSl (Seα ID: 103/104) Clone:p2L12
Figure imgf000111_0001
Figure imgf000112_0001
Hexokinase 3 (white cell) (Seq ID: 443/444) Clone:p2K16
Basement membrane-induced gene (Seα ID: 401/402) Clone:p2A4
Figure imgf000114_0001
matrix metalloproteinase 7 (Seα ID: 93/94) Clone:plL17
Figure imgf000115_0001
It will be appreciated that these genes induced by hypoxia preferentially in monocytes and macrophages, have known or suspected roles in immune processes. This discovery therefore illuminates specific immune responses of the macrophage which occur in regions of hypoxia, including in the rheumatoid arthritis synovium, in atherosclerotic plaques and in the lung of chronic occlusive pulmonary disease patients. These responses are unlikely to be discovered by screening for hypoxia inducible genes in non-monocyte / non- macrophage cell types.
In particular it will be appreciated that two of the above genes encode known or suspected Fc receptors which transduce inhibitory signals. Beta-Fc-gamma receptor II (SeqTD:- 59/60) encodes a well known receptor relevant to rheumatoid arthritis (Blom A.B. et al Arthritis Res 2000, 2:489-503) and the current clinical treatment of human inflamatory conditions (Samuelson A. et al Science 2001, 291:484-486). Secondly, IRCl (also known as CMRF-35H or CMRF-35-H9; Seq D:-135/136) encodes a protein of unknown biological function which has sequence homologies to Fc receptors of the IgA and IgM classes, and contains sequence motifs known as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) raising the possibility that it has a novel function analagous to Beta-Fc- gamma receptor II (Clark G.J. et al Tissue Antigens 2000, 55:101-109). Thsee data present a novel finding that since this gene is induced in hypoxic macrophages, it is likely to be significant to the inflammatory functions of this cell type in pathology. Moreover we demonstrate elsewhere in this specification that the gene expression of the gene IRCl in response to a variety of stimuli is suggestive of an anti-inflammarory function. In other words, the gene is induced in response to anti-inflammatory stimuli and is suppressed in response to pro-inflammatory stimuli. This data provides concrete support for an anti- inflammatory function of IRCl in the hypoxic macrophage in human pathology. This finding has utility in the design of therapeutic products, including therapeutic antibodies, small molecule inhibitors and other agonists or antagonists, for the treatment of inflammatory disorders involving the macrophage.
Genes with a greater response in primary endothelial cells Some genes, were found to be preferentially induced by hypoxia in endothelial cells, a cell type key to the process of angiogenesis. These genes, as listed below, are therefore identified as targets for angiogenesis-based therapies.
Figure imgf000117_0001
Expression data generated from the custom gene array for these genes in the aforementioned 11 cell types in normoxia or various periods of hypoxia is presented in the following tables. It will be appreciated from this data that the values for normalised expression are highest in hypoxic endothelial cell.
FL.I22690 fis. clone HSI11134. (Seα ID: 529/530) Clone:n2.I21
Figure imgf000118_0001
FL.I11110 fis. clone PLACE1005921. (Seα ID: 525/526) Clone:pZI4
Figure imgf000119_0001
Genes with a greater response in primary hepatocytes
A specific subset of genes (see below), were found to be preferentially induced by hypoxia in hepatocytes, a cell type of the liver and relavant to the treatment of hepatic disorders involving ischaemia.
Figure imgf000120_0001
Expression data generated from the custom gene array for these genes in the aforementioned 11 cell types in normoxia or various periods of hypoxia is presented in the following tables. It will be appreciated from this data that the values for normalised expression are highest in hypoxic hepatocytes.
Adrenergic. alpha-IB-, receptor (Sen ID: 395/396) Clone:p2.113
Figure imgf000121_0001
Hermanskv-Pudlak syndrome tvne-3 protein (Seα ID: 235/236) Clone:p2H2
Figure imgf000122_0001
Ceruloplasmin (Seα ID: 39/40) ClonernlNlO
Figure imgf000123_0001
Inter-alpha (globulin) inhibitor. H2 polypeptide (Seα ID: 95/96) Clone:plL3
Figure imgf000124_0001
Heat shock 70kD protein-like 1 (Seq ID: 83/84) Clone:plN3
Figure imgf000125_0001
heat-shock protein 40 (Seα ID: 79/80) Clone:plL2
Figure imgf000126_0001
Genes with a greater response in primary myocytes
The responses of two myocyte cell types to hypoxia was determined using the custom array. The response of skeletal muscle myocytes to hypoxia is of particular interest to the treatment of peripheral arterial disease and the response of cardiomyocytes to hypoxia is of particular interest to the treatment of cardiac ischaemia. Genes which respond to hypoxia in both these cell types may encode natural protective factors which may be utilised in the design of new therapies, and are listed below.
Figure imgf000127_0001
Expression data generated from the custom gene array for these genes in the aforementioned 11 cell types in normoxia or various periods of hypoxia is presented in the following tables. It will be appreciated from this data that the values for normalised expression are highest in hypoxic myocytes.
c21orf7 (Seα ID: 5/6) Clone:p2H10
Figure imgf000128_0001
Procollaeen-lvsine.2-oxoglutarate 5-dioxygenase 2 (Seα ID: 167/168) Clone:plM6
Figure imgf000129_0001
Genes with a greater response in primary epithelial cells
The responses to hypoxia of primary epithelial cells derived from mammary and renal tissues was determined using the custom array. The response of epithelial cell types to hypoxia is of particular interest because normal tissue homeostatsis is maintained in several key organs by a balance of gene products at the epithelial: stromal interface involving receptoπligand, celhmatrix (basement membrane), and other interactions. Disruption of this homeostasis, as may occur in response to hypoxia, leading to inappropriate reawakening of developemental remodelling processes may be a contributing factor in several pathologies including the processes of neoplasia and tumorigenesis.
The following genes were observed to be induced preferentially in mammary and / or renal epithelial cells.
Figure imgf000130_0001
Expression data generated from the custom gene array for these genes in the aforementioned 11 cell types in normoxia or various periods of hypoxia is presented in the following tables. It will be appreciated from this data that the values for normalised expression are highest in hypoxic epithelial cell types.
Figure imgf000131_0001
Hypothetical protein FI ,123306 (SeαID:63/64 and 255/256) Clone:plK21
Figure imgf000132_0001
creatine transporter (SeαID:195/196) Clone:p2C10
Figure imgf000133_0001
heat-shock protein 40 (SeαID:79/80) Clone:plL2
Figure imgf000134_0001
MDS019 (SeαID:475/476) Clone:p2E12
Figure imgf000135_0001
adrenomedullin (SeαID:13/14) Clone:p2H9
Figure imgf000136_0001
phorbolin-l-related protein (SeαID:383/384) Clone;p2K24
Figure imgf000137_0001
an iopoietin-like protein PP1158 (SeqID:21/22) Clone:plL15
Figure imgf000138_0001
spermatid nerinuclear RNA-binding protein (SeqID:199/200) Clone:nlM5
Figure imgf000139_0001
Example 4: Effects on gene expression when cells are treated with cytokines and/or other molecules
In order to further functionally annotate the genes contained in this specification experiments were performed to study their expression profiles in macrophages in response to cytokine factors. Cytokines are key mediators of inflammatory responses, so genes which change in expression in response to a particular cytokine may be implicated in the action of that cytokine. Furthermore those genes are implicated in disease processes involving the cytokines to which they respond. Tables are presented below showing this data, with quantitative data for the induction ratio compared to untreated cells, as determined using the custom gene array. In the final column of these tables "induction ratio" represents the fold change, compared to untreated cells. Negative values represent gene suppression, also known as under-expression or down-regulation. For example an induction ration of -2.0 represents a two-fold decrease in expression and an induction ration of -3.0 represents a three-fold decrease in expression. This differs from the type of calculation presented in example 3, in which down-regulation is expressed as a fraction (for example in example 3; 0.5 represents a two-fold decrease in expression and 0.333 represents a three-fold decrease in expression). Essentially these data are similar in type, but are presented differently for clarity.
Tumor necrosis factor alpha
Tumor necrosis factor alpha (TNF alpha) is a key cytokine implicated in a wide range of infectious, auto-immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, severe bacterial infection, septic shock, cerebral malaria, transplant rejection, allergic encephalomyelitis, cancer, gestational diabetes (GDM), insulin resistance syndrome, adult-onset diabetic patients, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Crohn disease, hyperandrogenism, alopecia areata, Japanese Guillain-Barre syndrome, mucocutaneous leishmaniasis, meningococcal disease, lepromatous leprosy, scarring trachoma and asthma. The significance of TNF alpha to human disease is clearly well established in the art. To investigate whether genes identified as hypoxia regulated may also respond to TNF alpha, cultures of primary macrophages were treated with lOOng/ml recombinant human TNF alpha and RNA was extracted after 24hr. The following genes were found to change in expression in response to TNF alpha.
Figure imgf000142_0001
Figure imgf000143_0001
Interleukin 1 beta
Interleukin 1 beta (LL1) mediates the panoply of host reactions collectively known as acute phase response and is a key cytokine implicated in a wide range of infectious, auto- immune and other inflammatory and neoplastic diseases including rheumatoid arthritis, cancer, high bone turnover, osteoporosis, cardiovascular disease, alzheimer's disease, ulcerative colitis and Crohn's disease, lupus erythematosus, cerebral ischaemia, diabetes mellitus. To investigate whether genes identified as hypoxia regulated may also respond to LL1, cultures of primary macrophages were treated with lOOng/ml recombinant human LL1 and RNA was extracted after 6 and 24hr. The following genes were found to change in response to this treatment, as determined using the custom gene array.
Figure imgf000144_0001
Figure imgf000145_0001
Lipopolysaccharide and gamma interferon
The combination of lipopolysaccharide and gamma interferon is commonly used way of stimulating macrophages to mimic acute bacterial infection, and causes the macrophage to assume a highly activated cellular phenotype. Lipopolysaccharide (LPS) (from E.coli 026:B6; Sigma) and gamma Interferon (IFN), both at lOOng/ml were added to cultures of primary human macrophages and gene expression changes were monitored using the custom gene array. The following genes were found to change in response to this treatment, as determined using the custom gene array.
Figure imgf000145_0002
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
IL-12, IL-15 and IL-17
As mentioned elsewhere in this specification the macrophage is a key cell type in rheumatoid arthritis (RA) involved in inflammation associated with the synovium. As well as being exposed to hypoxia these macrophages are exposed to a range of cytokines. These include TNF alpha and IL-1 beta which are significant to a wide range of inflammatory conditions; and genes which respond to these factors have been presented above.
Additionally we have measured the effects of a number of other cytokines associated with inflammation in RA, namely LL-12 (Sakkas L.I. et al Cell Immunol 1998 188: 105-110), LL-15 (Badolato R et al Blood 1997 90:2804-2809) and IL-17 (Chabaud M. et al Arthritis Res 2001 3: 168-177).
LL-12 is expressed by infiltrating macrophages and synovial cells in RA patients (Sakkas L.I. et al Cell Immunol 1998 188: 105-110) and the principal targets of this cytokine are T- cells. However, responses of macrophages to this cytokine will be relevant considering the association of this cytokine with RA, in which the macrophage plays a critical role. To investigate whether genes identified as hypoxia regulated may also respond to IL-12, cultures of primary macrophages were treated with 100 ng /ml recombinant human IL-12 (obtained from Preprotech) and RNA was extracted after 6 and 48 hours. The genes listed below were found to change in response to this treatment, as determined using the custom gene array. LL-15 is implicated in several diseases in which macrophages and hypoxia both feature as elements of the inflammatory state, such as in atherosclerosis (Wuttge DM et al Am J Pathol. 2001 159:417-23) and rheumatoid arthritis (Mclnnes IB et al Immunol Today. 1998 19:75-9). Although the main target of IL-15 is T-cells effects have also been shown on monocytes (Badolato R et al Blood. 1997 90:2804-9). Therefore genes which respond to both hypoxia and LL-15 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
To investigate whether genes identified as hypoxia regulated may also respond to IL-15, cultures of primary macrophages were treated with 100 ng /ml recombinant human IL-15 (obtained from Preprotech) and RNA was extracted after 24 hours. The genes listed below were found to change in response to this treatment, as determined using the custom gene array.
IL-17 has been shown to mediate inflammation and joint destruction in arthritis (Lubberts et al J.Immunol 2001 167: 1004-1013). IL-17 has also been shown to stimulate macrophages to release other key pro-inflammatory cytokines (Jovanovic et al J Immunol 1998 160:3513-21). Therefore genes which respond to both hypoxia and IL-17 are especially likely to be relevant to disease processes and have utility in the design of therapeutic products.
To investigate whether genes identified as hypoxia regulated may also respond to IL-17, cultures of primary macrophages were treated with 100 ng /ml recombinant human IL-17 (obtained from Preprotech) and RNA was extracted after 24 hours. The genes listed below were found to change in response to this treatment, as determined using the custom gene array.
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
IL4 andIL13
The cytokines IL4 and ILI 3 are produced by Th2 cells, and have very similar actions, being implicated in immune reactions associated with strong antibody and allergic responses. The effects of these cytokines are opposite to those of Thl type cytokines (such as gamma interferon), which are implicated in immune reactions associated with strong cell mediated reactions. Generally these two classes of cytokines are believed to antagonise one another. Hence genes which are suppressed in response to LL4 or ILI 3 (Th2 cytokines) may indicate a pro-inflamatory role in Thl responses (such as found in cancer, RA, and Crohn's disease) where they are likely to be induced, whereas genes which are induced in response to IL4 or IL13 are likely to have an anti-inflammatory role in Thl responses. The following genes were found to change in expression in response to these cytokines at lOOng/ml for 24 hours in primary human monocyte-derived macrophages.
Genes regulated in response to IL13 and/or IL4
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
IL-10
The cytokine IL-10 is a key anti-inflammatory cytokine which causes general downregulation of macrophage effector functions. Several hypoxia-regulated genes in this specification are responsive to this cytokine, implicating them in inflammatory macrophage functions. Genes which responded to lOOng/ml LL-10 at 24 hr in primary human macrophages are presented below.
Genes regulated hv IL-10
Figure imgf000161_0002
Figure imgf000162_0001
Figure imgf000163_0001
Superoxide
Superoxide radicals have frequently been associated with ischaemia reperfusion and several studies have shown that ischaemia/ reperfusion-associated tissue damage is largely due to superoxide radicals (reviewed in Salvemini D 2002; Nature Reviews Drug Discovery 1 : 367-374). Superoxide radicals are also generated in the inflamed rheumatoid synovium, possibly as a result of ischaemia / reperfusion (Allen R.E. et al 1989, The Lancet. 2:282-3; Allen R.E. et al 1987, Annals Rheum. Dis. 46:843-845). Several cell types including macrophages respond to superoxide radicals is a highly pro-inflammatory way. By studying the response of the genes within the current specification to superoxide, these genes are hence implicated in inflammatory macrophage functions, and have such utility in the design of therapeutics for diseases involving macrophages. Primary macrophages were exposed to superoxide for 18hr by adding a combination of 0.5 mM Xanthine and lOmU/ml Xanthine oxidase. Genes which change in expression as a result of this are presented in the following table. Negative values represent gene suppression or down-regulation. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression. This type of data presentation differs from that described for examples 1 and 3. Essentially the data is the same but is presented differently for clarity.
Genes regulated by superoxide
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Example 5: Gene expression changes in human tumors
One of the utilities of the genes identified herein relates to the diagnosis and treatment of human tumors, on the basis that hypoxia is frequently found in tumors, resulting in features of the course and treatment of the disease. For instance, tumor angiogenesis is required for growth of tumors, and this is regulated by factors induced by hypoxia.
A study has been performed to examine the expression of the genes of this specification in a selection of tumors of various origins, comparing expression with normal adjacent tissue from the same patient. For clarity, data analysis was performed such that an induction ratio is derived by comparing the expression of a gene in tumor material from a patient to the normal adjacent tissue of the same patient. Therefore this data is not intended to illustrate the absolute differences in expression of a gene between different patients, but rather, to illustrate the changes from normal to tumor tissue within each individual patient as an indicator of genes involved in tumorigenesis.
Patients are designated as letters and are detailed below:
A: Lung tissue affected with well differentiated squamous cell carcinoma derived from a 78 year old male. Comparison to normal adjacent lung tissue from the same patient.
B: Deum tissue affected with non-hodgkins lymphoma derived from a 49 year old male. Comparison to normal adjacent ileum tissue from the same patient.
C: Colon tissue affected with adenocarcinoma derived from a 69 year old male. Comparison to normal adjacent colon tissue from the same patient.
D: Colon tissue affected with moderately differentiated adenocarcinoma derived from a 74 year old female. Comparison to normal adjacent colon tissue from the same patient. E: Kidney tissue affected with carcinoma derived from a person of unknown age and sex. Comparison to normal adjacent kidney tissue from the same patient.
F: Kidney tissue affected with carcinoma derived from a 34 year old female. Comparison to normal adjacent kidney tissue from the same patient. G: Cervix tissue affected with endometrioid adenocarcinoma derived from a 70 year old female. Comparison to normal adjacent cervix tissue from the same patient.
H: Ovary tissue affected with adenocarcinoma derived from a 50 year old female. Comparison to normal adjacent ovary tissue from the same patient.
I: Ovary tissue affected with poorly differentiated adenocarcinoma derived from a 60 year old female.
J: Ovary tissue affected with moderately differentiated adenocarcinoma derived from a 41 year old female. Comparison to normal adjacent ovary tissue from the same patient.
K: Breast tissue affected with invasive ductal carcinoma derived from a 58 year old female. Comparison to normal adjacent breast tissue from the same patient.
Genes which are expressed higher in tumor versus normal tissue in at least one patient are presented below, as determined using the custom gene array. Negative values represent gene suppression or down-regulation as compared to adjacent normal tissue. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression. This type of data presentation differs from that described for examples 1 and 3. Essentially the data is the same but is presented differently for clarity. mRNA EXPRESSION RATIO IN TUMOR COMPARED TO NORMAL TISSUE
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Genes which are expressed lower in tumor versus normal tissue in at least one patient are presented below, as determined using the custom gene array Negative values represent gene suppression or down-regulation as compared to adjacent normal tissue. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression. mRNA EXPRESSION RATIO IN TUMOR COMPARED TO NORMAL TISSUE
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Example 6: Gene expression changes associated with chronic obstructive pulmonary disease
Genes contained within this specification, originally identified as being regulated by hypoxia in macrophages, have utility in the design of therapeutics and diagnostics for several disease areas. Chronic obstructive pulmonary disease (COPD) is an inflammatory disease to which no satisfactory cure exists. It is well established that the inflammatory process driving the pathophysiology of COPD, involves several cell types including the macrophage. Hypoxia has important effects of the inflammatory status of the macrophage. Hypoxia has been implicated in the pathology of this disease, where it causes irreversible loss of vessels and thickening of the vascular muscular coat, with resultant life-threatening pulmonary hypertension (Rabinovitch M. et al J.Heart Lung Transpl. 1999 18: 1041-1053).
In order to validate utility of the genes contained in this specification for use in the design of therapeutics to treat COPD, we have compared the expression of these genes between the lungs of two COPD patients to those of an age/sex matched healthy individual.
Below are listed genes which are expressed at higher levels in at least one of the COPD lungs as compared to the healthy lung, as determined using the custom gene array. . Negative values represent gene suppression or down-regulation as compared to the healthy donor. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression.
CQPD results
Figure imgf000175_0001
Figure imgf000176_0001
Below are listed genes which are expressed at lower levels in at least two of the COPD lungs as compared to the healthy lung, as determined using the custom gene array:
Figure imgf000176_0002
Example 7: Gene expression changes in artheroschlerosis
Genes contained within this specification, originally identified as being regulated by hypoxia in macrophages, have utility in the design of therapeutics and diagnostics for several disease areas. Atherosclerosis is the process of thickening of arterial walls, leading to several pathologies including coronory artery disease, peripheral arterial disease, stroke, and a series of other related diseases. It is well established in the art that macrophages are central to the formation and development and rupture of atherosclerotic plaques (Nature Drug Discovery Reviews; Feb 2002; 122-130.). For example transgenic mice which are deficient in proteins required for the accumulation of macrophages in atherosclerotic plaques (i.e. CCR2 or MCPl) display a resistance to this disease following feeding on high fat diets. Macrophages in atherosclerotic lesions accumulate cholesterol in the form of modified LDLs, acting as a storage resevoir. The environment of the plaque is likely to involve hypoxia (Gainer J.L. Atherosclerosis 1987 68:263-266), and the response of macrophages to this is likely to contribute to their role in the disease process.
In order to validate utility of the genes contained in this specification for use in the design of therapeutics to treat atherosclerosis-related disease, we have compared the expression of these genes between the aortas of two individuals not affected by atherosclerosis (who died of unrelated causes) to those of the aortas of three patients with atherosclerosis of that artery. In the following data negative values represent gene suppression or down-regulation as compared to the normal individuals. For example an induction ratio of -2 represents a 2 fold suppression; and an induction ratio of -3 represents a 3 fold suppression. Below are listed genes which are expressed at higher levels in at least two of the atherosclerotic arteries as compared to the mean expression levels of the two normal arteries, as determined using the custom gene array. All patients were male.
Figure imgf000178_0001
Figure imgf000179_0001
Below are listed genes which are expressed at lower levels in at least one of the atherosclerotic arteries as compared to the mean expression levels of the two normal arteries, as determined using the custom gene array. All patients were male.
Figure imgf000179_0002
Figure imgf000180_0001
Figure imgf000181_0001
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Discussion of the relevance of the individual clones
The Oxford BioMedica clone p2G21 represents Vps39/Nam6-like protein . The protein sequence encoded by Vps39/Vam6-like protein is represented in the public databases by the accession AAK58862 and is described in this patent by Seq ID 1. The nucleotide sequence is represented in the public sequence databases by the accession AF334400 and is described in this patent by Seq ID 2. Vps39/Vam6-like protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Vps39/Vam6-like protein is induced in response to TNFalpha, by a factor of 2.19 fold, indicating a positive role in pro-inflammatory responses involving this factor. Vps39/Nam6-like protein is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Vps39/Vam6-like protein was down-regulated 2.7, 1.64 and 1.75 fold in the three diseased patients compared to the control group. This indicates that Vps39/Vam6-like protein plays a role in the process of atherogenesis. Vps39/Vam6-like protein contains a citron homology domain which is a regulatory domain involved in macromolecular interactions and an alpha helical repeat region which shares homology to the Clathrin repeat.
The Oxford BioMedica clone p2Ll represents Kell blood group. The protein sequence encoded by Kell blood group is represented in the public databases by the accession AAH03135 and is described in this patent by Seq LD 3. The nucleotide sequence is represented in the public sequence databases by the accession BC003135 and is described in this patent by Seq ID 4. Kell blood group is up-regulated by greater than 2-fold by Epas. The Kell blood group contains a Peptidase family M13 domain.
The Oxford BioMedica clone p2H10 represents 27.2KDA protein C21ORF7. The protein sequence encoded by C21ORF7 is represented in the public databases by the accession P57077 and is described in this patent by Seq ID 5. The nucleotide sequence is represented in the public sequence databases by the accession NM_020152 and is described in this patent by Seq ID 6. C21ORF7 is up-regulated by greater than 2-fold by Epas. C21ORF7 is preferentially induced by hypoxia in myocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for cardiac ischaemia and ischemic limbs. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. C21ORF7 is induced by a factor of 4.73 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. C21ORF7 is repressed by a factor of 1.67 in response to IL-13 and 2.04 in response to IL-4, indicating a negative role in Th2 immune responses.
The Oxford BioMedica clone plM21 represents 5'-AMP-acitivated protein kinase, beta-2 subunit (AMPK). The protein sequence encoded by AMPK is represented in the public databases by the accession 043741 and is described in this patent by Seq ID 7. The nucleotide sequence is represented in the public sequence databases by the accession NM_005399 and is described in this patent by Seq ID 8. AMPK is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. AMPK is repressed by a factor of 1.56 in response to EL- 10, indicating a negative role in the response to IL-10. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, AMPK was down-regulated 1.75, 2.38 and 1.37 fold in the three diseased patients compared to the control group. This indicates that AMPK plays a role in the process of atherogenesis. AMPK negatively regulates fatty acid synthesis by phosphoryation of Acetyl-CoA carboxylase, and so its induction by hypoxia within developing atherosclerotic plaque may exacerbate disease progression. Inhibitors of AMPK may delay disease progression, and AMPK levels may be a prognostic marker.
The Oxford BioMedica clone p2G12 represents MMP-2. The protein sequence encoded by MMP-2 is represented in the public databases by the accession P08253 and is described in this patent by Seq ID 9. The nucleotide sequence is represented in the public sequence databases by the accession NM_004530 and is described in this patent by Seq LD 10. MMP-2 cleaves collagen-like sequences. MMP-2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, MMP-2 is induced in response to TNFalpha, by a factor of 2.3 fold, indicating a positive role in pro- inflammatory responses involving this factor. The cytokine Interleukin- 10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions. MMP-2 is induced by a factor of 2.49 in response to IL-10, indicating a positive role in the response to LL-10. MMP-2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. MMP-2 contains a number of conserved domains including a Matrix Metalloprotease N-terminal domain, Zinc-dependent metalloprotease domains, multiple Fibronectin type 2 domains and multiple Hemopexin-like repeats.
The Oxford BioMedica clone p2H14 represents Adam 8 precursor. The protein sequence encoded by Adam 8 is represented in the public databases by the accession P78325 and is described in this patent by Seq ID 11. The nucleotide sequence is represented in the public sequence databases by the accession NM_001109 and is described in this patent by Seq ID 12. Adam 8 is up-regulated by greater than 2-fold by Epas. Adam 8 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. Adam 8 contains multiple domains including an ADAM cysteine-rich domain, a reprolysin M12B zinc family metalloproteinase domain and a Snake disintegrin domain.
The Oxford BioMedica clone p2H9 represents the Adrenomedullin precursor. The protein sequence encoded by Adrenomedullin is represented in the public databases by the accession BAA07756 and is described in this patent by Seq LD 13. The nucleotide sequence is represented in the public sequence databases by the accession D43639 and is described in this patent by Seq LD 14. Adrenomedullin is a potent hypotensive and vasodilating agent. Adrenomedullin is up-regulated by greater than 2-fold by Epas. Adrenomedullin is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Adrenomedullin was down regulated 2.7 and 1.3 fold in two of the three diseased patients compared to the control group. Its repression by hypoxia within developing atherosclerotic plaque may exacerbate disease progression, and adrenomedullin levels may be a prognostic marker.
The Oxford BioMedica clone plL21 represents AF1Q transmembrane protein. The protein sequence encoded by AF1Q transmembrane protein is represented in the public databases by the accession Q 13015 and is described in this patent by Seq ID 15. The nucleotide sequence is represented in the public sequence databases by the accession NM_006818 and is described in this patent by Seq ID 16. AF1Q transmembrane protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, AF1Q transmembrane protein is induced in response to TNFalpha, by a factor of 2 fold, indicating a positive role in pro-inflammatory responses involving this factor. AF1Q is highly expressed in thymus and all leukaemic cell lines, and is believed to play a role in the pathogenesis of cancers of the myeloid and lymphoid lineages (PMID: 10025907). Our observation of the response of this gene to hypoxia implies its role in the pathogenesis of inflammatory diseases involving cells of these lineages, and this is supported by its induction by TNFalpha. The Oxford BioMedica clone p2C15 represents AMMECRl protein. The protein sequence encoded by AMMECRl protein was previously represented in the public databases by the accession XPJ313145 and is described in this patent by Seq ID 17. The nucleotide sequence was previously represented in the public sequence databases by the accession XM_013145 and is described in this patent by Seq ID 18. The publicly avilable sequence entries referenced in this patent have been removed from the public domain by request from the original author. AMMECRl is now represented in the public sequence databases by the Protein accession NP_056180, and nucleotide accession NM_015365. AMMECRl protein is up-regulated by greater than 2-fold by Epas. AMMECRl protein is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2I10 represents AMP deaminase 2 isoform L. The protein sequence encoded by AMP deaminase 2 isoform L is represented in the public databases by the accession Q01433 and is described in this patent by Seq ID 19. The nucleotide sequence is represented in the public sequence databases by the accession AK025706 and is described in this patent by Seq ED 20. AMP deaminase 2 isoform L plays a critical role in energy metabolism and catalyses the reaction AMP + H(2)O = IMP + NH(3). AMP deaminase 2 isoform L is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. AMP deaminase 2 isoform L is induced by a factor of 2.19 in response to IL-13 and 2.11 in response to IL-4, indicating a positive role in Th2 immune responses. AMP deaminase 2 isoform L is suppressed by a factor of 4.76 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, AMP deaminase 2 isoform L was down-regulated 1.54, 2.5 and 1.04 fold in the three diseased patients compared to the control group. This indicates that AMP deaminase 2 isoform L plays a role in the process of atherogenesis.
The Oxford BioMedica clone pi LI 5 represents Angiopoietin-like 4 protein. The protein sequence encoded by Angiopoietin-like 4 protein is represented in the public databases by the accession NP_057193 and is described in this patent by Seq ID 21. The nucleotide sequence is represented in the public sequence databases by the accession NM_016109 and is described in this patent by Seq ID 22. Angiopoietin-like 4 protein is up-regulated by greater than 2-fold by Epas. Angiopoietin-like 4 protein is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell- hormone interactions at epithelial cell surfaces. Angiopoietin-like 4 protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Angiopoietin-like 4 protein was up- regulated 2.27 fold in one of the patients. This indicates that Angiopoietin-like 4 protein plays a role in the inflammation associated with COPD. Angiopoietin-like 4 protein contains a Fibrinogen-related domain.
The Oxford BioMedica clone p2D17 represents Apoptosis-related RNA binding protein. The protein sequence encoded by Apoptosis-related RNA binding protein is represented in the public databases by the accession AAD 13760 and is described in this patent by Seq ID 23. The nucleotide sequence is represented in the public sequence databases by the accession AF090693 and is described in this patent by Seq ID 24. Apoptosis-related RNA binding protein is up-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2E6 represents Ataxin-1 ubiquitin like interacting protein. The protein sequence encoded by Ataxin-1 ubiquitin like interacting protein is represented in the public databases by the accession NP_064516 and is described in this patent by Seq ID 25. The nucleotide sequence is represented in the public sequence databases by the accession NM_020131 and is described in this patent by Seq ID 26. Ataxin-1 ubiquitin like interacting protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Ataxin-1 ubiquitin like interacting protein is repressed by a factor of 2.5 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. Ataxin-1 contains multiple Ubiquitin family and Ubiquitin associated domains.
The Oxford BioMedica clone p2H20 represents Band 4.1 -like protein 4. The protein sequence encoded by Band 4.1 -like protein 4 is represented in the public databases by the accession Q9HCS5 and is described in this patent by Seq ID 27. The nucleotide sequence is represented in the public sequence databases by the accession NM_022140 and is described in this patent by Seq ID 28. Band 4.1-like protein 4 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Band 4.1-like protein 4 is repressed by a factor of 2.17 in response to IL-13 and 1.82 in response to LL-4, indicating a negative role in Th2 immune responses. Band 4.1-like protein 4 contains a FERM domain. The FERM domain is found in a number of cytoskeleton- associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The Oxford BioMedica clone plN4 represents Calpactin 1 light chain (P10 protein). The protein sequence encoded by Calpactin 1 light chain is represented in the public databases by the accession P08206 and is described in this patent by Seq ID 29. The nucleotide sequence is represented in the public sequence databases by the accession NM_002966 and is described in this patent by Seq ID 30. Calpactin 1 light chain induces the dimerization of Annexin π and may function as a regulator of protein phosphoryaltion. Calpactin 1 light chain is up-regulated by greater than 2-fold by Epas. Calpactin 1 light chain is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Calpactin 1 light chain was down-regulated 1.85, 2.08 and 1.67 fold in the three diseased patients compared to the control group. This indicates that Calpactin 1 light chain plays a role in the process of atherogenesis. Calpactin 1 light chain contains a S 100 Calcium binding domain.
The Oxford BioMedica clone p2L3 represents CALU (Calumenin). The protein sequence encoded by Calumenin is represented in the public databases by the accession AAC 17216 and is described in this patent by Seq ID 31. The nucleotide sequence is represented in the public sequence databases by the accession AF013759 and is described in this patent by Seq ID 32. Calumenin is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Calumenin is repressed by a factor of 2.56 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Calumein is repressed by a factor of 1.79 in response to IL-13 and 2.56 in response to IL-4, indicating a negative role in Th2 immune responses. Calumenin is suppressed by a factor of 2.17 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. Calumenin is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ. These data are consistent with the recent observation that calumenin levels correlate inversely with metastatic potential of tumour cells (PMID: 12090472). Our observation of hypoxia induction has very important implications for the in vivo evolution of metastatic potential, because hypoxic conditions often prevail within tumours. This gene is a useful prognostic indicator and functional agonists should be anti-tumourigenic. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Calumein was down-regulated 4.76, 1.33 and 2.33 fold in the three diseased patients compared to the control group. This indicates that Calumenin plays a role in the process of atherogenesis.
The Oxford BioMedica clone plK17 represents cAMP-regulated phosphoprotein 19 (ARPP-19). The protein sequence encoded by ARPP-19 is represented in the public databases by the accession P56211 and is described in this patent by Seq ID 33. The nucleotide sequence is represented in the public sequence databases by the accession AF084555 and is described in this patent by Seq LD 34. ARPP-19, which is a substrate for cAMP-dependent protein kinase and may participate in cAMP-mediated signalling, is induced more than 2-fold by both Hif and Epas. Its induction by hypoxia has important implications for the maintenance of normal signalling. The superoxide radical is a potent stimulus frequently associated with ischemic conditions. Gene ID 34 is suppressed by a factor of 1.52 in response to superoxide. This is consistent with the recently proposed role for this gene in neurodegeneration. Decreased ARPP-19 is involved in pathomechanisms of Downs syndrome and Alzheimer's disease (PMID: 11771749). Based on our demonstration of the importance of this gene to ischaemic disease, both diagnostic and therapeutic opportunities have emerged.
The Oxford BioMedica clone plM12 represents CBP/P300-interacting transactivator with glu/asp rich carboxy-terminal domain. The protein sequence encoded by seq ID 35 is represented in the public databases by the accession AAF01263 and is described in this patent by Seq ID 35. The nucleotide sequence is represented in the public sequence databases by the accession AF129290 and is described in this patent by Seq ID 36. The sequence encoded by Seq ID 36 interferes with the binding of transcription factors HIF- la and STAT2 to p300/CBP and is induced by hypoxia and deferoxamine. The protein sequence encoded by seq ID 35 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The protein sequence encoded by seq ID 35 is induced by a factor of 1.87 at 6hr and 2.33 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone p2G20 represents CCR4-NOT transcription complex, subunit 4. The protein sequence encoded by CCR4-NOT is represented in the public databases by the accession NP_037448 and is described in this patent by Seq ID 37. The nucleotide sequence is represented in the public sequence databases by the accession NM_013316 and is described in this patent by Seq ID 38. CCR4-NOT is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. CCR4-NOT is suppressed by a factor of 2.04 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. CCR4-NOT contains an RNA recognition motif. The Oxford BioMedica clone pINIO represents Ceruloplasmin precursor (ferroxidase). The protein sequence encoded by Ceruloplasmin is represented in the public databases by the accession P00450 and is described in this patent by Seq ID 39. The nucleotide sequence is represented in the public sequence databases by the accession NM_000096 and is described in this patent by Seq ID 40. Ceruloplasmin is up-regulated by greater than 2- fold by Epas. Ceruloplasmin is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. Ceruloplasmin is induced by a factor of 2.73 in response to superoxide, which is consistent with its role as an anti-oxidant. . Ceruloplasmin is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Ceruloplasmin was up-regulated 3.57 fold in one of the patients and was up-regulated 3.59 fold in the other patient. This indicates that Ceruloplasmin plays a role in the inflammation associated with COPD. Ceruloplasmin is a blue, copper-binding glycoprotein found in plasma and may function as a copper transporter. Copper is essential for the process of angiogenesis and therefore inhibition of Ceruloplasmin would be an effective anti- angiogenesis strategy. Elevated ceruloplasmin levels have been shown recently to be associated with rheumatoid arthritis (PMLD: 12175089). Our demonstration of its hypoxia induction has laid the foundation for the use of this protein as a prognostic indicator and therapeutic target. The Oxford BioMedica clone p2H12 represents Chorein. The protein sequence encoded by Chorein is represented in the public databases by the accession BAB59128 and is described in this patent by Seq LD 41. The nucleotide sequence is represented in the public sequence databases by the accession AB023203 and is described in this patent by Seq LD 42. Chorein is up-regulated by greater than 2-fold by Epas. This response to hypoxia has important implications for the pathogenesis of neuro-ischaemia, because chorein is known to be associated with neuro-degeneration (PMID: 11381254). We expect chorein to be an important target for intervention in hypoxia-related neurodegenerative diseases such as stroke. The Oxford BioMedica clone p2C3 represents DEAD-box protein. The protein sequence encoded by DEAD-box protein is represented in the public databases by the accession NP_061135 and is described in this patent by Seq ID 43. The nucleotide sequence is represented in the public sequence databases by the accession NM_018665 and is described in this patent by Seq ED 44. DEAD-box protein is an ATP-dependent RNA helicase in the DEAD-box family. DEAD-box protein is up-regulated by greater than 2- fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. DEAD-box protein is repressed by a factor of 2.04 in response to LL- Vindicating a negative role in Th2 immune responses. The Oxford BioMedica clone p2B24 represents DLAT dihydrolipoamide acetyltransferase E2. The protein sequence encoded by DLAT dihydrolipoamide acetyltransferase E2 is represented in the public databases by the accession CAA68787 and is described in this patent by Seq ID 45. The nucleotide sequence is represented in the public sequence databases by the accession Y00978 and is described in this patent by Seq ID 46. DLAT dihydrolipoamide acetyltransferase E2 is a component of the human pyruvate dehydrogenase complex. DLAT dihydrolipoamide acetyltransferase E2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. DLAT dihydrolipoamide acetyltransferase E2 is repressed by a factor of 2.13 in response to IL-13 and 1.79 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, DLAT dihydrolipoamide acetyltransferase E2 was down-regulated 1.47, 2.27 and 1.39 fold in the three diseased patients compared to the control group. This indicates that DLAT dihydrolipoamide acetyltransferase E2 plays a role in the process of atherogenesis.
Dual specificity mitogen-activated protein kinase kinase 7 (MAPKK7) is represented in the public databases by the accession O14733 and is described in this patent by Seq ID 47. The nucleotide sequence is represented in the public sequence databases by the accession NM_005043 and is described in this patent by Seq ID 48. MAPKK7 activates the Jun kinases (JNK1 and JNK2). MAPKK7 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2G23 represents Equihbrative nucleoside transporter 1. The protein sequence encoded by Equihbrative nucleoside transporter 1 is represented in the public databases by the accession Q99808 and is described in this patent by Seq ID 49. The nucleotide sequence is represented in the public sequence databases by the accession NM_004955 and is described in this patent by Seq ID 50. Equihbrative nucleoside transporter 1 mediates both the influx and efflux of nucleosides across the membrane and belongs to the SLC29A family of transporters. Equihbrative nucleoside transporter 1 is up- regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plM9 represents Ets-domain transcription factor ERF. The protein sequence encoded by Ets-domain transcription factor ERF is represented in the public databases by the accession P50548 and is described in this patent by Seq ID 51. The nucleotide sequence is represented in the public sequence databases by the accession NM_006494 and is described in this patent by Seq ID 52. Ets-domain transcription factor ERF is a potent transcriptional repressor that binds to the HI element of the ETS2 promoter. It may regulate other genes involved in cellular proliferation. Ets-domain transcription factor ERF is phosphorylated by multiple kinases including probably ERK2. Ets-domain transcription factor ERF is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Ets-domain transcription factor ERF is repressed by a factor of 2.22 in response to IL-13 and 1.69 in response to IL- 4, indicating a negative role in Th2 immune responses.
Eukaryotic translation initiation factor 4E binding protein 1 is represented in the public databases by the accession BAB 18650 and is described in this patent by Seq LD 53. The nucleotide sequence is represented in the public sequence databases by the accession AB044548 and is described in this patent by Seq ID 54. Eukaryotic translation initiation factor 4E binding protein 1 is up-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone pi 123 represents EVI2A protein precursor. The protein sequence encoded by EVI2A is represented in the public databases by the accession P22794 and is described in this patent by Seq ID 55 and Seq ID 57. The nucleotide sequence is represented in the public sequence databases by the accession NM_014210 and is described in this patent by Seq ID 56 and Seq ID 58. EVI2A is a membrane protein that may possibly complex with itself or other proteins to form a cell-surface receptor. EVI2A is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plN2 represents Fc fragment of IgG low affinity 2b (FC- gamma RII-B). The protein sequence encoded by FC-gamma RII-B is represented in the public databases by the accession P31994 and is described in this patent by Seq ID 59. The nucleotide sequence is represented in the public sequence databases by the accession NM_004001 and is described in this patent by Seq ID 60. FC-gamma RII-B is involved in a variety of effector and regulatory functions such as phagocytosis of immune compexes and modulation of antibody production by B-cells. FC-gamma RII-B is up-regulated by greater than 2-fold by Epas. FC-gamma RII-B is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. FC- gamma RII-B is induced by a factor of 1.84 at 6hr and 1.99 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. FC-gamma RII-B is induced by a factor of 4.67 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. FC-gamma RII-B is induced by a factor of 5.29 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. FC-gamma RII-B is induced by a factor of 2.46 in response to EL- 10, indicating a positive role in the response to IL-10.
The Oxford BioMedica clone plK20 represents FOS-like antigen 2 (FRA2). The protein sequence encoded by FRA2 is represented in the public databases by the accession PI 5408 and is described in this patent by Seq ID 61 and Seq ID 63. The nucleotide sequence is represented in the public sequence databases by the accession NM_005253 and is described in this patent by Seq ID 62 and Seq ID 64. FRA2 is up-regulated by greater than 2-fold by Epas. FRA2 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. FRA2 forms part of a heterodimeric transcription factor activator protein 1 (API), and thus plays a crucial role in transcriptional regulation. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. FRA2 is induced by a factor of 1.75 in response to IL-13 and 2.11 in response to IL-4, indicating a positive role in Th2 immune responses. FRA2 is induced by a factor of 3.81 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. FRA2 is induced by a factor of 2.36 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. FRA2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FRA2 was down-regulated 2.27 and 2.33 fold in two of the three diseased patients compared to the control group. This indicates that FRA2 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2B23 represents G/T mismatch specific thymine DNA glycosylase. The protein sequence encoded by G/T mismatch specific thymine DNA glycosylase is represented in the public databases by the accession Q 13569 and is described in this patent by Seq ID 65. The nucleotide sequence is represented in the public sequence databases by the accession NM_003211 and is described in this patent by Seq ID 66. G/T mismatch specific thymine DNA glycosylase functions to correct G/T mispairs to G/C pairs. It is capable of hydrolyzing the Carbon-Nitrogen bond between the sugar- phosphate backbone of the DNA and a mispaired Thymine. G/T mismatch specific thymine DNA glycosylase belongs to the MUG/TDG family of DNA glycosylases. G/T mismatch specific thymine DNA glycosylase is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2G15 represents Glutamate cysteine ligase, (gamma-ECS). The protein sequence encoded by gamma-ECS is represented in the public databases by the accession P48506 and is described in this patent by Seq ID 67. The nucleotide sequence is represented in the public sequence databases by the accession NM_001498 and is described in this patent by Seq ID 68. Glutamate cysteine ligase is the first and rate limiting step in de novo Glutathione biosynthesis. gamma-ECS is up-regulated by greater than 2-fold by Epas. gamma-ECS is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, gamma-ECS was up-regulated 7.58 and 3.95 fold in two of the three diseased patients compared to the control group. This indicates that gamma-ECS plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2C5 represents Glutamine synthetase. The protein sequence encoded by Glutamine synthetase is represented in the public databases by the accession P15104 and is described in this patent by Seq ID 69. The nucleotide sequence is represented in the public sequence databases by the accession AL161952 and is described in this patent by Seq ID 70. Glutamine synthetase is up-regulated by greater than 2-fold by Epas. Glutamine synthetase is induced by a factor of 3.09 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Glutamine synthetase is induced by a factor of 3.51 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Glutamine synthetase is induced by a factor of 2.36 in response to IL-10, indicating a positive role in the response to IL-10. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Glutamine synthetase was up-regulated 2.26 fold in one of the patientsand was up-regulated 1.88 fold in the other patient. This indicates that Glutamine synthetase plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2H15 represents Glutamate receptor 2 precursor. The protein sequence encoded by Glutmate receptor 2 is represented in the public databases by the accession P44262 and is described in this patent by Seq ID 71. The nucleotide sequence is represented in the public sequence databases by the accession NM_000826 and is described in this patent by Seq ID 72. Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. Glutamate receptor 2 is up- regulated by greater than 2-fold by both Hif and Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Glutamate receptor 2 was down-regulated 2.7 and 5.56 fold in two of the three diseased patients compared to the control group. This indicates that Glutmate receptor 2 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plMlO represents Glycine amidinotransferase, mitochondrial precursor. The protein sequence encoded by Glycine amidinotransferase is represented in the public databases by the accession P50440 and is described in this patent by Seq ID 73. The nucleotide sequence is represented in the public sequence databases by the accession NM_001482 and is described in this patent by Seq ID 74. Glycine amidinotransferase is the first and rate limiting step in the biosynthesis of Creatine. Glycine amidinotransferase is up-regulated by greater than 2-fold by Epas. Glycine amidinotransferase is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Glycine amidinotransferase is induced by a factor of 2 in response to IL-13 and 1.69 in response to EL-4, indicating a positive role in Th2 immune responses. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Glycine amidinotransferase is repressed in response to TNFalpha, by a factor of 2.5 fold, indicating a negative role in pro-inflammatory responses involving this factor. Glycine amidinotransferase is suppressed by a factor of 3.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone plL19 represents Growth factor receptor GRB2 adapter protein. The protein sequence encoded by Growth factor receptor GRB2 adapter protein is represented in the public databases by the accession P29354 and is described in this patent by Seq ID 75. The nucleotide sequence is represented in the public sequence databases by the accession NM_002086 and is described in this patent by Seq ID 76. Growth factor receptor GRB2 adapter protein associates with activated Tyrosine-phosphorylated EGF receptors and PDGF receptors via its SH2 domain. Growth factor receptor GRB2 adapter protein also assocaites with other cellular Tyrosine-phosphorylated proteins such as IRS-1, SHC and LNK. Growth factor receptor GRB2 adapter protein is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Growth factor receptor GRB2 adapter protein was up-regulated 3.53, 2.65 and 1.13 fold in the three diseased patients compared to the control group. This indicates that Growth factor receptor GRB2 adapter protein plays a role in the process of atherogenesis.
The Oxford BioMedica clone pi LI 6 represents GTF2I repeat domain containing 1, isoform 1. The protein sequence encoded by GTF2I repeat domain containing 1, isoform 1 is represented in the public databases by the accession NP_057412 and is described in this patent by Seq ID 77. The nucleotide sequence is represented in the public sequence databases by the accession NM_016328 and is described in this patent by Seq ID 78. The sequence encoded by Seq ID 77 contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene is deleted in Williams- Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7ql l.23. GTF2I repeat domain containing 1, isoform 1 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. GTF2I repeat domain containing 1, isoform 1 is induced by a factor of 2.32 at 6hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. GTF2I repeat domain containing 1, isoform 1 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, GTF2I repeat domain containing 1, isoform 1 was down-regulated 1.61, 1.37 and 2.08 fold in the three diseased patients compared to the control group. This indicates that GTF2I repeat domain containing 1, isoform 1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plL2 represents Heat shock 40KDA protein 1. The protein sequence encoded by Heat shock 40KDA protein 1 is represented in the public databases by the accession NP_006136 and is described in this patent by Seq ID 79. The nucleotide sequence is represented in the public sequence databases by the accession NM_006145 and is described in this patent by Seq ID 80. Heat shock 40KDA protein 1 is up-regulated by greater than 2-fold by Hif. Heat shock 40KDA protein 1 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. Heat shock 40KDA protein 1 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Heat shock 40KDA protein 1 was up- regulated 5.32 fold in one of the patientsHeat shock 40KDA protein 1 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Heat shock 40KDA protein 1 was down-regulated 6.67, 4.76 and 2.94 fold in the three diseased patients compared to the control group. This indicates that Heat shock 40KDA protein 1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I21 represents Heat shock 70KDA protein 6 (HSP70B). The protein sequence encoded by HSP70B is represented in the public databases by the accession PI 7066 and is described in this patent by Seq ID 81. The nucleotide sequence is represented in the public sequence databases by the accession NM_002155 and is described in this patent by Seq ID 82. HSP70B is up-regulated by greater than 2-fold by Hif. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, HSP70B was up-regulated 5.72 fold in one of the patients. HSP70B plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone plN3 represents Heat shock protein 70KD protein 1-HOM. The protein sequence encoded by Heat shock protein 70KD protein 1-HOM is represented in the public databases by the accession P34931 and is described in this patent by Seq ID 83. The nucleotide sequence is represented in the public sequence databases by the accession NM_005527 and is described in this patent by Seq ID 84. Heat shock protein 70KD protein 1-HOM belongs to the heat shock protein 70 family but is not regulated by heat shock. Heat shock protein 70KD protein 1-HOM is up-regulated by greater than 2- fold by Hif. Heat shock protein 70KD protein 1-HOM is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Heat shock protein 70KD protein 1-HOM is induced in response to TNFalpha, by a factor of 2.72 fold, indicating a positive role in pro- inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions. Heat shock protein 70KD protein 1-HOM is repressed by a factor of 2.38 in response to IL-10, indicating a negative role in the response to IL-10. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Heat shock protein 70KD protein 1-HOM is repressed in response to Interleukin- 1, by a factor of 2.78 fold at 6hr and 5.56 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Heat shock protein 70KD protein 1-HOM is suppressed by a factor of 4 at 6hr and 1.72 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. Heat shock protein 70KD protein 1-HOM is repressed by a factor of 3.7 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro- inflammatory responses involving this factor. Heat shock protein 70KD protein 1-HOM is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Heat shock protein 70KD protein 1-HOM was up-regulated 17.95 fold in one of the patients and was up-regulated 1.62 fold in the other patient. This indicates that Heat shock protein 70KD protein 1-HOM plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Heat shock protein 70KD protein 1-HOM was changed in expression - 2.63, -1.72 and -2.13 fold in the three diseased patients compared to the control group. This indicates that Heat shock protein 70KD protein 1-HOM plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I17 represents Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein. The protein sequence encoded by p2I17 is represented in the public databases by the accession Q15011 and is described in this patent by Seq ID 85. The nucleotide sequence is represented in the public sequence databases by the accession NM_014685 and is described in this patent by Seq ID 86. p2I17 is up-regulated by greater than 2-fold by Hif. The sequence encoded by Seq ID 85 is suppressed by a factor of 2.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The sequence encoded by Seq ID 85 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2El l represents Huntingtin associated protein interacting protein. The protein sequence encoded by Huntingtin associated protein interacting protein is represented in the public databases by the accession O60229 and is described in this patent by Seq ID 87. The nucleotide sequence is represented in the public sequence databases by the accession NM_003947 and is described in this patent by Seq ID 88. Huntingtin associated protein interacting protein is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Huntingtin associated protein interacting protein is induced in response to TNFalpha, by a factor of 6.34 fold, indicating a positive role in pro-inflammatory responses involving this factor. Huntingtin associated protein interacting protein is induced by a factor of 2.08 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro- inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti- inflammatory cytokine which causes general dampening of macrophage effector functions. Huntingtin associated protein interacting protein is repressed by a factor of 2.33 in response to IL-10, indicating a negative role in the response to IL-10. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Huntingtin associated protein interacting protein is repressed in response to Interleukin- 1, by a factor of 6.25 fold at 6hr and 7.69 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. Huntingtin associated protein interacting protein is suppressed by a factor of 8.33 at 6hr and 4.35 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. Huntingtin associated protein interacting protein is repressed by a factor of 3.13 in response to EL-13 and 1.52 in response to IL-4, indicating a negative role in Th2 immune responses. Huntingtin associated protein interacting protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Huntingtin associated protein interacting protein was up-regulated 4.3 fold in one of the patients and was up-regulated 2.34 fold in the other patient. This indicates that Huntingtin associated protein interacting protein plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Huntingtin associated protein interacting protein was changed in expression 1.19, 2.08 and 1.31 fold in the three diseased patients compared to the control group. This indicates that Huntingtin associated protein interacting protein plays a role in the process of atherogenesis.
The Oxford BioMedica clone plL20 represents the Interleukin- 16 precursor. The protein sequence encoded by IL-16 is represented in the public databases by the accession Q 14005 and is described in this patent by Seq ID 89. The nucleotide sequence is represented in the public sequence databases by the accession M90391 and is described in this patent by Seq ID 90. IL-16 stimulates a migratory response in CD4+ lymphocytes, monocytes and eosinophils. It also induces T-cell expression of Interleukin 2 receptor. IL-16 is up- regulated by greater than 2-fold by Epas. IL-16 is suppressed by a factor of 2.44 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone plPl represents Interleukin- 1 beta precursor. The protein sequence encoded by Interleukin- 1 beta is represented in the public databases by the accession P01584 and is described in this patent by Seq ID 91. The nucleotide sequence is represented in the public sequence databases by the accession NM_000576 and is described in this patent by Seq ID 92. Interleukin- 1 beta is produced by activated Macrophages and stimulates thymocyte proliferation by inducing IL-2 release, B-cell maturation and proliferation, and Fibroblast growth factor activity. Interleukin- 1 proteins are involved in the inflammatory response and stimulate the release of Postaglandin and Collagenase from synovial cells. Interleukin- 1 beta is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 beta is induced by a factor of 2.09 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. Interleukin- 1 beta is induced by a factor of 75.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Interleukin- 1 beta is induced by a factor of 27.58 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. Interleukin- 1 beta is repressed by a factor of 2.33 in response to IL-13 and 2.44 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Interleukin- 1 beta was up-regulated 2.41 fold in one of the patients. This indicates that Interleukin- 1 beta plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone plL17 represents MMP7. The protein sequence encoded by MMP7 is represented in the public databases by the accession P09237 and is described in this patent by Seq ID 93. The nucleotide sequence is represented in the public sequence databases by the accession NM_002423 and is described in this patent by Seq ID 94. MMP7 functions to degrade Casein, Gelatins and Fibronectin. MMP7 is up-regulated by greater than 2-fold by both Hif and Epas. MMP7 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, MMP7 is induced in response to TNFalpha, by a factor of 2.84 fold, indicating a positive role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, MMP7 was changed in expression 6.37, 4.43 and -1.37 fold in the three diseased patients compared to the control group. This indicates that MMP7 plays a role in the process of atherogenesis. The Oxford BioMedica clone plL3 represents Inter-alpha-trypsin inhibitor heavy chain H- 2 precursor. The protein sequence encoded by Inter-alpha-trypsin inhibitor heavy chain H- 2 is represented in the public databases by the accession PI 9823 and is described in this patent by Seq ID 95. The nucleotide sequence is represented in the public sequence databases by the accession NM_002216 and is described in this patent by Seq ED 96. Inter- alpha-trypsin inhibitor heavy chain H-2 may act as a carrier of Hyaluron in serum. Inter- alpha-trypsin inhibitor heavy chain H-2 is up-regulated by greater than 2-fold by Epas. Inter-alpha-trypsin inhibitor heavy chain H-2 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Inter-alpha-trypsin inhibitor heavy chain H-2 was up-regulated 1.98 fold in one of the patients and was up-regulated 2.48 fold in the other patient. This indicates that Inter-alpha-trypsin inhibitor heavy chain H-2 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2H6 represents Interleukin 18 binding protein (IL18BP). The protein sequence encoded by IL18BP is represented in the public databases by the accession NP_005690 and is described in this patent by Seq ID 97. The nucleotide sequence is represented in the public sequence databases by the accession NM_005699 and is described in this patent by Seq ID 98. IL18BP is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. IL18BP is repressed by a factor of 2.08 in response to IL-13 and 1.61 in response to IL-4, indicating a negative role in Th2 immune responses. IL18BP is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, IL18BP was changed in expression 3.61, 1.46 and 1.04 fold in the three diseased patients compared to the control group. This indicates that IL18BP plays a role in the process of atherogenesis.
The Oxford BioMedica clone plN6 represents Kell blood group gylcoprotein. The protein sequence encoded by Kell blood group gylcoprotein is represented in the public databases by the accession P23276 and is described in this patent by Seq ID 99. The nucleotide sequence is represented in the public sequence databases by the accession NM_000420 and is described in this patent by Seq ED 100. Kell blood group gylcoprotein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Kell blood group gylcoprotein is repressed in response to Interleukin- 1, by a factor of 3.23 fold at 6hr and 2.94 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. Kell blood group gylcoprotein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Kell blood group gylcoprotein was changed in expression -1.41, -2.38 and -1.37 fold in the three diseased patients compared to the control group. This indicates that Kell blood group gylcoprotein plays a role in the process of atherogenesis.
The Oxford BioMedica clone plM23 represents LEVI domain only 7. The protein sequence encoded by LEVI domain only 7 is represented in the public databases by the accession NP_005349 and is described in this patent by Seq ID 101. The nucleotide sequence is represented in the public sequence databases by the accession NM_005358 and is described in this patent by Seq ID 102. The LEVI domain is a cysteine-rich sequence motif that binds zinc atoms to form a specific protein-binding interface for protein-protein interactions. LEVI domain only 7 is up-regulated by greater than 2-fold by Epas. LIM domain only 7 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis^
The Oxford BioMedica clone p2L12 represents 19A24 protein. The protein sequence encoded by 19A24 protein is represented in the public databases by the accession CAB81950 and is described in this patent by Seq ID 103. The nucleotide sequence is represented in the public sequence databases by the accession AJ276429 and is described in this patent by Seq ID 104. 19A24 protein is a member of the immunoglobulin superfamily receptors and is expressed on activated lymphocytes and promotes homotypic B-cell adhesion. 19A24 protein is up-regulated by greater than 2-fold by both Hif and Epas. 19A24 protein is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. 19A24 protein is induced by a factor of 3.94 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. 19A24 protein is suppressed by a factor of 3.45 at 6hr and 1.89 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, 19A24 protein was changed in expression -2.04, -1.96 and -1.3 fold in the three diseased patients compared to the control group. This indicates that 19A24 protein plays a role in the process of atherogenesis. The Oxford BioMedica clone p2D20 represents LOC92097 similar to phenylalanine 4 hydroxlase (PAH). The protein sequence encoded by LOC92097 is represented in the public databases by the accession XP_012169 and is described in this patent by Seq ID 105. The nucleotide sequence was previously represented in the public sequence databases by the accession XM_012169 and is described in this patent by Seq ID 106. The nucleotide and protein accessions described above have been removed from the public databases and therefore LOC92097 is now represented by the nucleotide accession NM_000277 and the protein accession NP_000268. LOC92097 is up-regulated by greater than 2-fold by Epas. Hydroxylation is used to target proteins for degradation by the proteosomal degradation pathway, and it is important to note that there are likely to be undiscovered transcription factor isoforms which are relevant to the control of the cellular response to hypoxia. In particular, we have shown that the transcriptional response to hypoxia is tissue-specific, and such a differential response may be mediated by different isoforms of the controlling transcription factors. We propose that the protein sequence encoded by LOC92097 is induced by hypoxia as part of a mechanism involving targeting for proteosomal degradation.
The Oxford BioMedica clone p2I3 represents LOC92660 sulphotransferase, cytosohc. The protein sequence encoded by LOC92660 was represented in the public databases by the accession XP_016802 and is described in this patent by Seq ID 107. The nucleotide sequence was represented in the public sequence databases by the accession XM_016802 and is described in this patent by Seq ID 108. The nucleotide and protein accessions described above have been removed from the public databases and therefore LOC92660 sulphotransferase, cytosohc is now represented by the nucleotide accession NM_003166 and the protein accession NPJ303157. LOC92660 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, LOC92660 is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor. LOC92660 is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. LOC92660 is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC92660 was changed in expression - 1.72, -2.17 and -1.3 fold in the three diseased patients compared to the control group. This indicates that LOC92660 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2D22 represents LOC92879 sodium and chlorine dependent creatine transporter 2. The protein sequence encoded by LOC92879 was represented in the public databases by the accession XP_047748 and is described in this patent by Seq ID 109. The nucleotide sequence was represented in the public sequence databases by the accession XM_047748 and is described in this patent by Seq ID 110. The nucleotide and protein accessions described above have been removed from the public databases and therefore LOC92879 is now represented by the nucleotide accession NM_003166 and the protein accession NP_003157. LOC92879 is up-regulated by greater than 2-fold by Epas. LOC92879 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC92879 was changed in expression 2.52, 2.44 and 1.24 fold in the three diseased patients compared to the control group. This indicates that LOC92879 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I3 represents LOC93383 sulphotransferase, cytosohc. The protein sequence encoded by LOC93383 was represented in the public databases by the accession XP_051071 and is described in this patent by Seq ID 111. The nucleotide sequence was represented in the public sequence databases by the accession XM_051071 and is described in this patent by Seq ID 112. The nucleotide and protein accessions described above have been removed from the public databases and therefore LOC93383 sulphotransferase, cytosohc is now represented by the nucleotide accession NM_003166 and the protein accession NP_003157. LOC93383 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, LOC93383 is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor. LOC93383 is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. LOC93383 is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC93383 was changed in expression - 1.72, -2.17 and -1.3 fold in the three diseased patients compared to the control group. This indicates that LOC93383 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plKlO represents TIS11A protein TS11 (ZFP-36) and is located on chromosome 19q 13. The protein sequence encoded by ZFP-36 is represented in the public databases by the accession P26651 and is described in this patent by Seq LD 113. The nucleotide sequence is represented in the public sequence databases by the accession NM_003407 and is described in this patent by Seq ID 114. ZFP-36 is up-regulated by greater than 2-fold by Epas. ZFP-36 is induced by a factor of 2.59 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. ZFP-36 negatively regulates TNF-α synthesis (Taylor et al, Immunity 1996 May;4(5):445- 54). TNF-α is an important pro-inflammatory cytokine which contributes to the pathology of a number of diseases including rheumatoid arthritis. Thus our finding that ZFP-36 is induced by the hypoxic response enables the use of this gene for diagnosis and intervention in diseases which involve the hypoxic response. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, ZFP-36 was suppressed 2.78 fold in one of the patients. This is consistent with a role for ZFP-36 in the suppression of the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, ZFP-36 was changed in expression -1.16, 2.21 and 3.49 fold in the three diseased patients compared to the control group. Thus in at least some patients ZFP-36 plays a role in the process of atherogenesis.
Lysyl oxidase is represented in the public databases by the accession AAB21243 and is described in this patent by Seq ID 115. The nucleotide sequence is represented in the public sequence databases by the accession S78694 and is described in this patent by Seq ID 116. Lysyl oxidase is an extracellular enzyme that is responsible for the posttranslational oxidative deamination of peptidyl Lysine residues in precursors to fibrous Collagen and Elastin. Lysyl oxidase is up-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone plLlO represents MMP-12. The protein sequence encoded by MMP-12 is represented in the public databases by the accession P39900 and is described in this patent by Seq ID 117. The nucleotide sequence is represented in the public sequence databases by the accession NM_002426 and is described in this patent by Seq ID 118. MMP-12 is involved in tissue injury and remodelling. MMP-12 is up- regulated by greater than 2-fold by Epas. MMP-12 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. MMP-12 is induced by a factor of 5.64 in response to EL-13 and 4.07 in response to LL-4, indicating a positive role in Th2 immune responses. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. MMP-12 is induced by a factor of 3.81 in response to IL- 10, indicating a positive role in the response to IL-10. MMP-12 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. The Oxford BioMedica clone p2Cl l represents MEGFIO protein. The protein sequence encoded by MEGFIO protein is represented in the public databases by the accession NP_115822 and is described in this patent by Seq ID 119. The nucleotide sequence is represented in the public sequence databases by the accession NM_032446 and is described in this patent by Seq ID 120. MEGFIO protein is up-regulated by greater than 2- fold by Hif.
The Oxford BioMedica clone plM4 represents Metastasis suppressor protein. The protein sequence encoded by Metastasis suppressor protein is represented in the public databases by the accession NP_055566 and is described in this patent by Seq ID 121. The nucleotide sequence is represented in the public sequence databases by the accession NM_014751 and is described in this patent by Seq ID 122. Metastasis suppressor protein is up-regulated by greater than 2-fold by Epas. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Metastasis suppressor protein is induced by a factor of 2.72 in response to IL-10, indicating a positive role in the cellular response to IL-10.
The Oxford BioMedica clone plM20 represents MHC class-I chain-related protein A. The protein sequence encoded by MHC class-I chain-related protein A is represented in the public databases by the accession NP_000238 and is described in this patent by Seq ID 123. The nucleotide sequence is represented in the public sequence databases by the accession NM_000247 and is described in this patent by Seq ID 124. MHC class-I chain- related protein A functions as a stress-induced antigen that is broadly recognized by intestinal epithelial gamma delta T cells. MHC class-I chain-related protein A is up- regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, MHC class-I chain-related protein A was changed in expression -2.5, -2.86 and 1.13 fold in the three diseased patients compared to the control group. This indicates that MHC class-I chain-related protein A plays a role in the process of atherogenesis. The Oxford BioMedica clone plN14 represents Mitochondrial uncoupling protein 1. The protein sequence encoded by Mitochondrial uncoupling protein 1 is represented in the public databases by the accession NP_068380 and is described in this patent by Seq ID 125. The nucleotide sequence is represented in the public sequence databases by the accession NM_021734 and is described in this patent by Seq ID 126. Mitochondrial uncoupling protein 1 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Mitochondrial uncoupling protein 1 is repressed by a factor of 2.13 in response to IL-13 and 1.92 in response to IL-4, indicating a negative role in Th2 immune responses. Mitochondrial uncoupling protein 1 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone plN9 represents Monocyte differentiation antigen CD 14 precursor. The protein sequence encoded by CD 14 is represented in the public databases by the accession P08571 and is described in this patent by Seq ID 127. The nucleotide sequence is represented in the public sequence databases by the accession NM_000591 and is described in this patent by Seq ID 128. CD 14 is up-regulated by greater than 2-fold by Epas. CD14 co-operates with MD-2 and TLR4 to mediate the innate immune response to bacterial lipopolysaccharide. CD 14 is induced by a factor of 2.14 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections. CD 14 acts via MyD88, TIRAP and TRAF6, leading to NF-Kappa-B activation, cytokine secretion and the inflammatory response. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected, by hypoxia, CD14 is repressed in response to Interleukin- 1, by a factor of 16.67 fold at 6hr and 8.33 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. CD14 is suppressed by a factor of 10 at 6hr and 8.33 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. CD14 is repressed by a factor of 2.5 in response to IL-13 and 2.7 in response to IL-4, indicating a negative role in Th2 immune responses. CD 14 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
Myo-inositol monophosphatase A3 is represented in the public databases by the accession AAK52336 and is described in this patent by Seq ID 129 and Seq ID 131. The nucleotide sequence is represented in the public sequence databases by the accession NM_017813 and is described in this patent by Seq ID 130 and Seq ID 132. Myo-inositol monophosphatase A3 is up-regulated by greater than 2-fold by Hif. The Oxford BioMedica clone plM8 represents Myosin IXB (unconventional myosin-9B). The protein sequence encoded by Myosin LXB is represented in the public databases by the accession Q 13459 and is described in this patent by Seq ID 133. The nucleotide sequence is represented in the public sequence databases by the accession NM_004145 and is described in this patent by Seq LD 134. Myosin IXB is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Myosin XB is repressed in response to Interleukin- 1, by a factor of 4.35 fold at 6hr and 4.17 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Myosin LXB is suppressed by a factor of 2.56 at 6hr and 2.63 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Myosin LXB was up-regulated 2.1 fold in one of the patients. This indicates that Myosin IXB plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2H16 represents a NK inhibitory receptor (IRCl). The protein sequence encoded by NK inhibitory receptor (IRCl) is represented in the public databases by the accession CAB66145 and is described in this patent by Seq ID 135. The nucleotide sequence is represented in the public sequence databases by the accession AJ224864 and is described in this patent by Seq ID 136. NK inhibitory receptor (IRCl)is up-regulated by greater than 2-fold by Epas. NK inhibitory receptor (IRCl) is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. NK inhibitory receptor (IRCl) is induced by a factor of 2.14 in response to IL-13 and 2.38 in response to IL-4, indicating a positive role in Th2 immune responses. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, NK inhibitory receptor (IRCl) is repressed in response to TNFalpha, by a factor of 2.5 fold, indicating a negative role in pro-inflammatory responses involving this factor. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. NK inhibitory receptor (IRCl) is repressed in response to Interleukin- 1, by a factor of 3.85 fold at 6hr and 2.94 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. NK inhibitory receptor (IRCl) is suppressed by a factor of 2.17 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. Down-regulation of NK inhibitory receptor (ERCl) by pro-inflammatory cytokines is consistent with the role of these cytokines, but our observation of its hypoxia-induction is a surprising finding which implies the utility of this important molecule in the control of the response to ischaemic insult. The Oxford BioMedica clone p2C9 represents C-type lectin, superfamily member 2 (CLECSF2). The protein sequence encoded by CLECSF2 is represented in the public databases by the accession CAA65480 and is described in this patent by Seq ID 137. The nucleotide sequence is represented in the public sequence databases by the accession X96719 and is described in this patent by Seq ID 138. CLECSF2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. CLECSF2 is induced by a factor of 2 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. CLECSF2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone plL7 represents Ovarian carcinoma immunoreactive antigen. The protein sequence encoded by Ovarian carcinoma immunoreactive antigen is represented in the public databases by the accession NP_060300 and is described in this patent by Seq ID 139. The nucleotide sequence is represented in the public sequence databases by the accession NM_017830 and is described in this patent by Seq ID 140. Ovarian carcinoma immunoreactive antigen is up-regulated by greater than 2-fold by Epas. Ovarian carcinoma immunoreactive antigen is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. Ovarian carcinoma immunoreactive antigen is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. Ovarian carcinoma immunoreactive antigen is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Ovarian carcinoma immunoreactive antigen was changed in expression -1.64, -2.38 and - 2.17 fold in the three diseased patients compared to the control group. This indicates that Ovarian carcinoma immunoreactive antigen plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2D21 represents P1CDC21 protein, member of the MCM family of chromatin binding proteins. The protein sequence encoded by P1CDC21 protein is represented in the public databases by the accession CAA52801 and is described in this patent by Seq ID 141. The nucleotide sequence is represented in the public sequence databases by the accession X74792 and is described in this patent by Seq ID 142. P1CDC21 protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. P1CDC21 protein is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. The Oxford BioMedica clone p2E7 represents PD2 protein. The protein sequence encoded by PD2 protein is represented in the public databases by the accession CAC20564 and is described in this patent by Seq ID 143. The nucleotide sequence is represented in the public sequence databases by the accession NM_019088 and is described in this patent by Seq ID 144. PD2 protein is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, PD2 protein was changed in expression -2.5, -2.5 and -1.15 fold in the three diseased patients compared to the control group. This indicates that PD2 protein plays a role in the process of atherogenesis.
The Oxford BioMedica clone plL14 represents Peanut like-2 (PNUTL2). The protein sequence encoded by PNUTL2 is represented in the public databases by the accession AAG45673 and is described in this patent by Seq ID 145. The nucleotide sequence is represented in the public sequence databases by the accession AF176379 and is described in this patent by Seq ID 146. PNUTL2 acts to enhance cell death induced by TGF-beta. PNUTL2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. PNUTL2 is induced by a factor of 2.7 at 6hr and 1.62 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. PNUTL2 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. PNUTL2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. PNUTL2 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, PNUTL2 was changed in expression -3.45, -2.17 and -2.5 fold in the three diseased patients compared to the control group. This indicates that PNUTL2 plays a role in the process of atherogenesis. PNUTL2 is induced specifically by P53 (PMID: 10962554), and in accordance with this induction it has been shown to play a role in the induction of apoptosis (PMID: 11146656). Its suppression in atherosclerotic aorta may contribute to the hyperplasia associated with this disease.
The Oxford BioMedica clone p2D20 represents phenylalanine hydroxlase (PAH). The protein sequence encoded by PAH is represented in the public databases by the accession AAC51772 and is described in this patent by Seq D 147. The nucleotide sequence is represented in the public sequence databases by the accession U49897 and is described in this patent by Seq ID 148. PAH is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2C16 represents Phospholipid transfer protein. The protein sequence encoded by Phospholipid transfer protein is represented in the public databases by the accession P55058 and is described in this patent by Seq ID 149. The nucleotide sequence is represented in the public sequence databases by the accession NM_006227 and is described in this patent by Seq ID 150. Phospholipid transfer protein is up-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2L10 represents Pituitary homebox 1. The protein sequence encoded by Pituitary homebox 1 is represented in the public databases by the accession P78337 and is described in this patent by Seq ID 151. The nucleotide sequence is represented in the public sequence databases by the accession NM_002653 and is described in this patent by Seq ID 152. Pituitary homebox 1 is up-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone plN8 represents Pituitary tumour-transforming protein. The protein sequence encoded by plN8 is represented in the public databases by the accession NP_004210 and is described in this patent by Seq ID 153. The nucleotide sequence is represented in the public sequence databases by the accession NM_004219 and is described in this patent by Seq ID 154. Pituitary tumour-transforming protein is up- regulated by greater than 2-fold by Epas. Pituitary tumour-transforming protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. Pituitary tumour-transforming protein contains two PXXP motifs which are known to be required for its transforming and tumourigenic activities. The Oxford BioMedica clone p2L9 represents Plasma protease Cl inhibitor precursor. The protein sequence encoded by p2L9 is represented in the public databases by the accession P05155 and is described in this patent by Seq ID 155. The nucleotide sequence is represented in the public sequence databases by the accession NM_000062 and is described in this patent by Seq ID 156. Plasma protease Cl inhibitor is up-regulated by greater than 2-fold by Epas. Plasma protease Cl inhibitor is induced by a factor of 8.15 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. Plasma protease Cl inhibitor precursor is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone plM16 represents Plasminogen activator inhibitor-2 precursor (PAI-2). The protein sequence encoded by plM16 is represented in the public databases by the accession P05120 and is described in this patent by Seq ID 157. The nucleotide sequence is represented in the public sequence databases by the accession NM_002575 and is described in this patent by Seq ID 158. PAI-2 is known to inhibit Urokinase-type plasminogen activator. PAI-2 is up-regulated by greater than 2-fold by Epas. PAI-2 is induced by a factor of 2.42 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. PAI-2 is induced by a factor of 3 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone plM15 represents Pleckstrin homology-like domain, family A, member 1. The protein sequence encoded by plM15 is represented in the public databases by the accession S58222 and is described in this patent by Seq ID 159. The nucleotide sequence is represented in the public sequence databases by the accession AF220656 and is described in this patent by Seq ID 160. plM15 is up-regulated by greater than 2-fold by Epas. The sequence encoded by Seq ID 159 is suppressed by a factor of 7.69 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The sequence encoded by Seq ID 159 is suppressed by a factor of 2.56 in response to superoxide, indicating an anti- inflammatory function in ischaemia/reperfusion. The sequence encoded by Seq ID 159 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. The Oxford BioMedica clone plK12 represents Polyamine oxidase isoform- 1. The protein sequence encoded by Polyamine oxidase isoform- 1 is represented in the public databases by the accession AAK55763 and is described in this patent by Seq ID 161. The nucleotide sequence is represented in the public sequence databases by the accession AY033889 and is described in this patent by Seq ED 162. Polyamine oxidase isoform- 1 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Polyamine oxidase isoform- 1 is induced by a factor of 2.34 in response to IL-13 and 4.14 in response to IL-4, indicating a positive role in Th2 immune responses. Polyamine oxidase isoform- 1 is repressed by a factor of 2.27 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. Polyamine oxidase isoform- 1 catabolizes polyamines to produce 3-Aminopropanal. Often the substrates are toxic xenobiotics, but 3- Aminopropanal is a reactive aldehyde that mediates cell death in a number of cell types, including neuronal necrosis and glial apoptosis. (PMID: 11943872). The induction of this gene by cytokines which stimulate the Th2 response implies a role in inflammatory disease and tissue re-modelling. However, in a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Polyamine oxidase isoform- 1 was suppressed 2.56 fold in one of the patients and was down-regulated 3.13 fold in the other patient. There is evidence that IL-17 is the critical cytokine for neutrophil recruitment (PMID: 12171537), which is one of the key features of COPD (PMID: 12052325). Thus the repression of Polyamine oxidase isoform- 1 in COPD is consistent with the presence of elevated levels of IL-17, and Polyamine oxidase isoform- 1 may be a useful agent in the constructive recovery from COPD. The Oxford BioMedica clone plM22 represents a potential splice variant of Lysyl oxidase. The protein sequence encoded by plM22 is represented in the public databases by the accession P28300 and is described in this patent by Seq ID 163. The nucleotide sequence is represented in the public sequence databases by the accession NM_002317 and is described in this patent by Seq ID 164. The sequence encoded by Seq ID 164 is up- regulated by greater than 2-fold by Epas. The sequence encoded by Seq ID 164 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, The sequence encoded by Seq ID 164 was up-regulated 2.7 fold in one of the patients. This indicates that the sequence encoded by Seq ID 164 plays a role in the inflammation associated with COPD, and is consistent with the known role of lysyl oxidase in collagen and elastin cross-linking and tissue re-modelling. Our observation of the hypoxia induction of this molecule raises the important use of antagonists for the treatment of ischaemic disease.
The Oxford BioMedica clone plM6 represents Procollagen lysine, 2-oxoglutarate 5- dioxygenase 2 precursor (LH2). The protein sequence encoded by plM6 is represented in the public databases by the accession O00469 and is described in this patent by Seq ID 165 and 167. The nucleotide sequence is represented in the public sequence databases by the accession NM_000935 and is described in this patent by Seq ID 166 and Seq ID 168. LH2 is up-regulated by greater than 2-fold by both Hif and Epas. plM6 is preferentially induced by hypoxia in myocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for cardiac ischaemia and ischemic limbs. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, LH2 was up-regulated 1.83 fold in one of the patients and was up-regulated 2.57 fold in the other patient. This indicates that LH2 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LH2 was changed in expression -1.27, - 3.57 and 1.28 fold in the three diseased patients compared to the control group. This indicates that LH2 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plL23 represents Protein kinase Njmu-Rl. The protein sequence encoded by Protein kinase Njmu-Rl is represented in the public databases by the accession Q9HAS0 and is described in this patent by Seq ID 169. The nucleotide sequence is represented in the public sequence databases by the accession NM_022344 and is described in this patent by Seq ID 170. Protein kinase Njmu-Rl is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Protein kinase Njmu-Rl is induced by a factor of 2.78 at 6hr and 2.07 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Protein kinase Njmu-Rl is repressed by a factor of 2.5 in response to IL-10, indicating a negative role in the response to IL-10. Protein kinase Njmu-Rl is suppressed by a factor of 2.5 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. Protein kinase Njmu-Rl is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Protein kinase Njmu-Rl was changed in expression -5, -1.09 and -1.37 fold in the three diseased patients compared to the control group. This indicates that Protein kinase Njmu-Rl plays a role in the process of atherogenesis.
The Oxford BioMedica clone pi LI represents Protein tyrosine phosphatase receptor type, f polypeptide. The protein sequence encoded by plLl is represented in the public databases by the accession P10586 and is described in this patent by Seq ID 171. The nucleotide sequence is represented in the public sequence databases by the accession NM_002840 and is described in this patent by Seq ID 172. Protein tyrosine phosphatase receptor type, f polypeptide is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Protein tyrosine phosphatase receptor type, f polypeptide is repressed by a factor of 2.08 at 24hr in response to the pro-inflammatory cytokine Interleukin-17, indicating a negative role in pro-inflammatory responses involving this factor. The Oxford BioMedica clone p2D16 represents Protein tyrosine phosphatase receptor type, sigma. The protein sequence encoded by p2D16 is represented in the public databases by the accession NP_002841 and is described in this patent by Seq ID 173. The nucleotide sequence is represented in the public sequence databases by the accession NM_002850 and is described in this patent by Seq ID 174. Protein tyrosine phosphatase receptor type, sigma is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Protein tyrosine phosphatase receptor type, sigma is induced by a factor of 2.04 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone plM3 represents Protein tyrosine phosphatase, non-receptor type 1. The protein sequence encoded by plM3 is represented in the public databases by the accession PI 8031 and is described in this patent by Seq ID 175. The nucleotide sequence is represented in the public sequence databases by the accession NM_002827 and is described in this patent by Seq ID 176. Protein tyrosine phosphatase, non-receptor type 1 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plM18 represents nuclear receptor subfamily 5, group A, member 2 (NR5A2). The protein sequence encoded by NR5A2 is represented in the public databases by the accession O00482 and is described in this patent by Seq ID 177. The nucleotide sequence is represented in the public sequence databases by the accession AF146343 and is described in this patent by Seq ID 178. NR5A2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. NR5A2 is induced by a factor of 1.72 at 6hr and 2.18 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone p2C6 represents Pyrroline-5-carboxylate synthetase. The protein sequence encoded by p2C6 is represented in the public databases by the accession
XP_005713 and is described in this patent by Seq ID 179. The nucleotide sequence is represented in the public sequence databases by the accession XM_005713 and is described in this patent by Seq ID 180. Pyrroline-5-carboxylate synthetase is up-regulated by greater than 2-fold by Hif. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Pyrroline-5-carboxylate synthetase was changed in expression -2.04, -2.44 and -1.12 fold in the three diseased patients compared to the control group. This indicates that Pyrroline- 5-carboxylate synthetase plays a role in the process of atherogenesis.
The Oxford BioMedica clone plLl l represents RAS-related protein RAB-l lB. The protein sequence encoded by RAS-related protein RAB-l lB is represented in the public databases by the accession Q 15907 and is described in this patent by Seq ID 181. The nucleotide sequence is represented in the public sequence databases by the accession NM_004218 and is described in this patent by Seq ID 182. RAS-related protein RAB-l lB is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, RAS-related protein RAB-l lB is repressed in response to Interleukin- 1, by a factor of 3.85 fold at 6hr and 2.86 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. RAS-related protein RAB-l lB is suppressed by a factor of 2.22 at 6hr and 1.96 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. RAS-related protein RAB-l lB is repressed by a factor of 1.92 in response to IL-13 and 2.33 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, RAS-related protein RAB-l lB was up-regulated 1.95 fold in one of the patientsand was up-regulated 2.75 fold in the other patient. This indicates that RAS-related protein RAB-l lB plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, RAS-related protein RAB-1 IB was changed in expression -1.56, -2.38 and -1.75 fold in the three diseased patients compared to the control group. This indicates that RAS-related protein RAB-1 IB plays a role in the process of atherogenesis.
The Oxford BioMedica clone plL4 represents SCA2. The protein sequence encoded by SCA2 is represented in the public databases by the accession AAB 19200 and is described in this patent by Seq ID 183. The nucleotide sequence is represented in the public sequence databases by the accession U70323 and is described in this patent by Seq TD 184. SCA2 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, SCA2 is induced in response to TNFalpha, by a factor of 2.19 fold, indicating a positive role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, SCA2 was changed in expression 1.05, 2.18 and 1.38 fold in the three diseased patients compared to the control group. This indicates that SCA2 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I2 represents a SEC7 homolog. The protein sequence encoded by p2I2 is represented in the public databases by the accession NP_036587 and is described in this patent by Seq ID 185. The nucleotide sequence is represented in the public sequence databases by the accession NM_012455 and is described in this patent by Seq ID 186. The SEC7 homolog is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2M5 represents Serine threonine protein kinase. The protein sequence encoded by Serine threonine protein kinase is represented in the public databases by the accession NP_009202 and is described in this patent by Seq ID 187. The nucleotide sequence is represented in the public sequence databases by the accession AB023182 and is described in this patent by Seq ID 188. Serine threonine protein kinase is up-regulated by greater than 2-fold by Epas. Serine threonine protein kinase is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2I18 represents Sialic acid binding Ig-like lectin 7. The protein sequence encoded by p2I18 is represented in the public databases by the accession NP_055200 and is described in this patent by Seq ID 189. The nucleotide sequence is represented in the public sequence databases by the accession NM_014385 and is described in this patent by Seq ID 190. Sialic acid binding Ig-like lectin 7 is up-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone p2H13 represents a gene that is similar to Upregulated by 1,25-dihydroxyvitamin D-3. The protein sequence encoded by p2H13 is represented in the public databases by the accession XP_041721 and is described in this patent by Seq ID 191. The nucleotide sequence is represented in the public sequence databases by the accession AK026436 and is described in this patent by Seq ID 192. The sequence encoded by SEQ ID 192 is up-regulated by greater than 2-fold by Hif. The Oxford BioMedica clone plK24 represents Solute carrier family 22 (extraneuronal monoamine transporter). The protein sequence encoded by Solute carrier family 22 is represented in the public databases by the accession NP_068812 and is described in this patent by Seq ID 193. The nucleotide sequence is represented in the public sequence databases by the accession NM_021977 and is described in this patent by Seq ID 194. Solute carrier family 22 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Solute carrier family 22 is repressed by a factor of 1.79 in response to IL-13 and 2.27 in response to IL-4, indicating a negative role in Th2 immune responses. Solute carrier family 22 is suppressed by a factor of 2.22 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Solute carrier family 22 was changed in expression -1.32, -5.56 and 1.06 fold in the three diseased patients compared to the control group. This indicates that Solute carrier family 22 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2C10 represents Solute carrier family 6 (neurotransmitter, creatine) CTl. The protein sequence encoded by p2C10 is represented in the public databases by the accession P48029 and is described in this patent by Seq ID 195. The nucleotide sequence is represented in the public sequence databases by the accession NM_005629 and is described in this patent by Seq ID 196. The seqeunce encoded by Seq ID 195 is essential for the uptake of Creatine. CTl is up-regulated by greater than 2-fold by Epas. CTl is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. CTl is suppressed by a factor of 2 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. CTl is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. CTl is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2D22 represents Solute carrier family 6 member 8 which is located on chromosome X. The protein sequence encoded by p2D22 is represented in the public databases by the accession CAA91442 and is described in this patent by Seq ID 197. The nucleotide sequence is represented in the public sequence databases by the accession Z66539 and is described in this patent by Seq ID 198. Solute carrier family 6 member 8 is up-regulated by greater than 2-fold by Epas. Solute carrier family 6 member 8 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Solute carrier family 6 member 8 was changed in expression 2.52, 2.44 and 1.24 fold in the three diseased patients compared to the control group. This indicates that Solute carrier family 6 member 8 plays a role in the process of atherogenesis. The Oxford BioMedica clone plM5 represents Spermatid perinuclear RNA-binding protein. The protein sequence encoded by plM5 is represented in the public databases by the accession AF333337 and is described in this patent by Seq ID 199. The nucleotide sequence is represented in the public sequence databases by the accession AL136866 and is described in this patent by Seq ID 200. Spermatid perinuclear RNA-binding protein is up-regulated by greater than 2-fold by Hif. Spermatid perinuclear RNA-binding protein is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Spermatid perinuclear RNA-binding protein is repressed by a factor of 2.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. Spermatid perinuclear RNA-binding protein is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2L13 represents a splice variant of Fibronectin,. The protein sequence encoded by p2L13 is represented in the public databases by the accession P02751 and is described in this patent by Seq ID 201. The nucleotide sequence is represented in the public sequence databases by the accession X02761 and is described in this patent by Seq ID 202. The sequence encoded by SEQ ID 202 is up-regulated by greater than 2-fold by both Hif and Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The sequence encoded by SEQ ID 202 is repressed by a factor of 2.22 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, The sequence encoded by SEQ ID 202 is repressed in response to Interleukin- 1, by a factor of 14.29 fold at 6hr and 14.29 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. The sequence encoded by SEQ ID 202 is suppressed by a factor of 10 at 6hr and 11.11 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. The sequence encoded by SEQ ID 202 is suppressed by a factor of 2.56 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by SEQ ID 202 was changed in expression -2.44, 1.42 and -2.08 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by SEQ ID 202 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2E9 represents Splice variant of KIAA1536 protein. The protein sequence encoded by p2E9 is represented in the public databases by the accession BAA96060 and is described in this patent by Seq LD 203. The nucleotide sequence is represented in the public sequence databases by the accession AB040969 and is described in this patent by Seq ID 204. The sequence encoded by SEQ ID 204 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by SEQ ID 204 was changed in expression -1.75, -2.5 and -1.61 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by SEQ ID 204 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I7 represents STXBP1. The protein sequence encoded by p2I7 is represented in the public databases by the accession AAC39689 and is described in this patent by Seq LD 205. The nucleotide sequence is represented in the public sequence databases by the accession AF004563 and is described in this patent by Seq ID 206. STXBP1 is implicated in vesicle trafficking and neurotransmitter release. STXBP1 is up- regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, STXBP1 was changed in expression 1.78, 11.31 and 1.77 fold in the three diseased patients compared to the control group. This indicates that STXBP1 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2I3 represents SULTIAI sulphotransferase, cytosohc. The protein sequence encoded by SULTIAI is represented in the public databases by the accession AAC51816 and is described in this patent by Seq ID 207. The nucleotide sequence is represented in the public sequence databases by the accession U52852 and is described in this patent by Seq ID 208. SULTIAI is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, SULTIAI is induced in response to TNFalpha, by a factor of 2.61 fold, indicating a positive role in pro-inflammatory responses involving this factor. SULTIAI is suppressed by a factor of 2.44 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. SULTIAI is repressed by a factor of 2.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, SULTIAI was changed in expression - 1.72, -2.17 and -1.3 fold in the three diseased patients compared to the control group. This indicates that SULTIAI plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2H17 represents Tensin. The protein sequence encoded by Tensin is represented in the public databases by the accession NP_072174 and is described in this patent by Seq ID 209. The nucleotide sequence is represented in the public sequence databases by the accession NM_022648 and is described in this patent by Seq ID 210. Tensin is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. Tensin is repressed by a factor of 2.04 in response to IL-13 and 1.64 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Tensin was changed in expression -1.64, -2.27 and 1.22 fold in the three diseased patients compared to the control group. This indicates that Tensin plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2G16 represents TNF 4- IBB ligand. The protein sequence encoded by p2G16 is represented in the public databases by the accession P41273 and is described in this patent by Seq ID 211. The nucleotide sequence is represented in the public sequence databases by the accession NM_003811 and is described in this patent by Seq ID 212. TNF 4- IBB ligand may have a role in activation-induced cell death. TNF 4- 1BB ligand is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNF 4- IBB ligand is induced by a factor of 2.43 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
The Oxford BioMedica clone plN15 represents the Tyrosine kinase, Syk. The protein sequence encoded by Syk is represented in the public databases by the accession P43405 and is described in this patent by Seq ID 213. The nucleotide sequence is represented in the public sequence databases by the accession NM_003177 and is described in this patent by Seq ED 214. Syk is up-regulated by greater than 2-fold by both Hif and Epas. Syk is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Syk is repressed in response to Interleukin- 1, by a factor of 3.7 fold at 6hr and 3.23 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. Syk is suppressed by a factor of 2.17 at 6hr and 1.61 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. Syk is suppressed by a factor of 2.04 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors. Syk is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2A22 represents Ubiquitin associated protein. The protein sequence encoded by Ubiquitin associated protein is represented in the public databases by the accession NPJ357609 and is described in this patent by Seq ID 215. The nucleotide sequence is represented in the public sequence databases by the accession NM_016525 and is described in this patent by Seq ID 216. Ubiquitin associated protein is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Ubiquitin associated protein is repressed by a factor of 2.86 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Ubiquitin associated protein was suppressed 2.04 fold in one of the patients. This indicates that Ubiquitin associated protein plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Ubiquitin associated protein was changed in expression 3.7, 2.8 and -1.09 fold in the three diseased patients compared to the control group. This indicates that Ubiquitin associated protein plays a role in the process of atherogenesis. The Oxford BioMedica clone p2I5 represents an unnamed protein product. The protein sequence encoded by p2I5 is represented in the public databases by the accession BAB55306 and is described in this patent by Seq ID 217. The nucleotide sequence is represented in the public sequence databases by the accession AK027699 and is described in this patent by Seq ID 218. The sequence encoded by SEQ ID 218 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by SEQ ID 218 is induced by a factor of 2.65 at 6hr and 1.71 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor. The sequence encoded by SEQ ID 218 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by SEQ ID 218 was changed in expression -2, -2.38 and -2.56 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by SEQ ID 218 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2Il represents Villin 1. The protein sequence encoded by p2Il is represented in the public databases by the accession P09327 and is described in this patent by Seq ID 219. The nucleotide sequence is represented in the public sequence databases by the accession NM_007127 and is described in this patent by Seq ID 220. Villin 1 is up-regulated by greater than 2-fold by Epas. Villin 1 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
Yes-associated protein homolog DKFZp596I1419 is represented in the public databases by the accession CAB43275 and is described in this patent by Seq ID 221. The nucleotide sequence is represented in the public sequence databases by the accession AL050107 and is described in this patent by Seq ID 222. The seqeunce encoded by SEQ ID 222 is up- regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plN7 represents YYl and E4TF1 associated factor apoptin associated protein APAP1. The protein sequence encoded by plN7 is represented in the public databases by the accession BAA89486 and is described in this patent by Seq ID 223 and SEQ ID 225. The nucleotide sequence is represented in the public sequence databases by the accession AB029551 and is described in this patent by Seq ID 224 and Seq ID 226. YYl and E4TF1 associated factor apoptin associated protein APAP1 is up-regulated by greater than 2-fold by Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, YYl and E4TF1 associated factor apoptin associated protein APAP1 was up-regulated 2.07 fold in one of the patientsand was up-regulated 1.63 fold in the other patient. This indicates that YYl and E4TF1 associated factor apoptin associated protein APAP1 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, YYl and E4TF1 associated factor apoptin associated protein APAP1 was changed in expression -1.35, -2.33 and 1.52 fold in the three diseased patients compared to the control group. This indicates that YYl and E4TF1 associated factor apoptin associated protein APAP1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Ll l represents Acinus L. The protein sequence encoded by Acinus L is represented in the public databases by the accession AAD56724 and is described in this patent by Seq ID 227. The nucleotide sequence is represented in the public sequence databases by the accession AF 12476 and is described in this patent by Seq ED 228. Acinus L is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Acinus L is induced in response to TNFalpha, by a factor of 3.11 fold, indicating a positive role in pro-inflammatory responses involving this factor. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Acinus L is repressed in response to Interleukin- 1, by a factor of 2.63 fold at 6hr and 3.23 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Acinus L is suppressed by a factor of 4.17 at 6hr and 2.38 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. Acinus L is repressed by a factor of 2.17 in response to EL- Vindicating a negative role in Th2 immune responses. Acinus L is suppressed by a factor of 2.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Acinus L was up-regulated 2.91 fold in one of the patientsAcinus L plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2H5 represents the hypothetical protein KIAA0742 . The protein sequence encoded by p2H5 is represented in the public databases by the accession BAA34462 and is described in this patent by Seq ID 229. The nucleotide sequence is represented in the public sequence databases by the accession ABO 18285 and is described in this patent by Seq ID 230. KIAA0742 is up-regulated by greater than 2-fold by both Hif and Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, KIAA0742 was up-regulated 19.8 fold in one of the patientsand was up-regulated 7.4 fold in the other patient. This indicates that KIAA0742 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone plN12 represents the hypothetical protein KLAA1147 . The protein sequence encoded by p IN 12 is represented in the public databases by the accession BAA86461 and is described in this patent by Seq ID 231. The nucleotide sequence is represented in the public sequence databases by the accession AB032973 and is described in this patent by Seq LD 232. KIAA1147 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, KIAA1147 is induced in response to TNFalpha, by a factor of 2.39 fold, indicating a positive role in pro-inflammatory responses involving this factor. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. KIAA1147 is induced by a factor of 2.93 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, KIAA1147 was changed in expression -1.69, -2.56 and -1.61 fold in the three diseased patients compared to the control group. This indicates that KIAA1147 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plN5 represents the hypothetical protein DKFZP564B167. The protein sequence encoded by plN5 is represented in the public databases by the accession NP_056230 and is described in this patent by Seq ID 233. The nucleotide sequence is represented in the public sequence databases by the accession NM_015415 and is described in this patent by Seq ID 234. DKFZP564B167 is up-regulated by greater than 2-fold by Epas. DKFZP564B167 is suppressed by a factor of 3.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2H2 represents the hypothetical protein FLJ22704. The protein sequence encoded by p2H2 is represented in the public databases by the accession XP_051421 and is described in this patent by Seq ID 235. The nucleotide sequence is represented in the public sequence databases by the accession XM_051421 and is described in this patent by Seq ID 236. FLJ22704 is up-regulated by greater than 2-fold by Epas. FLJ22704 is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, FLJ22704 is induced in response to TNFalpha, by a factor of 2.02 fold, indicating a positive role in pro-inflammatory responses involving this factor. FLJ22704 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, FLJ22704 was up-regulated 2.05 fold in one of the patientsand was up-regulated 2.07 fold in the other patient. This indicates that FLJ22704 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ22704 was changed in expression 1.09, -2.08 and -1.14 fold in the three diseased patients compared to the control group. This indicates that FLJ22704 plays a role in the process of atherogenesis.
The Oxford BioMedica clone pi LI 2 represents the hypothetical protein PRO0195 . The protein sequence encoded by plL12 is represented in the public databases by the accession NP_054838 and is described in this patent by Seq ID 237. The nucleotide sequence is represented in the public sequence databases by the accession NM_014119 and is described in this patent by Seq ID 238. The sequence encoded by Seq ID 238 is up- regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 238 was changed in expression -1.69, 10.69 and 1.16 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 238 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2C17 represents the hypothetical protein DKFZp434I225. The protein sequence encoded by p2C17 is represented in the public databases by the accession CAB56026 and is described in this patent by Seq ID 239. The nucleotide sequence is represented in the public sequence databases by the accession ALl 17637 and is described in this patent by Seq ED 240. The sequence encoded by Seq ID 240 is up- regulated by greater than 2-fold by Hif. The sequence encoded by Seq ID 240 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 240 was changed in expression -3.03, -1.02 and -2.13 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 240 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Hl l represents the hypothetical protein Estradiol induced. The protein sequence encoded by p2Hl l is represented in the public databases by the accession NP_055182 and is described in this patent by Seq ID 241 and Seq ID 243. The nucleotide sequence is represented in the public sequence databases by the accession NM_014367 and is described in this patent by Seq ID 242 and Seq ID 244. The sequence encoded by Seq ID 242 is up-regulated by greater than 2-fold by Hif. The sequence encoded by Seq ID 242 is suppressed by a factor of 2.86 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2H4 represents the hypothetical protein FLJ 10199. The protein sequence encoded by p2H4 is represented in the public databases by the accession NP_060492 and is described in this patent by Seq ID 245. The nucleotide sequence is represented in the public sequence databases by the accession NM_018022 and is described in this patent by Seq ID 246. FLJ10199 is up-regulated by greater than 2-fold by both Hif and Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ 10199 was changed in expression 2.44, 2.03 and 1.1 fold in the three diseased patients compared to the control group. This indicates that FLJ 10199 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2H7 represents the hypothetical protein FLJ 10276. The protein sequence encoded by p2H7 is represented in the public databases by the accession NP_060515 and is described in this patent by Seq ID 247. The nucleotide sequence is represented in the public sequence databases by the accession NM_018045 and is described in this patent by Seq ID 248. FLJ 10276 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ 10276 was changed in expression -1.18, -2.5 and 1.09 fold in the three diseased patients compared to the control group. This indicates that FLJ 10276 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2L7 represents the hypothetical protein FLJ 13758 which is a putative tumour suppressor. The protein sequence encoded by p2L7 is represented in the public databases by the accession NP_115761 and is described in this patent by Seq ID 249. The nucleotide sequence is represented in the public sequence databases by the accession NM_032385 and is described in this patent by Seq ID 250. FLJ 13758 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. FLJ13758 is repressed by a factor of 2.7 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. FLJ 13758 is suppressed by a factor of 2.04 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. FLJ13758 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. The Oxford BioMedica clone p2C13 represents the hypothetical protein FLJ20315. The protein sequence encoded by p2C13 is represented in the public databases by the accession NP_060233 and is described in this patent by Seq ID 251. The nucleotide sequence is represented in the public sequence databases by the accession NM_017763 and is described in this patent by Seq ID 252. FLJ20315 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ20315 was changed in expression -1.72, -2.04 and -1.67 fold in the three diseased patients compared to the control group. This indicates that FLJ20315 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2D24 represents the hypothetical protein FLJ20628. The protein sequence encoded by p2D24 is represented in the public databases by the accession NP_060380 and is described in this patent by Seq ID 253. The nucleotide sequence is represented in the public sequence databases by the accession BC010365 and is described in this patent by Seq TD 254. FLJ20628 is up-regulated by greater than 2-fold by Hif. FLJ20628 is induced by a factor of 61.96 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. FLJ20628 is induced by a factor of 10.81 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone plK21 represents the hypothetical protein, FLJ23306. The protein sequence encoded by plK21 is represented in the public databases by the accession BAB 15603 and is described in this patent by Seq ID 255. The nucleotide sequence is represented in the public sequence databases by the accession AK026959 and is described in this patent by Seq ID 256. FLJ23306 is up-regulated by greater than 2-fold by Epas. FLJ23306 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, FLJ23306 is induced in response to TNFalpha, by a factor of 2.01 fold, indicating a positive role in pro-inflammatory responses involving this factor. FLJ23306 is induced by a factor of 2.55 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. FLJ23306 is induced by a factor of 2.06 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. FLJ23306 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FLJ23306 was changed in expression -2.27, -1.96 and 1.5 fold in the three diseased patients compared to the control group. This indicates that FLJ23306 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2G14 represents the hypothetical protein, FLJ23312. The protein sequence encoded by p2G14 is represented in the public databases by the accession NP_079028 and is described in this patent by Seq ID 257. The nucleotide sequence is represented in the public sequence databases by the accession NM_024752 and is described in this patent by Seq ID 258. FLJ23312 is up-regulated by greater than 2-fold by Epas. The Oxford BioMedica clone plM7 represents the hypothetical protein, MGC4595. The protein sequence encoded by plM7 is represented in the public databases by the accession NP_116127 and is described in this patent by Seq ID 259. The nucleotide sequence is represented in the public sequence databases by the accession NM_032738 and is described in this patent by Seq ED 260. MGC4595 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. MGC4595 is repressed by a factor of 1.67 in response to IL-13 and 2.27 in response to IL- 4, indicating a negative role in Th2 immune responses. MGC4595 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, MGC4595 was changed in expression -1.56, -2.04 and -1.47 fold in the three diseased patients compared to the control group. This indicates that MGC4595 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2G22 represents the hypothetical protein, PP5395. The protein sequence encoded by p2G22 is represented in the public databases by the accession NP_068378 and is described in this patent by Seq ID 261. The nucleotide sequence is represented in the public sequence databases by the accession NM_021732 and is described in this patent by Seq ID 262. PP5395 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plM19 represents a hypothetical protein similar to CGI-78. The protein sequence encoded by plM19 is represented in the public databases by the accession NP_057106 and is described in this patent by Seq ID 263. The nucleotide sequence is represented in the public sequence databases by the accession NM_031301 and is described in this patent by Seq ID 264. The sequence encoded by Seq ID 264 is up- regulated by greater than 2-fold by Epas. The sequence encoded by Seq ID 264 is induced by a factor of 2.18 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions, the sequence encoded by Seq ID 264 is induced by a factor of 2.19 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2Hl represents the hypothetical protein, XP_038788. The protein sequence encoded by p2Hl is represented in the public databases by the accession XP_038788 and is described in this patent by Seq ID 265. The nucleotide sequence is represented in the public sequence databases by the accession AK002171 and is described in this patent by Seq ID 266. XP_038788 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. XP_038788 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to EL- 10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. XP_038788 is repressed by a factor of 1.96 in response to IL-13 and 2.33 in response to IL-4, indicating a negative role in Th2 immune responses. XP_038788 is suppressed by a factor of 3.57 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, XP_038788 was changed in expression 1.08, -3.03 and 1.24 fold in the three diseased patients compared to the control group. This indicates that XP_038788 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2H3 represents the hypothetical protein, XP_047730. The protein sequence encoded by p2H3 is represented in the public databases by the accession XP_047730 and is described in this patent by Seq ID 267. The nucleotide sequence is represented in the public sequence databases by the accession AK023833 and is described in this patent by Seq ID 268. XP_047730 is up-regulated by greater than 2-fold by both Hif and Epas. XP_047730 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. XP_047730 is induced by a factor of 2.05 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. XP_047730 is suppressed by a factor of 2.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro- inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, XP_047730 was changed in expression -1.19, -2.86 and -1.22 fold in the three diseased patients compared to the control group. This indicates that XP_047730 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I13 represents the cDNA FLJ14112 fis clone, MAMMA 1001683. The protein sequence encoded by p2I13 is described in this patent by Seq ID 269. The nucleotide sequence is represented in the public sequence databases by the accession AK024174 and is described in this patent by Seq ID 270. p2I13 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 270 is induced by a factor of 2.51 at 6hr and 1.66 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 270 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 270 was changed in expression -2.86, -3.33 and -2.33 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 270 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2G24 represents the cDNA clone, YR92D05. The protein sequence encoded by p2G24 is described in this patent by Seq ID 271. The nucleotide sequence is represented in the public sequence databases by the accession AF085961 and is described in this patent by Seq ID 272. YR92D05 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. YR92D05 is induced by a factor of 2.55 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. YR92D05 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2D18 represents the cDNA clone, IMAGE:4588421. The protein sequence encoded by p2D18 is described in this patent by Seq LD 273. The nucleotide sequence is represented in the public sequence databases by the accession BG422848 and is described in this patent by Seq LD 274. The sequence encoded by Seq ID 274 is up-regulated by greater than 2-fold by Hif. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 274 was changed in expression -1.64, - 2.27 and -1.39 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 274 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2C18 represents the cDNA FLJ23111 fis clone, LNG07835. The protein sequence encoded by p2C18 is described in this patent by Seq ED 275. The nucleotide sequence is represented in the public sequence databases by the accession AK026764 and is described in this patent by Seq ID 276. The sequence encoded by Seq ID 276 is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 276 is induced by a factor of 2.19 at 6hr and 1.56 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 276 was changed in expression -2.86, -2.86 and -2 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 276 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2G13 represents an EST. The protein sequence encoded by p2G13 is described in this patent by Seq ID 277. The nucleotide sequence is represented in the public sequence databases by the accession BG774858 and is described in this patent by Seq ID 278. The sequence encoeded by Seq ID 278 is up-regulated by greater than 2- fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The sequence encoeded by Seq ID 278 is repressed by a factor of 1.92 in response to IL-13 and 2 in response to IL-4, indicating a negative role in Th2 immune responses.
An EST is described in this patent by Seq ID 279. The nucleotide sequence is represented in the public sequence databases by the accession T66907 and is described in this patent by Seq ID 280. The seqeunce encoded by Seq ID 279 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plL9 represents an EST. The protein sequence encoded by plL9 is described in this patent by Seq ID 281. The nucleotide sequence is represented in the public sequence databases by the accession R84242 and is described in this patent by Seq ID 282. The sequence encoeded by Seq ID 282 is up-regulated by greater than 2-fold by Epas. The sequence encoeded by Seq ID 282 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone plL22 represents an EST. The protein sequence encoded by plL22 is described in this patent by Seq ID 283. The nucleotide sequence is represented in the public sequence databases by the accession T83864 and is described in this patent by Seq ID 284. The sequence encoeded by Seq ID 284 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoeded by Seq ID 284 is induced by a factor of 2.87 at 6hr and 2.17 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The sequence encoeded by Seq ID 284 is repressed by a factor of 2.27 in response to IL-10, indicating a negative role in the response to IL-10. plL22 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoeded by Seq ID 284 was changed in expression -2.04, 1.83 and 1.2 fold in the three diseased patients compared to the control group. This indicates that the sequence encoeded by Seq ED 284 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2E4 represents an EST. The protein sequence encoded by p2E4 is described in this patent by Seq ID 285. The nucleotide sequence is represented in the public sequence databases by the accession AA704858 and is described in this patent by Seq ED 286. The sequence encoeded by Seq ID 286 is up-regulated by greater than 2- fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoeded by Seq ID 286 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. The sequence encoeded by Seq ID 286 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoeded by Seq ID 286 was changed in expression 5.09, 3.38 and -1.15 fold in the three diseased patients compared to the control group. This indicates that the sequence encoeded by Seq ID 286 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2C14 represents an EST. The protein sequence encoded by p2C14 is described in this patent by Seq ID 287. The nucleotide sequence is represented in the public sequence databases by the accession T64894 and is described in this patent by Seq ID 288. p2C14 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 288 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The seqeunce encoded by Seq ID 288 is repressed by a factor of 3.85 in response to IL-13 and 2.5 in response to IL-4, indicating a negative role in Th2 immune responses.
The Oxford BioMedica clone p2I8 represents an EST. The protein sequence encoded by p2I8 is described in this patent by Seq ID 289. The nucleotide sequence is represented in the public sequence databases by the accession AI032477 and is described in this patent by Seq ID 290. The seqeunce encoded by Seq ID 290 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 290 is induced by a factor of 2.09 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 290 is repressed by a factor of 2.17 in response to IL-10, indicating a negative role in the response to IL-10. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 290 was changed in expression -2.13, 1.65 and -1.67 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 290 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I9 represents an EST. The protein sequence encoded by p2I9 is described in this patent by Seq ID 291. The nucleotide sequence is represented in the public sequence databases by the accession AI056809 and is described in this patent by Seq ID 292. The seqeunce encoded by Seq ID 292 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 292 is induced by a factor of 3.35 at 6hr and 1.57 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The seqeunce encoded by Seq ID 292 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 292 was changed in expression -3.85, -3.23 and -2.27 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 292 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Il 1 represents an EST. The protein sequence encoded by p2Il l is described in this patent by Seq ID 293. The nucleotide sequence is represented in the public sequence databases by the accession AI032945 and is described in this patent by Seq ID 294. The seqeunce encoded by Seq ID 294 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 294 is induced by a factor of 2.31 at 6hr and 1.87 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 294 is repressed by a factor of 3.03 in response to IL-10, indicating a negative role in the response to IL-10. p2Il l is suppressed by a factor of 2.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The seqeunce encoded by Seq ID 294 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 294 was changed in expression -3.33, 1.52 and -1.35 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq TD 294 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I19 represents an EST. The protein sequence encoded by p2I19 is described in this patent by Seq ID 295. The nucleotide sequence is represented in the public sequence databases by the accession AI189495 and is described in this patent by Seq ID 296. The seqeunce encoded by Seq ID 296 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ED 296 is induced by a factor of 2.69 at 6hr and 1.5 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The seqeunce encoded by Seq ID 296 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 296 was changed in expression -2.94, -4.17 and -2.63 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 296 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2El represents an EST. The protein sequence encoded by p2El is described in this patent by Seq ID 297. The nucleotide sequence is represented in the public sequence databases by the accession AA679426 and is described in this patent by Seq ID 298. The seqeunce encoded by Seq ID 298 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plMl represents an EST. The protein sequence encoded by plMl is described in this patent by Seq ID 299. The nucleotide sequence is represented in the public sequence databases by the accession T98458 and is described in this patent by Seq ID 300. The seqeunce encoded by Seq ID 300 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 300 is induced by a factor of 2.97 at 6hr and 1.63 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The seqeunce encoded by Seq ID 300 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 300 was changed in expression -3.13, -2.5 and -2.08 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 300 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2B2 represents an EST. The protein sequence encoded by p2B2 is described in this patent by Seq ED 301. The nucleotide sequence is represented in the public sequence databases by the accession T83558 and is described in this patent by Seq ID 302. The seqeunce encoded by Seq ID 302 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 302 is induced by a factor of 2.51 at 6hr and 1.75 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 302 is repressed by a factor of 2.22 in response to IL-10, indicating a negative role in the response to IL-10. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 302 was changed in expression -2.86, 1.03 and - 1.64 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 302 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A13 represents an EST. The protein sequence encoded by p2A13 is described in this patent by Seq ID 303. The nucleotide sequence is represented in the public sequence databases by the accession BE219865 and is described in this patent by Seq ID 304. The seqeunce encoded by Seq ID 304 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 304 was changed in expression 3.35, 2.64 and 1.09 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 304 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2E3 represents an EST. The protein sequence encoded by p2E3 is described in this patent by Seq ID 305. The nucleotide sequence is represented in the public sequence databases by the accession AA701314 and is described in this patent by Seq ID 306. The seqeunce encoded by Seq ED 306 is up-regulated by greater than 2-fold by Epas. The seqeunce encoded by Seq ID 306 is suppressed by a factor of 2 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2E2 represents an EST. The protein sequence encoded by p2E2 is described in this patent by Seq ID 307. The nucleotide sequence is represented in the public sequence databases by the accession AW161661 and is described in this patent by Seq ID 308. The seqeunce encoded by Seq ID 308 is up-regulated by greater than 2-fold by Epas. The seqeunce encoded by Seq ID 308 is suppressed by a factor of 2.94 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The seqeunce encoded by Seq ID 308 is suppressed by a factor of 2.17 in response to superoxide, indicating an anti- inflammatory function in ischaemia/reperfusion. The seqeunce encoded by Seq ID 308 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2E10 represents an EST. The protein sequence encoded by p2E10 is described in this patent by Seq ID 309. The nucleotide sequence is represented in the public sequence databases by the accession AA626254 and is described in this patent by Seq ID 310. The seqeunce encoded by Seq ID 310 is up-regulated by greater than 2-fold by Hif. The seqeunce encoded by Seq ID 310 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 310 was changed in expression -1.08, -2.17 and - 1.54 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 310 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2C8 represents an EST. The protein sequence encoded by p2C8 is described in this patent by Seq ID 311. The nucleotide sequence is represented in the public sequence databases by the accession BF971135 and is described in this patent by Seq ID 312. The seqeunce encoded by Seq ID 312 is up-regulated by greater than 2-fold by Hif. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The seqeunce encoded by Seq ID 312 is induced by a factor of 2.09 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The seqeunce encoded by Seq ID 312 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 312 was changed in expression -1.61, -2.13 and 1.12 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 310 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2Gl l represents an EST. The protein sequence encoded by p2Gl 1 is described in this patent by Seq ID 313. The nucleotide sequence is represented in the public sequence databases by the accession AK027199 and is described in this patent by Seq ID 314. The seqeunce encoded by Seq ID 314 is up-regulated by greater than 2-fold by Epas. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The seqeunce encoded by Seq ID 314 is induced by a factor of 2.09 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2G19 represents an EST. The protein sequence encoded by p2G19 is described in this patent by Seq ID 315. The nucleotide sequence is represented in the public sequence databases by the accession AA700141 and is described in this patent by Seq ID 316. The seqeunce encoded by Seq ID 316 is up-regulated by greater than 2-fold by Epas. p2G19 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2H18 represents an EST. The protein sequence encoded by p2H18 is described in this patent by Seq ID 317. The nucleotide sequence is represented in the public sequence databases by the accession AW968530 and is described in this patent by Seq ID 318. The seqeunce encoded by Seq ID 318 is up-regulated by greater than 2-fold by Hif. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 318 was changed in expression -1.47, -2.27 and -1.2 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 318 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2H24 represents an EST. The protein sequence encoded by p2H24 is described in this patent by Seq ID 319. The nucleotide sequence is represented in the public sequence databases by the accession AI032695 and is described in this patent by Seq ID 320. The seqeunce encoded by Seq ID 320 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2I4 represents an EST. The protein sequence encoded by p2I4 is described in this patent by Seq ID 321. The nucleotide sequence is represented in the public sequence databases by the accession AV705233 and is described in this patent by Seq ID 322. The seqeunce encoded by Seq ID 322 is up-regulated by greater than 2-fold by Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the seqeunce encoded by Seq ID 322 was up-regulated 2.22 fold in one of the patientsand was up- regulated 2.87 fold in the other patient. This indicates that the seqeunce encoded by Seq ID 322 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 322 was changed in expression 1.28, -2.78 and -1.22 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 322 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I14 represents an EST. The protein sequence encoded by p2I14 is described in this patent by Seq ID 323. The nucleotide sequence is represented in the public sequence databases by the accession BG423026 and is described in this patent by Seq ED 324. The seqeunce encoded by Seq ID 324 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 324 is repressed by a factor of 2.04 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 324 is repressed by a factor of 2.44 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. The seqeunce encoded by Seq ED 324 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2I15 represents an EST. The protein sequence encoded by p2I15 is described in this patent by Seq ID 325. The nucleotide sequence is represented in the public sequence databases by the accession AI032956 and is described in this patent by Seq ID 326. The seqeunce encoded by Seq ID 326 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 326 is induced by a factor of 2.17 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The seqeunce encoded by Seq ID 326 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 326 was changed in expression -1.96, - 3.85 and -2.27 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 326 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2L4 represents an EST. The protein sequence encoded by p2L4 is described in this patent by Seq ID 327. The nucleotide sequence is represented in the public sequence databases by the accession AK025119 and is described in this patent by Seq ID 328. The seqeunce encoded by Seq ID 328 is up-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2L5 represents an EST. The protein sequence encoded by p2L5 is described in this patent by Seq ID 329. The nucleotide sequence is represented in the public sequence databases by the accession HI 1671 and is described in this patent by Seq ED 330. The seqeunce encoded by Seq ID 330 is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The seqeunce encoded by Seq LD 330 is repressed by a factor of 2 in response to IL- Vindicating a negative role in Th2 immune responses.
The Oxford BioMedica clone p2L6 represents an EST. The protein sequence encoded by p2L6 is described in this patent by Seq ID 331. The nucleotide sequence is represented in the public sequence databases by the accession AW581935 and is described in this patent by Seq ID 332. The seqeunce encoded by Seq ED 332 is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, the seqeunce encoded by Seq ID 332 is repressed in response to Interleukin- 1, by a factor of 2.94 fold at 6hr and 2.63 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor.
An EST (In Intron for cypl9) is described in this patent by Seq ID 333. The nucleotide sequence is represented in the public sequence databases by the accession BG005535 and is described in this patent by Seq ID 334. The sequence encoded by Seq ID 334 is up- regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plL24 represents an EST (In Intron for cypl9). The protein sequence encoded by plL24 is described in this patent by Seq ID 335. The nucleotide sequence is represented in the public sequence databases by the accession BG005535 and is described in this patent by Seq ID 336. plL24 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The seqeunce encoded by Seq ID 336 is repressed by a factor of 1.56 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The seqeunce encoded by Seq ID 336 is repressed by a factor of 2.08 in response to IL-13 and 1.69 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 336 was changed in expression -2.17, -1.89 and -1.12 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 336 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2H8 represents an EST (In Intron for DD96). The protein sequence encoded by p2H8 is described in this patent by Seq ID 337. The nucleotide sequence is represented in the public sequence databases by the accession AA699567 and is described in this patent by Seq ED 338. The seqeunce encoded by Seq ID 338 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 338 is repressed by a factor of 2.7 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor.
The Oxford BioMedica clone p2H19 represents an EST (In intron for LOC87246). The protein sequence encoded by p2H19 is described in this patent by Seq ID 339. The nucleotide sequence is represented in the public sequence databases by the accession T83663 and is described in this patent by Seq ID 340. The seqeunce encoded by Seq ID 340 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2H22 represents an EST (In intron of UBP1). The protein sequence encoded by p2H22 is described in this patent by Seq ID 341. The nucleotide sequence is represented in the public sequence databases by the accession AI023339 and is described in this patent by Seq ID 342. The seqeunce encoded by Seq ID 342 is up- regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2H21 represents an EST (In intron of ZMPSTE24). The protein sequence encoded by p2H21 is described in this patent by Seq ID 343. The nucleotide sequence is represented in the public sequence databases by the accession AI032679 and is described in this patent by Seq ID 344. The seqeunce encoded by Seq ID 344 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 344 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor.
An EST (within an intron to ABLEVI) is described in this patent by Seq ID 345. The nucleotide sequence is represented in the public sequence databases by the accession W92780 and is described in this patent by Seq ID 346. The sequence encoded by Seq ID 346 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2I20 represents an EST (In intron to CTSB). The protein sequence encoded by p2I20 is described in this patent by Seq LD 347. The nucleotide sequence is represented in the public sequence databases by the accession BF828079 and is described" in this patent by Seq ID 348. The seqeunce encoded by Seq ID 348 is up- regulated by greater than 2-fold by both Hif and Epas. The seqeunce encoded by Seq ED 348 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 348 was changed in expression -1.2, -2 and -1.79 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 348 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2G10 represents an EST (In Intron to ELL2). The protein sequence encoded by p2G10 is described in this patent by Seq ID 349. The nucleotide sequence is represented in the public sequence databases by the accession BG928580 and is described in this patent by Seq ED 350. The seqeunce encoded by Seq ID 350 is up- regulated by greater than 2-fold by Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the seqeunce encoded by Seq ID 350 was up-regulated 3.9 fold in one of the patientsand was up-regulated 2.74 fold in the other patient. This indicates that the seqeunce encoded by Seq ID 350 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2L2 represents an EST (In Intron to FIJI 1577). The protein sequence encoded by p2L2 is described in this patent by Seq ID 351. The nucleotide sequence is represented in the public sequence databases by the accession T83845 and is described in this patent by Seq ID 352. The seqeunce encoded by Seq ID 352 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The seqeunce encoded by Seq ID 352 is repressed by a factor of 1.69 in response to IL-13 and 2.04 in response to IL-4, indicating a negative role in Th2 immune responses.
The Oxford BioMedica clone p2Cl represents an EST (In intron to HAL). The protein sequence encoded by p2Cl is described in this patent by Seq ID 353. The nucleotide sequence is represented in the public sequence databases by the accession BF902949 and is described in this patent by Seq ID 354. The seqeunce encoded by Seq ID 354 is up- regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 354 is induced by a factor of 2.15 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor. The seqeunce encoded by Seq ID 354 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 354 was changed in expression -3.23, -2.33 and -1.96 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 354 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I16 represents an EST (In Intron to HDAC8). The protein sequence encoded by p2I16 is described in this patent by Seq ID 355. The nucleotide sequence is represented in the public sequence databases by the accession All 24813 and is described in this patent by Seq ID 356. The seqeunce encoded by Seq ID 356 is up- regulated by greater than 2-fold by both Hif and Epas. The seqeunce encoded by Seq ID 356 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 356 was changed in expression -5.88, 2.01 and -2.44 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 356 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2G17 represents an EST (In Intron to SLC21A11). The protein sequence encoded by p2G17 is described in this patent by Seq ID 357. The nucleotide sequence is represented in the public sequence databases by the accession AW976431 and is described in this patent by Seq ID 358. The seqeunce encoded by Seq ID 358 is up-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2H23 represents an EST (In intron). The protein sequence encoded by p2H23 is described in this patent by Seq ID 359. The nucleotide sequence is represented in the public sequence databases by the accession AI022630 and is described in this patent by Seq ID 360. The seqeunce encoded by Seq ID 360 is up-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 360 was changed in expression 2.12, 1.46 and -1.04 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 360 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2I6 represents an EST 2q37.1. The protein sequence encoded by p2I6 is described in this patent by Seq ID 361. The nucleotide sequence is represented in the public sequence databases by the accession AA281534 and is described in this patent by Seq ID 362. p2I6 is up-regulated by greater than 2-fold by Epas. p2I6 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone plMl 1 represents an EST located on chromosome lpl2. The protein sequence encoded by plMl l is described in this patent by Seq ID 363. The nucleotide sequence is represented in the public sequence databases by the accession AA007687 and is described in this patent by Seq ID 364. the seqeunce encoded by Seq ED 364 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions, the seqeunce encoded by Seq ID 364 is repressed by a factor of 2.63 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell- cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease, the seqeunce encoded by Seq ID 364 is repressed by a factor of 2.04 in response to IL-13 and 2.13 in response to IL-4, indicating a negative role in Th2 immune responses. The seqeunce encoded by Seq ID 364 is suppressed by a factor of 2.38 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 364 was changed in expression -1.64, -3.23 and -1.43 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 364 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2C4 represents an EST located on chromosome lp32. The protein sequence encoded by p2C4 is described in this patent by Seq ID 365. The nucleotide sequence is represented in the public sequence databases by the accession AA977628 and is described in this patent by Seq ID 366. The seqeunce encoded by Seq ID 366 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The seqeunce encoded by Seq ID 366 is repressed by a factor of 2.08 in response to IL-13 and 1.92 in response to IL-4, indicating a negative role in Th2 immune responses. The seqeunce encoded by Seq ID 366 is suppressed by a factor of 2.13 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The Oxford BioMedica clone p2D23 represents an EST located on chromosome lp34. The protein sequence encoded by p2D23 is described in this patent by Seq ID 367. The nucleotide sequence is represented in the public sequence databases by the accession AA883805 and is described in this patent by Seq ID 368. The seqeunce encoded by Seq ID 368 is up-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The seqeunce encoded by Seq ID 368 is induced by a factor of 2.52 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the seqeunce encoded by Seq ID 368 was up-regulated 2.11, 2.11 and 1.02 fold in the three diseased patients compared to the control group. This indicates that the seqeunce encoded by Seq ID 368 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2L8 represents an EST located on chromosome 20ql 1. The protein sequence encoded by p2L8 is described in this patent by Seq ID 369. The nucleotide sequence is represented in the public sequence databases by the accession H79736 and is described in this patent by Seq ID 370. The sequence encoded by Seq ID 370 is up-regulated by greater than 2-fold by Epas. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The sequence encoded by Seq ID 370 is repressed by a factor of 1.56 in response to IL-10, indicating a negative role in the response to IL-10. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The sequence encoded by Seq ID 370 is repressed by a factor of 2.63 in response to EL-13 and 1.82 in response to IL-4, indicating a negative role in Th2 immune responses. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the sequence encoded by Seq ID 370 was up-regulated 2.27 fold in one of the patientsand was up-regulated 1.78 fold in the other patient. This indicates that the sequence encoded by Seq ID 370 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone plL8 represents an EST located on chromosome 2ql3. The protein sequence encoded by plL8 is described in this patent by Seq ID 371. The nucleotide sequence is represented in the public sequence databases by the accession R84375 and is described in this patent by Seq ID 372. The sequence encoded by Seq ID 372 is up-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 372 is induced by a factor of 2.68 at 6hr and 1.67 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. The sequence encoded by Seq ID 372 is repressed by a factor of 2.38 in response to IL-10, indicating a negative role in the response to IL-10. The sequence encoded by Seq ID 372 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 372 was changed in expression -3.85, -1.69 and -2 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 372 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2E5 represents an EST located on chromosome 8pl2. The protein sequence encoded by p2E5 is described in this patent by Seq ID 373. The nucleotide sequence is represented in the public sequence databases by the accession AA704849 and is described in this patent by Seq ID 374. The sequence encoded by Seq ID 374 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, the sequence encoded by Seq ID 374 is repressed in response to Interleukin- 1, by a factor of 3.57 fold at 6hr and 2.5 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 374 is suppressed by a factor of 2.27 at 6hr and 1.96 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 374 is repressed by a factor of 2.38 in response to IL-13 and 2.56 in response to IL-4, indicating a negative role in Th2 immune responses. The sequence encoded by Seq ID 374 is suppressed by a factor of 2.08 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 374 was changed in expression -2.17, -1.92 and -1.67 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 374 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plN13 represents an EST located on chromosome 12pl3. The protein sequence encoded by plN13 is described in this patent by Seq ID 375. The nucleotide sequence is represented in the public sequence databases by the accession W86870 and is described in this patent by Seq ID 376. plN13 is up-regulated by greater than 2-fold by both Hif and Epas. plN13 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, plN13 was changed in expression -2.38, -2 and -1.82 fold in the three diseased patients compared to the control group. This indicates that plN13 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2C2 represents an EST located on chromosome 3p22.3. The protein sequence encoded by p2C2 is described in this patent by Seq ED 377. The nucleotide sequence is represented in the public sequence databases by the accession AA878193 and is described in this patent by Seq ID 378. The nucleotide sequence encoded by Seq ID 377 is up-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The nucleotide sequence encoded by Seq ID 377 is induced by a factor of 2.29 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 377 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the nucleotide sequence encoded by Seq ID 377 was changed in expression -1.33, -3.7 and -2.78 fold in the three diseased patients compared to the control group. This indicates that the nucleotide sequence encoded by Seq ID 377 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2D19 represents an EST located on chromosome 6q27. The protein sequence encoded by p2D19 is described in this patent by Seq ID 379. The nucleotide sequence is represented in the public sequence databases by the accession T95117 and is described in this patent by Seq ID 380. The nucleotide sequence encoded by Seq ED 380 is up-regulated by greater than 2-fold by Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the nucleotide sequence encoded by Seq ID 377 was up- regulated 2.08 fold in one of the patients. This indicates that the nucleotide sequence encoded by Seq ID 380 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2I12 represents an EST upstream to D?LA2 gamma (~500bp). The protein sequence encoded by p2I12 is described in this patent by Seq ID 381. The nucleotide sequence is represented in the public sequence databases by the accession AI168105 and is described in this patent by Seq ID 382. The nucleotide sequence encoded by Seq ID 382 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The nucleotide sequence encoded by Seq ID 382 is induced by a factor of 3.57 at 6hr and 2.08 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 382 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the nucleotide sequence encoded by Seq ID 382 was changed in expression -2.7, -1.69 and -1.27 fold in the three diseased patients compared to the control group. This indicates that the nucleotide sequence encoded by Seq ID 382 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2K24 represents phorbolin-1 -related protein. The protein sequence encoded by p2K24 is represented in the public databases by the accession AAD00090 and is described in this patent by Seq ID 383. The nucleotide sequence is represented in the public sequence databases by the accession U61084 and is described in this patent by Seq ID 384. The nucleotide sequence encoded by Seq ID 384 is down- regulated by greater than 2-fold by Epas. p2K24 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The nucleotide sequence encoded by Seq ID 384 is induced by a factor of 2.9 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro- inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 384 is induced by a factor of 27.74 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The nucleotide sequence encoded by Seq ID 384 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2K2 represents a putative breast epithelial stromal interaction protein . The protein sequence encoded by p2K2 is represented in the public databases by the accession AAK73753 and is described in this patent by Seq ID 385. The nucleotide sequence is represented in the public sequence databases by the accession AF396928 and is described in this patent by Seq ED 386. The nucleotide sequence encoded by Seq ID 386 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.05 at 6hr and 5.3 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 386 is induced by a factor of 12.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.17 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. The nucleotide sequence encoded by Seq ID 386 is induced by a factor of 24.61 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The nucleotide sequence encoded by Seq ID 386 is induced by a factor of 3.96 in response to superoxide, indicating a pro- inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2J7 represents 71 kDa 2'5' oligoadenylate synthetase. The protein sequence encoded by p2J7 is represented in the public databases by the accession AAA60607 and is described in this patent by Seq ID 387. The nucleotide sequence is represented in the public sequence databases by the accession M87434 and is described in this patent by Seq ID 388. 71 kDa 2'5' oligoadenylate synthetase is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. 71 kDa 2' 5' oligoadenylate synthetase is induced by a factor of 2.07 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. 71 kDa 2'5' oligoadenylate synthetase is induced by a factor of 5.97 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. 71 kDa 2' 5' oligoadenylate synthetase is induced by a factor of 2.04 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. 71 kDa 2'5' oligoadenylate synthetase is induced by a factor of 12.32 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. 71 kDa 2'5' oligoadenylate synthetase is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
2 '-5 Oligoadenylate synthetase 2 is represented in the public databases by the accession P29728 and is described in this patent by Seq ID 389. The nucleotide sequence is represented in the public sequence databases by the accession NM_016817 and is described in this patent by Seq ID 390. The sequence encoded by Seq ID 390 is down- regulated by greater than 2-fold by Hif.
60S ribosomal protein is represented in the public databases by the accession P38663 and is described in this patent by Seq ID 391. The nucleotide sequence is represented in the public sequence databases by the accession NM_000986 and is described in this patent by Seq ID 392. The sequence encoded by Seq ID 392 is down-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone plP18 represents ADP-ribosyl cyclase 1 (CD38). The protein sequence encoded by plP18 is represented in the public databases by the accession P28907 and is described in this patent by Seq ID 393. The nucleotide sequence is represented in the public sequence databases by the accession NM_001775 and is described in this patent by Seq ID 394. CD38 synthesizes cyclic ADP-ribose, a second messenger for glucose-induced insulin secretion. plP18 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. plP18 is repressed by a factor of 2.08 in response to IL- Vindicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, plP18 was changed in expression -1.75, -3.85 and -1.23 fold in the three diseased patients compared to the control group. This indicates that plP18 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2JV represents the Alpha- lb adrenergic receptor. The protein sequence encoded by p2J 13 is represented in the public databases by the accession P35368 and is described in this patent by Seq ID 395. The nucleotide sequence is represented in the public sequence databases by the accession NM_000679 and is described in this patent by Seq ID 396. Alpha- lb adrenergic receptor is down-regulated by greater than 2-fold by both Hif and Epas. Alpha- lb adrenergic receptor is preferentially induced by hypoxia in hepatocytes, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for hepatic diseases. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Alpha- lb adrenergic receptor is induced in response to TNFalpha, by a factor of 2.1 fold, indicating a positive role in pro- inflammatory responses involving this factor. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. Alpha- lb adrenergic receptor is suppressed by a factor of 2.04 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. Alpha- lb adrenergic receptor is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Alpha- lb adrenergic receptor was changed in expression 1.37, 2.53 and 1.77 fold in the three diseased patients compared to the control group. This indicates that Alpha- lb adrenergic receptor plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2K21 represents Apolipoprotein L, 6. The protein sequence encoded by p2K21 is represented in the public databases by the accession NP_085144 and is described in this patent by Seq ED 397. The nucleotide sequence is represented in the public sequence databases by the accession NM_030641 and is described in this patent by Seq ID 398. Apolipoprotein L, 6 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Apolipoprotein L, 6 is induced by a factor of 2.18 at 6hr and 1.52 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. Apolipoprotein L, 6 is induced by a factor of 2.08 at 24hr in response to the pro- inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. Apolipoprotein L, 6 is induced by a factor of 5.37 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Apolipoprotein L, 6 is induced by a factor of 2.04 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2J3 represents Ataxin 7. The protein sequence encoded by p2J3 is represented in the public databases by the accession 015265 and is described in this patent by Seq ID 399. The nucleotide sequence is represented in the public sequence databases by the accession NM_000333 and is described in this patent by Seq ED 400. Ataxin 7 is down-regulated by greater than 2-fold by Hif. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Ataxin 7was changed in expression -1.03, 3.36 and 1.12 fold in the three diseased patients compared to the control group. This indicates that Ataxin 7 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A4 represents Basement membrane induced gene. The protein sequence encoded by p2A4 is represented in the public databases by the accession NP_004839 and is described in this patent by Seq ID 401. The nucleotide sequence is represented in the public sequence databases by the accession NM_004848 and is described in this patent by Seq ID 402. Basement membrane induced gene is down- regulated by greater than 2-fold by Hif. p2A4 is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Basement membrane induced gene is induced by a factor of 2.54 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Basement membrane induced gene is induced by a factor of 2.09 in response to superoxide, indicating a pro- inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2A3 represents BCM-like membrane protein precursor. The protein sequence encoded by p2A3 is represented in the public databases by the accession
NP_064510 and is described in this patent by Seq ID 403. The nucleotide sequence is represented in the public sequence databases by the accession NM_020125 and is described in this patent by Seq ID 404. BCM-like membrane protein precursor encodes a member of the CD2 family of cell surface proteins involved in lymphocyte activation. BCM-like membrane protein is down-regulated by greater than 2-fold by Epas. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. BCM-like membrane protein is induced by a factor of 2.34 in response to IL-10, indicating a positive role in the response to IL-10. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, BCM-like membrane protein was changed in expression 2.62, 1.7 and -1.12 fold in the three diseased patients compared to the control group. This indicates that p2A3 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plP23 represents Beta-l,2-galactosyltransferase 7. The protein sequence encoded by plP23 is represented in the public databases by the accession Q9NY97 and is described in this patent by Seq ID 405. The nucleotide sequence is represented in the public sequence databases by the accession NM_006577 and is described in this patent by Seq ID 406. Beta-l,2-galactosyltransferase 7 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Beta-l,2-galactosyltransferase 7 is induced by a factor of 2.34 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor. Beta-l,2-galactosyltransferase 7 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Beta-l,2-galactosyltransferase 7 was suppressed 4.55 fold in one of the patients. This indicates that Beta- 1,2- galactosyltransferase 7 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2K8 represents Butyrate transcript 1. The protein sequence encoded by p2K8 is represented in the public databases by the accession BAB55101 and is described in this patent by Seq ID 407. The nucleotide sequence is represented in the public sequence databases by the accession AK027421 and is described in this patent by Seq ED 408. Butyrate transcript 1 is down-regulated by greater than 2-fold by Hif. p2K8 is suppressed by a factor of 2.56 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. Butyrate transcript 1 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2Al represents CD40L receptor precursor protein (TNFRSF5). The protein sequence encoded by p2Al is represented in the public databases by the accession P25942 and is described in this patent by Seq ID 409. The nucleotide sequence is represented in the public sequence databases by the accession NM_001250 and is described in this patent by Seq ID 410. Defects in TNFRSF5 are the cause of type 3 hyper-IgM immunodeficiency (HIGM3), an autosomal recessive disorder which includes an inability of B cells to undergo isotype switching, one of the final differentiation steps in the humoral immune system, an inability to mount an antibody-specific immune response, and a lack of germinal center formation. TNFRSF5 is down-regulated by greater than 2- fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, TNFRSF5 is induced in response to TNFalpha, by a factor of 2.1 fold, indicating a positive role in pro-inflammatory responses involving this factor. TNFRSF5 is induced by a factor of 4.34 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. TNFRSF5 is induced by a factor of 2.62 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. TNFRSF5 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2A6 represents CD83 antigen precursor. The protein sequence encoded by p2A6 is represented in the public databases by the accession Q01151 and is described in this patent by Seq ID 411. The nucleotide sequence is represented in the public sequence databases by the accession NM_004233 and is described in this patent by Seq ID 412. CD83 is down-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone p2K6 represents Chromosome associated kinesin (KIF4A). The protein sequence encoded by p2K6 is represented in the public databases by the accession O95239 and is described in this patent by Seq ID 413. The nucleotide sequence is represented in the public sequence databases by the accession NM_012310 and is described in this patent by Seq ID 414. KLF4A is required for mitotic chromosomal positioning and bipolar spindle stabilization. KTF4A is down-regulated by greater than 2- fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. KIF4A is repressed by a factor of 4.35 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. KJF4A is suppressed by a factor of 2.44 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. KTF4A is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, KIF4A was changed in expression 1.48, 4.16 and 1.62 fold in the three diseased patients compared to the control group. This indicates that KEF4A plays a role in the process of atherogenesis.
The hypothetical extension of GS3686 is represented in the public databases by the accession NP_006811 and is described in this patent by Seq ID 415. The nucleotide sequence is represented in the public sequence databases by the accession NM_006820 and is described in this patent by Seq ID 416. The sequence encoded by Seq ED 416 is down- regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2E21 represents the putative celular retinol binding protein, CRBPIII. The protein sequence encoded by p2E21 is represented in the public databases by the accession AAK14975 and is described in this patent by Seq ED 417. The nucleotide sequence is represented in the public sequence databases by the accession AF212239 and is described in this patent by Seq ED 418. CRBPIII is down-regulated by greater than 2- fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. CRBPIII is repressed by a factor of 2.38 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. CRBPIII is repressed by a factor of 2.08 in response to IL- Vindicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, CRBPIII was changed in expression 3.37, 2.13 and -1.03 fold in the three diseased patients compared to the control group. This indicates that CRBPIII plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2E23 represents Cytochrome P450 27, mitochondrial precursor (CYP27A1). The protein sequence encoded by p2E23 is represented in the public databases by the accession Q02318 and is described in this patent by Seq ID 419. The nucleotide sequence is represented in the public sequence databases by the accession NM_000784 and is described in this patent by Seq ID 420. CYP27A1 is a member of the cytochrome P450 family and functions to maintain cholesterol hemeostasis. Defects in CYP27A1 are the cause of cerebrotendinous xanthomatosis, a rare sterol storage disorder characterized clinically by progressive neurologic dysfunction, premature atherosclerosis, and cataracts. CYP27A1 is down-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, CYP27A1 was changed in expression 3.48, 2.19 and -1.47 fold in the three diseased patients compared to the control group. This indicates that CYP27A1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Jl l represents Dihydrolipoamide dehydrogenase mitochondrial precursor (DLD). The protein sequence encoded by p2Jl l is represented in the public databases by the accession P09622 and is described in this patent by Seq ID 421. The nucleotide sequence is represented in the public sequence databases by the accession NM_000108 and is described in this patent by Seq ID 422. Defects in DLD are a acause of congential infantile lactic acidosis. DLD is down-regulated by greater than 2-fold by Epas. The Oxford BioMedica clone p2J8 represents Dual specificity phosophatase 2. The protein sequence encoded by p2J8 is represented in the public databases by the accession Q05923 and is described in this patent by Seq ID 423. The nucleotide sequence is represented in the public sequence databases by the accession NM_004418 and is described in this patent by Seq ID 424. Dual specificity phosophatase 2 regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2. Dual specificity phosophatase 2 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Dual specificity phosophatase 2 is induced by a factor of 2.54 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. Dual specificity phosophatase 2 is suppressed by a factor of 5 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Dual specificity phosophatase 2 is suppressed by a factor of 3.57 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. Dual specificity phosophatase 2 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2J12 represents fatty acid binding protein 4 (FABP4). The protein sequence encoded by p2J12 is represented in the public databases by the accession AAH03672 and is described in this patent by Seq ID 425. The nucleotide sequence is represented in the public sequence databases by the accession BC003672 and is described in this patent by Seq ID 426. FABP4 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. FABP4 is induced by a factor of 4.58 in response to IL-V and 4.13 in response to IL-4, indicating a positive role in Th2 immune responses. FABP4 is suppressed by a factor of 4.76 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. FABP4 is suppressed by a factor of 4.55 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. FABP4 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FABP4 was changed in expression 2.73, - 2.7 and 1.3 fold in the three diseased patients compared to the control group. This indicates that FABP4 plays a role in the process of atherogenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, FABP4 was changed in expression 2.73, -2.7 and 1.3 fold in the three diseased patients compared to the control group. This indicates that FABP4 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2EV represents T-cell death associated gene 8. The protein sequence encoded by p2EV is represented in the public databases by the accession NP_003599 and is described in this patent by Seq ID 427. The nucleotide sequence is represented in the public sequence databases by the accession NM_003608 and is described in this patent by Seq ID 428. T cell death-associated gene 8, is a G protein- coupled receptor that is a specific psychosine receptor. Accumulation of psychosine occurs in a rare heritable metabolic disorder called Globoid cell leukodystrophy, and leads to death of oligodendrocytes and Schwann cells of the central and peripheral nervous systems. T cell death-associated gene 8 is down-regulated by greater than 2-fold by Hif. T cell death- associated gene 8 is induced by a factor of 3.23 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. T cell death-associated gene 8 is induced by a factor of 2.41 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The Oxford BioMedica clone p2I24 represents guanylate binding protein 1 (GBP1). The protein sequence encoded by p2I24 is represented in the public databases by the accession AAH02666 and is described in this patent by Seq ID 429. The nucleotide sequence is represented in the public sequence databases by the accession M55542 and is described in this patent by Seq ID 430. GBP1 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. GBP1 is induced by a factor of 6.91 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. GBP1 is induced by a factor of 2.28 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. GBP1 is induced by a factor of 2.23 in response to IL- Vindicating a positive role in Th2 immune responses. GBP1 is induced by a factor of 34.62 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. GBP1 is induced by a factor of 4.24 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, GBP1 was changed in expression -1.59, -2.44 and -1.14 fold in the three diseased patients compared to the control group. This indicates that GBP1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Jl represents Guanine nucleotide binding protein beta subunit 4. The protein sequence encoded by p2Jl is represented in the public databases by the accession NP_067642 and is described in this patent by Seq ID 431. The nucleotide sequence is represented in the public sequence databases by the accession AK001890 and is described in this patent by Seq ID 432. Guanine nucleotide binding protein beta subunit 4 is down-regulated by greater than 2-fold by both Hif and Epas. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors.
The Oxford BioMedica clone p2K17 represents HBV associated factor(splice variant of XAP4). The protein sequence encoded by p2K17 is represented in the public databases by the accession NP_006453 and is described in this patent by Seq ID 433. The nucleotide sequence is represented in the public sequence databases by the accession NM_006462 and is described in this patent by Seq ID 434. The sequence encoded by Seq ID 434 is down- regulated by greater than 2-fold by Epas. The sequence encoded by Seq ID 434 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. The Oxford BioMedica clone p2A12 represents Heat shock cognate 71 KDA protein. The protein sequence encoded by p2A12 is represented in the public databases by the accession P19120 and is described in this patent by Seq IDs 435 and 437. The nucleotide sequence is represented in the public sequence databases by the accession NM_006597 and is described in this patent by Seq IDs 436 and 438. Heat shock cognate 71KDA protein is down-regulated by greater than 2-fold by Epas. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, Heat shock cognate 71 KDA protein was up-regulated 4.49 fold in one of the patients Heat shock cognate 71 KDA protein plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Heat shock cognate 71 KDA protein was changed in expression -1.49, -2.86 and -1.15 fold in the three diseased patients compared to the control group. This indicates that Heat shock cognate 71 KDA protein plays a role in the process of atherogenesis.
The Oxford BioMedica clone plP24 represents Heparanase. The protein sequence encoded by plP24 is represented in the public databases by the accession NP_006656 and is described in this patent by Seq ID 439. The nucleotide sequence is represented in the public sequence databases by the accession AF155510 and is described in this patent by Seq ID 440. Heparanase is down-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone p2M2 represents Heparin sulfate N-deacetylase/N- sulfotransferase (N-HSST). The protein sequence encoded by p2M2 is represented in the public databases by the accession P52849 and is described in this patent by Seq ID 441. The nucleotide sequence is represented in the public sequence databases by the accession NM_005114 and is described in this patent by Seq ID 442. N-HSST is down-regulated by greater than 2-fold by Hif. N-HSST is induced by a factor of 2.09 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. N-HSST is induced by a factor of 3.34 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. N-HSST is induced by a factor of 7.49 in response to IL-10, indicating a positive role in the response to IL-10. N-HSST is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, N-HSST was up-regulated 2.59 fold in one of the patients. This indicates that N- HSST plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2K16 represents Hexokinase type III. The protein sequence encoded by p2K16 is represented in the public databases by the accession P52790 and is described in this patent by Seq ID 443. The nucleotide sequence is represented in the public sequence databases by the accession NM_002115 and is described in this patent by Seq LD 444. Hexokinase type III is down-regulated by greater than 2-fold by Epas. Hexokinase type III is preferentially induced by hypoxia in monocytes/macrophages, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving monocytes/macrophages and hypoxia. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Hexokinase type III is repressed in response to Interleukin- 1, by a factor of 2.5 fold at 6hr and 2.86 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Hexokinase type III is suppressed by a factor of 3.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Hexokinase type III is suppressed by a factor of 3.03 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2K22 represents HLF-1 Alpha. The protein sequence encoded by p2K22 is represented in the public databases by the accession Q 16665 and is described in this patent by Seq ID 445. The nucleotide sequence is represented in the public sequence databases by the accession NM_001530 and is described in this patent by Seq ID 446. HIF-lAlpha is down-regulated by greater than 2-fold by Epas. HIF-lAlpha is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. The Oxford BioMedica clone plP19 represents Interferon induced protein 41. The protein sequence encoded by plP19 is represented in the public databases by the accession NP_004500 and is described in this patent by Seq ID 447. The nucleotide sequence is represented in the public sequence databases by the accession NM_004509 and is described in this patent by Seq ID 448. Interferon induced protein 41 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interferon induced protein 41 is induced by a factor of 2.89 at 24hr in response to the pro- inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Interferon induced protein 41 was changed in expression 4.02, 2.47 and -1.14 fold in the three diseased patients compared to the control group. This indicates that Interferon induced protein 41 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2Al l represents Interferon induced protein with tetracopeptide repeats 1. The protein sequence encoded by p2Al l is represented in the public databases by the accession P09914 and is described in this patent by Seq IDs 449 and 451. The nucleotide sequence is represented in the public sequence databases by the accession NM_001548 and is described in this patent by Seq IDs 450 and 452. The nucelotide sequence encoded by Seq ED 450 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The nucelotide sequence encoded by Seq ID 450 is induced by a factor of 2.39 at 6hr and 3.98 at 48hr in response to the pro- inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The nucelotide sequence encoded by Seq ID 450 is induced by a factor of 42.58 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. p2Al l is induced by a factor of 2.14 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. The nucelotide sequence encoded by Seq ID 450 is induced by a factor of 30.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, the nucelotide sequence encoded by Seq ID 450 is repressed in response to TNFalpha, by a factor of 3.23 fold, indicating a negative role in pro-inflammatory responses involving this factor. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the nucelotide sequence encoded by Seq ID 450 was suppressed 2.33 fold in one of the patients and was down-regulated 1.75 fold in the other patient. This indicates that p2Al l plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the nucelotide sequence encoded by Seq ID 450 was changed in expression -3.13, -1.92 and -1.37 fold in the three diseased patients compared to the control group. This indicates that the nucelotide sequence encoded by Seq ID 450 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A9 represents Interferon induced transmembrane protein 1 (CD225). The protein sequence encoded by p2A9 is represented in the public databases by the accession P13164 and is described in this patent by Seq ID 453. The nucleotide sequence is represented in the public sequence databases by the accession NM_003641 and is described in this patent by Seq ID 454. CD225 is implcated in the control of cell growth. CD225 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. CD225 is induced by a factor of 2.29 at 24hr in response to the pro- inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. CD225 is induced by a factor of 41.17 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. CD225 is induced by a factor of 2.15 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. CD225 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, CD225 was changed in expression -2.08, -2.17 and -1.32 fold in the three diseased patients compared to the control group. This indicates that CD225 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A7 represents Interferon stimulated gene. The protein sequence encoded by p2A7 is represented in the public databases by the accession NP_002192 and is described in this patent by Seq ID 455. The nucleotide sequence is represented in the public sequence databases by the accession NM_002201 and is described in this patent by Seq ID 456. The sequence encoded by Seq ID 456 is down- regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 456 is induced by a factor of 3.76 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 456 is induced by a factor of 49.46 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The sequence encoded by Seq ID 456 is induced by a factor of 2.15 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The sequence encoded by Seq ID 456 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
Interferon stimulated gene is represented in the public databases by the accession NP_002192 and is described in this patent by Seq ID 457. The nucleotide sequence is represented in the public sequence databases by the accession NM_002201 and is described in this patent by Seq ID 458. The sequence encoded by Seq ED 458 is down- regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2K7 represents KCNJ11 potassium inwardly-rectifying channel. The protein sequence encoded by p2K7 is represented in the public databases by the accession XP_006398 and is described in this patent by Seq ID 459. The nucleotide sequence is represented in the public sequence databases by the accession XM_006398 and is described in this patent by Seq ID 460. The sequence encoded by Seq ID 460 is down- regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 460 is repressed by a factor of 5.56 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor. The sequence encoded by Seq ID 460 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 460 was changed in expression 3.93, 2.03 and 3.13 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 460 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2B3 represents Krueppel-like factor 5. The protein sequence encoded by p2B3 is represented in the public databases by the accession Q 13887 and is described in this patent by Seq ID 461. The nucleotide sequence is represented in the public sequence databases by the accession NM_001730 and is described in this patent by Seq ID 462. Krueppel-like factor 5 is a transcription factor that binds to GC box promoter elements. Krueppel-like factor 5 is down-regulated by greater than 2-fold by both Hif and Epas. Krueppel-like factor 5 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Krueppel- like factor 5 was changed in expression 4.55, 3.46 and 1.39 fold in the three diseased patients compared to the control group. This indicates that Krueppel-like factor 5 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2J24 represents LOC89960 similar to ribosomal protien L7. The protein sequence encoded by p2J24 is represented in the public databases by the accession XPJ327637 and is described in this patent by Seq ID 463. The nucleotide sequence is represented in the public sequence databases by the accession XM_027637 and is described in this patent by Seq ID 464. LOC89960 is down-regulated by greater than 2- fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, LOC89960 was changed in expression -1.79, -2.22 and -1.16 fold in the three diseased patients compared to the control group. This indicates that LOC89960 plays a role in the process of atherogenesis. Homeodomain-interacting protein kinase 2 is represented in the public databases by the accession Q9H2X6 and is described in this patent by Seq ID 465. The nucleotide sequence is represented in the public sequence databases by the accession NM_022740 and is described in this patent by Seq ID 466. The sequence encoded by Seq ID 466 is down- regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone p2Kl l represents Nuclear factor RIP140. The protein sequence encoded by p2Kl l is represented in the public databases by the accession P48552 and is described in this patent by Seq ID 467. The nucleotide sequence is represented in the public sequence databases by the accession NM_003489 and is described in this patent by Seq ID 468. Nuclear factor RIP140 modulates the transcriptional activation by the Estrogen receptor. Nuclear factor RIP 140 is down- regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Nuclear factor RIP 140 is induced in response to TNFalpha, by a factor of 2.07 fold, indicating a positive role in pro-inflammatory responses involving this factor. The cytokine Inteleukin-10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. Nuclear factor RIP140 is repressed by a factor of 2.33 in response to IL-10, indicating a negative role in the response to IL-10. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Nuclear factor RIP140 is repressed in response to Interleukin- 1, by a factor of 2.63 fold at 6hr and 3.23 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Nuclear factor RIP 140 is suppressed by a factor of 3.03 at 6hr and 1.92 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. Nuclear factor RIP 140 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. Nuclear factor RIP140 is repressed by a factor of 3.13 in response to IL-13 and 2.08 in response to IL-4, indicating a negative role in Th2 immune responses.
The Oxford BioMedica clone p2K19 represents Nucleolar RNA helicase II (dead box protein 21). The protein sequence encoded by p2K19 is represented in the public databases by the accession Q9NR30 and is described in this patent by Seq ID 469. The nucleotide sequence is represented in the public sequence databases by the accession NM_004728 and is described in this patent by Seq ID 470. Nucleolar RNA helicase II can unwind double- stranded RNA and can fold or introduce a secondary structure to a single-stranded RNA. Nucleolar RNA helicase II is down-regulated by greater than 2-fold by Epas. Nucleolar RNA helicase II is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2A10 represents pyruvate dehydrogenase kinase 4 (PDK4). The protein sequence encoded by p2A10 is represented in the public databases by the accession AAC50669 and is described in this patent by Seq ID 471. The nucleotide sequence is represented in the public sequence databases by the accession U51617 and is described in this patent by Seq ID 472. PDK4 is down-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2E15 represents Peptide transporter 3. The protein sequence encoded by p2E15 is represented in the public databases by the accession NP_057666 and is described in this patent by Seq ID 473. The nucleotide sequence is represented in the public sequence databases by the accession NM_016582 and is described in this patent by Seq ID 474. Peptide transporter 3 is down-regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2E12 represents Phorbolin like protein MDS019. The protein sequence encoded by p2E12 is represented in the public databases by the accession NP_068594 and is described in this patent by Seq ID 475. The nucleotide sequence is represented in the public sequence databases by the accession NM_021822 and is described in this patent by Seq ID 476. MDS019 is down-regulated by greater than 2-fold by Hif. MDS019 is preferentially induced by hypoxia in epithelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products for disease involving cell-cell and cell-hormone interactions at epithelial cell surfaces. MDS019 is induced by a factor of 3.12 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. MDS019 is induced by a factor of 2.32 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, MDS019 is repressed in response to Interleukin- 1, by a factor of 4 fold at 6hr and 2.27 fold at 24hr, indicating a negative role in pro- inflammatory responses involving this factor. MDS019 is suppressed by a factor of 2.94 at 6hr and 2 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a negative role in pro-inflammatory responses involving this factor. MDS019 is repressed by a factor of 2.5 in response to IL-13 and 1.72 in response to IL-4, indicating a negative role in Th2 immune responses. MDS019 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
A possible splice variant of proteasome subunit alpha type 3 is represented in the public databases by the accession P25788 and is described in this patent by Seq ID 477. The nucleotide sequence is represented in the public sequence databases by the accession AI417084 and is described in this patent by Seq ID 478. The sequence encoded by Seq ID 478 is down-regulated by greater than 2-fold by Epas.
The Oxford BioMedica clone p2K14 represents Proteasome subunit alpha type 3. The protein sequence encoded by p2K14 is represented in the public databases by the accession P25788 and is described in this patent by Seq ID 479. The nucleotide sequence is represented in the public sequence databases by the accession NM_002788 and is described in this patent by Seq ID 480. The sequence encoded by Seq ID 480 is down- regulated by greater than 2-fold by Epas. The seqeunce encoded by Seq ID 480 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2E24 represents RAL guanine nucleotide dissociation stimulator-like 1. The protein sequence encoded by p2E24 is represented in the public databases by the accession Q9NZL6 and is described in this patent' by Seq ID 481. The nucleotide sequence is represented in the public sequence databases by the accession NM_015149 and is described in this patent by Seq ID 482. RAL guanine nucleotide dissociation stimulator-like 1 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. RAL guanine nucleotide dissociation stimulator-like 1 is induced by a factor of 2.06 in response to IL-13 and 2.01 in response to IL-4, indicating a positive role in Th2 immune responses. RAL guanine nucleotide dissociation stimulator-like 1 is induced by a factor of 14.54 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. RAL guanine nucleotide dissociation stimulator-like 1 is induced by a factor of 5.18 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The cytokine Interleukin- 10 is a key anti-inflammatory cytokine which causes general dampening of macrophage effector functions. RAL guanine nucleotide dissociation stimulator-like 1 is induced by a factor of 3.46 in response to IL-10, indicating a positive role in the response to IL-10. RAL guanine nucleotide dissociation stimulator-like 1 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2K23 represents Ribosomal protein S6 kinase alpha 1 (90 KDA ). The protein sequence encoded by p2K23 is represented in the public databases by the accession Q 15418 and is described in this patent by Seq ID 483. The nucleotide sequence is represented in the public sequence databases by the accession NM_002953 and is described in this patent by Seq ID 484. Ribosomal protein S6 kinase alpha 1 has been implicated in the activation of the Mitogen-activaed kinase cascade. Ribosomal protein S6 kinase alpha 1 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, Ribosomal protein S6 kinase alpha 1 is induced in response to TNFalpha, by a factor of 2.1 fold, indicating a positive role in pro- inflammatory responses involving this factor. Interleukin- 1 is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to Interleukin- 1 therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. Ribosomal protein S6 kinase alpha 1 is repressed in response to Interleukin- 1, by a factor of 3.23 fold at 6hr and 3.13 fold at 24hr, indicating a negative role in pro-inflammatory responses involving this factor. Ribosomal protein S6 kinase alpha 1 is suppressed by a factor of 4.17 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Ribosomal protein S6 kinase alpha 1 was changed in expression -2.33, -3.23 and -1.82 fold in the three diseased patients compared to the control group. This indicates that Ribosomal protein S6 kinase alpha 1 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2J23 represents Ring finger protein 21, interferon responsive. The protein sequence encoded by p2J23 is represented in the public databases by the accession NP_067629 and is described in this patent by Seq ID 485. The nucleotide sequence is represented in the public sequence databases by the accession NM_021616 and is described in this patent by Seq ID 486. Ring finger protein 21 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Ring finger protein 21 is induced by a factor of 2.26 at 6hr and 2.08 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. Ring finger protein 21 is induced by a factor of 2.62 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. Ring finger protein 21 is induced by a factor of 2.02 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2K20 represents Serine/threonine protein phosphatase 2A 55 KDA regulatory subunit B, alpha isoform. The protein sequence encoded by p2K20 is represented in the public databases by the accession Q00007 and is described in this patent by Seq ID 487. The nucleotide sequence is represented in the public sequence databases by the accession NM_002717 and is described in this patent by Seq ED 488. The sequence encoded by Seq ID 488 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 488 is induced by a factor of 2.06 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone p2A19 represents Sialytransferase 9. The protein sequence encoded by p2A19 is represented in the public databases by the accession NP_003887 and is described in this patent by Seq ID 489. The nucleotide sequence is represented in the public sequence databases by the accession NM_003896 and is described in this patent by Seq ID 490. Sialytransferase 9 is down-regulated by greater than 2-fold by both Hif and Epas. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. Sialytransferase 9 is suppressed by a factor of 2.38 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, Sialytransferase 9 was changed in expression -1.19, -2.27 and -1.19 fold in the three diseased patients compared to the control group. This indicates that Sialytransferase 9 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2J6 represents Similar to interferon induced protein 35. The protein sequence encoded by p2J6 is represented in the public databases by the accession P80217 and is described in this patent by Seq ID 491. The nucleotide sequence is represented in the public sequence databases by the accession BC0OV56 and is described in this patent by Seq ID 492. The sequence encoded by Seq ID 492 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. The sequence encoded by Seq ID 492 is repressed by a factor of 2 in response to IL-13 indicating a negative role in Th2 immune responses. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 492 was changed in expression 2.83, 1.73 and -1.05 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 492 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plP17 represents Similar to viral hemorrhagic septicaemia virus induced gene 1. The protein sequence encoded by plP17 is represented in the public databases by the accession XP_039079 and is described in this patent by Seq ID 493. The nucleotide sequence is represented in the public sequence databases by the accession AF026941 and is described in this patent by Seq ID 494. The sequence encoded by Seq ED 494 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 494 is induced by a factor of 4.61 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 494 is induced by a factor of 31.36 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The sequence encoded by Seq ID 494 is induced by a factor of 3.49 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2I22 represents Small inducible cytokine BIO precursor (CXCLIO). The protein sequence encoded by p2I22 is represented in the public databases by the accession P02778 and is described in this patent by Seq ID 495. The nucleotide sequence is represented in the public sequence databases by the accession NM_001565 and is described in this patent by Seq ID 496. CXCLIO is chemotactic fro monocytes and T- lymphocytes. It binds to CXCR3. CXCLIO is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. CXCLIO is induced by a factor of 2.04 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. CXCLIO is induced by a factor of 30.39 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. CXCLIO is induced by a factor of 2.44 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. CXCLIO is induced by a factor of 86.78 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. CXCLIO is repressed by a factor of 1.54 in response to LL-13 and 2.17 in response to IL-4, indicating a negative role in Th2 immune responses. CXCLIO is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, CXCLIO was up-regulated 2.92 fold in one of the patients. This indicates that CXCLIO plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2B5 represents Synaptotagmin 6. The protein sequence encoded by p2B5 is represented in the public databases by the accession XP_040019 and is described in this patent by Seq ID 497. The nucleotide sequence is represented in the public sequence databases by the accession AK024280 and is described in this patent by Seq ID 498. Synaptotagmin 6 is down-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone plP21 represents TNF ligand superfamily member 10 (TRAIL). The protein sequence encoded by plP21 is represented in the public databases by the accession P50591 and is described in this patent by Seq ID 499. The nucleotide sequence is represented in the public sequence databases by the accession NM_003810 and is described in this patent by Seq ID 500. TRAIL is involved in apoptosis via many TNF receptors. TRAIL is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TRAIL is induced by a factor of 4.55 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro- inflammatory responses involving this factor. TRAIL is induced by a factor of 39.52 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2F2 represents TRAF and TNF receptor-associated protein. The protein sequence encoded by p2F2 is represented in the public databases by the accession NP_057698 and is described in this patent by Seq ID 501. The nucleotide sequence is represented in the public sequence databases by the accession NM_016614 and is described in this patent by Seq ID 502. The sequence encoded by Seq ID 502 is down- regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, the sequence encoded by Seq ID 502 was changed in expression 2.91, 2 and 1.18 fold in the three diseased patients compared to the control group. This indicates that the sequence encoded by Seq ID 502 plays a role in the process of atherogenesis.
The Oxford BioMedica clone plP20 represents Tyrosine protein kinase (Lyn). The protein sequence encoded by plP20 is represented in the public databases by the accession P07948 and is described in this patent by Seq ID 503. The nucleotide sequence is represented in the public sequence databases by the accession NM_002350 and is described in this patent by Seq ED 504. Lyn is down-regulated by greater than 2-fold by both Hif and Epas. Lyn is induced by a factor of 3.9 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. Lyn is induced by a factor of 4.33 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. Lyn is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2KV represents Ubiqitin conjugating enzyme E2-17 KDA 1. The protein sequence encoded by p2KV is represented in the public databases by the accession P51668 and is described in this patent by Seq ID 505. The nucleotide sequence is represented in the public sequence databases by the accession BC005980 and is described in this patent by Seq ID 506. The sequence encoded by Seq ID 506 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 506 is induced by a factor of 1.99 at 6hr and 2.57 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 506 is induced by a factor of 2.22 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. The sequence encoded by Seq ID 506 is induced by a factor of 2.13 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion.
The Oxford BioMedica clone p2A8 represents Ubiquitin cross-reactive protein precursor (inteferon induced 17 KDA protein). The protein sequence encoded by p2A8 is represented in the public databases by the accession P05161 and is described in this patent by Seq ID 507. The nucleotide sequence is represented in the public sequence databases by the accession NM_005101 and is described in this patent by Seq ID 508. The sequence encoded by Seq ED 508 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. The sequence encoded by Seq ID 508 is induced by a factor of 1.53 at 6hr and 3.14 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. The sequence encoded by Seq ID 508 is induced by a factor of 10.14 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro- inflammatory responses involving this factor. The sequence encoded by Seq ID 508 is induced by a factor of 41.88 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors. The superoxide radical is a potent pro- inflammatory stimulus frequently associated with ischemic conditions. The sequence encoded by Seq ID 508 is induced by a factor of 3.08 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. The sequence encoded by Seq ID 508 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, the sequence encoded by Seq ID 508 was suppressed 3.03 fold in one of the patients and was down- regulated 2.5 fold in the other patient. This indicates that the sequence encoded by Seq ID 508 plays a role in the inflammation associated with COPD. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, The sequence encoded by Seq ID 508 was changed in expression -2.78, -4.35 and -1.61 fold in the three diseased patients compared to the control group. This indicates that The sequence encoded by Seq ID 508 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2K12 represents UNC93 homolog B. The protein sequence encoded by p2K12 is represented in the public databases by the accession NP_112192 and is described in this patent by Seq ID 509. The nucleotide sequence is represented in the public sequence databases by the accession NM_030930 and is described in this patent by Seq ED 510. UNC93 homolog B is down-regulated by greater than 2-fold by both Hif and Epas.
Vesicle-associated membrane protein 5 is represented in the public databases by the accession O95183 and is described in this patent by Seq ID 511. The nucleotide sequence is represented in the public sequence databases by the accession NM_006634 and is described in this patent by Seq ID 512. The sequence encoded by Seq ID 512 is down- regulated by greater than 2-fold by Hif.
The Oxford BioMedica clone p2K5 represents Zinc finger protein GLU (Glioma- associated oncogene). The protein sequence encoded by p2K5 is represented in the public databases by the accession P08151 and is described in this patent by Seq ID 513. The nucleotide sequence is represented in the public sequence databases by the accession NM_005269 and is described in this patent by Seq ID 514. GLU is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. GLU is repressed by a factor of 2.27 at 24hr in response to the pro- inflammatory cytokine Interleukin- 17, indicating a negative role in pro-inflammatory responses involving this factor. GLU is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, GLU was changed in expression 7.33, 4.3 and 2.41 fold in the three diseased patients compared to the control group. This indicates that GLU plays a role in the process of atherogenesis. The Oxford BioMedica clone p2J10 represents a hypothetical protein from EVIAGE:3685398 . The protein sequence encoded by p2J10 is represented in the public databases by the accession AAH05986 and is described in this patent by Seq LD 515. The nucleotide sequence is represented in the public sequence databases by the accession BC005986 and is described in this patent by Seq ID 516. p2J10 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2J10 is induced by a factor of 2.41 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. p2J10 is induced by a factor of 2.31 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The Oxford BioMedica clone p2A17 represents Hypothetical protein HSPC196. The protein sequence encoded by p2A17 is represented in the public databases by the accession AAF36116 and is described in this patent by Seq ID 517. The nucleotide sequence is represented in the public sequence databases by the accession AF151030 and is described in this patent by Seq LD 518. p2A17 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. p2A17 is repressed by a factor of 1.79 in response to LL-13 and 2.5 in response to IL-4, indicating a negative role in Th2 immune responses. p2A17 is suppressed by a factor of 2.44 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2J9 represents Hypothetical protein KIAA0937. The protein sequence encoded by p2J9 is represented in the public databases by the accession BAA76781 and is described in this patent by Seq LD 519. The nucleotide sequence is represented in the public sequence databases by the accession AB023154 and is described in this patent by Seq ID 520. p2J9 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, p2J9 is repressed in response to TNFalpha, by a factor of 2.27 fold, indicating a negative role in pro-inflammatory responses involving this factor. p2J9 is suppressed by a factor of 3.23 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors.
The Oxford BioMedica clone p2K9 represents Hypothetical protein KIAA1268. The protein sequence encoded by p2K9 is represented in the public databases by the accession BAA86582 and is described in this patent by Seq ID 521. The nucleotide sequence is represented in the public sequence databases by the accession AB033094 and is described in this patent by Seq LD 522. p2K9 is down-regulated by greater than 2-fold by both Hif and Epas.
The Oxford BioMedica clone p2J19 represents Hypothetical protein FLJ 10111. The protein sequence encoded by p2J19 is represented in the public databases by the accession NP_060469 and is described in this patent by Seq TD 523. The nucleotide sequence is represented in the public sequence databases by the accession NM_017999 and is described in this patent by Seq ED 524. p2J19 is down-regulated by greater than 2-fold by both Hif and Epas. The Oxford BioMedica clone p2J4 represents Hypothetical protein FLJ11110. The protein sequence encoded by p2J4 is represented in the public databases by the accession NP_060796 and is described in this patent by Seq ID 525. The nucleotide sequence is represented in the public sequence databases by the accession NM_018326 and is described in this patent by Seq LD 526. p2J4 is down-regulated by greater than 2-fold by Hif. p2J4 is preferentially induced by hypoxia in endothelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving endothelial cells and hypoxia, in particular angiogenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2J4 was changed in expression 2.58, 2.15 and 1.39 fold in the three diseased patients compared to the control group. This indicates that p2J4 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2E14 represents Hypothetical protein FLJ20073. The protein sequence encoded by p2E14 is represented in the public databases by the accession XP_004986 and is described in this patent by Seq ID 527. The nucleotide sequence is represented in the public sequence databases by the accession BF345327 and is described in this patent by Seq ID 528. p2E14 is down-regulated by greater than 2-fold by Hif. The Oxford BioMedica clone p2J21 represents Hypothetical protein FLJ22690. The protein sequence encoded by p2J21 is represented in the public databases by the accession NP_078987 and is described in this patent by Seq ID 529. The nucleotide sequence is represented in the public sequence databases by the accession NM_024711 and is described in this patent by Seq ID 530. p2J21 is down-regulated by greater than 2-fold by both Hif and Epas. p2J21 is preferentially induced by hypoxia in endothelial cells, indicating utility of the encoded protein in the design of therapeutic, prognostic and diagnostic products addressing diseases involving endothelial cells and hypoxia, in particular angiogenesis. p2J21 is induced by a factor of 4.37 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. p2J21 is induced by a factor of 2.19 in response to superoxide, indicating a pro-inflammatory function in ischaemia/reperfusion. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. p2J21 is repressed by a factor of 1.69 in response to EL-13 and 2.08 in response to LL-4, indicating a negative role in Th2 immune responses.
The Oxford BioMedica clone p2I23 represents Hypothetical protein MGC: 16207. The protein sequence encoded by p2I23 is represented in the public databases by the accession NP_116156 and is described in this patent by Seq ID 531. The nucleotide sequence is represented in the public sequence databases by the accession BC007379 and is described in this patent by Seq ID 532. p2I23 is down-regulated by greater than 2-fold by both Hif and Epas. p2I23 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2A5 represents cDNA FLJ14296 fis. The protein sequence encoded by p2A5 is described in this patent by Seq ID 533. The nucleotide sequence is represented in the public sequence databases by the accession AK024358 and is described in this patent by Seq ID 534. p2A5 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, p2A5 is repressed in response to TNFalpha, by a factor of 2.94 fold, indicating a negative role in pro-inflammatory responses involving this factor. p2A5 is repressed by a factor of 2.33 in response to LL-4, indicating a negative role in Th2 immune responses. p2A5 is suppressed by a factor of 4.17 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. p2A5 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the lungs of a group of two chronic obstructive pulmonary disease (COPD) patients to that of an equivalent healthy donor, p2A5 was suppressed 2.33 fold in one of the patients. This indicates that p2A5 plays a role in the inflammation associated with COPD.
The Oxford BioMedica clone p2J22 represents an EST. The protein sequence encoded by p2J22 is described in this patent by Seq ID 535. The nucleotide sequence is represented in the public sequence databases by the accession AI261490 and is described in this patent by Seq ID 536. p2J22 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2J22 is induced by a factor of 3.22 at 6hr and 1.85 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone p2J17 represents an EST. The protein sequence encoded by p2J17 is described in this patent by Seq ID 537. The nucleotide sequence is represented in the public sequence databases by the accession AI201094 and is described in this patent by Seq ID 538. p2J17 is down-regulated by greater than 2-fold by both Hif and Epas. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. p2J17 is suppressed by a factor of 2 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. p2J17 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2J17 was changed in expression 3.62, 2.19 and 1.1 fold in the three diseased patients compared to the control group. This indicates that p2J17 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A21 represents an EST. The protein sequence encoded by p2A21 is described in this patent by Seq ID 539. The nucleotide sequence is represented in the public sequence databases by the accession BG434444 and is described in this patent by Seq ID 540. p2A21 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2A21 is induced by a factor of 2.55 at 6hr and 2.79 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. p2A21 is induced by a factor of 28.76 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. p2A21 is induced by a factor of 2.32 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. p2A21 is induced by a factor of 22.32 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro-inflammatory responses involving these factors. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, p2A21 is repressed in response to TNFalpha, by a factor of 2.17 fold, indicating a negative role in pro-inflammatory responses involving this factor. p2A21 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis.
The Oxford BioMedica clone p2Kl represents an EST. The protein sequence encoded by p2Kl is described in this patent by Seq ID 541. The nucleotide sequence is represented in the public sequence databases by the accession AI216317 and is described in this patent by Seq ID 542. p2Kl is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2Kl is repressed by a factor of 2.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a negative role in pro- inflammatory responses involving this factor. The Oxford BioMedica clone p2E22 represents an EST. The protein sequence encoded by p2E22 is described in this patent by Seq ID 543. The nucleotide sequence is represented in the public sequence databases by the accession N62378 and is described in this patent by Seq ED 544. p2E22 is down-regulated by greater than 2-fold by both Hif and Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2E22 was changed in expression 3.37, 2.63 and -1.06 fold in the three diseased patients compared to the control group. This indicates that p2E22 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2J14 represents an EST. The protein sequence encoded by p2J14 is described in this patent by Seq ID 545. The nucleotide sequence is represented in the public sequence databases by the accession AI452941 and is described in this patent by Seq ID 546. p2J14 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2J14 is repressed by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a negative role in pro-inflammatory responses involving this factor. p2J14 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2J14 was changed in expression -2.5, -2.44 and -1.32 fold in the three diseased patients compared to the control group. This indicates that p2J14 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2B4 represents an EST. The protein sequence encoded by p2B4 is described in this patent by Seq ID 547. The nucleotide sequence is represented in the public sequence databases by the accession P2B4 and is described in this patent by Seq ED 548. p2B4 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2B4 is induced by a factor of 2.61 at 6hr and 2.88 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. p2B4 is induced by a factor of 25.13 at 24hr in response to the pro-inflammatory cytokine Interleukin- 15, indicating a positive role in pro-inflammatory responses involving this factor. p2B4 is induced by a factor of 2.04 at 24hr in response to the pro-inflammatory cytokine Interleukin- 17, indicating a positive role in pro-inflammatory responses involving this factor. p2B4 is induced by a factor of 22.33 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a role in macrophage activation and pro- inflammatory responses involving these factors. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. TNFalpha is an inflammatory cytokine, which acts on macrophages, and has been shown to be central to the pathophysiology and treatment of diseases including rheumatoid arthritis. Genes that change in expression in response to TNFalpha therefore have utility in the design of therapeutic, prognostic and diagnostic products for such inflammatory conditions. As well being implicated in disease phenotypes by virtue of being affected by hypoxia, p2B4 is repressed in response to TNFalpha, by a factor of 2.38 fold, indicating a negative role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone p2J15 represents an EST. The protein sequence encoded by p2J15 is described in this patent by Seq ID 549. The nucleotide sequence is represented in the public sequence databases by the accession BF110534 and is described in this patent by Seq ID 550. p2J15 is down-regulated by greater than 2-fold by both Hif and Epas. p2J15 is suppressed by a factor of 3.7 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The Oxford BioMedica clone p2J16 represents an EST. The protein sequence encoded by p2J16 is described in this patent by Seq ID 551. The nucleotide sequence is represented in the public sequence databases by the accession AA922121 and is described in this patent by Seq ID 552. p2J16 is down-regulated by greater than 2-fold by both Hif and Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2J16 was changed in expression -1.06, 1.88 and 2.44 fold in the three diseased patients compared to the control group. This indicates that p2J16 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2A2 represents an EST. The protein sequence encoded by p2A2 is described in this patent by Seq ID 553. The nucleotide sequence is represented in the public sequence databases by the accession N52875 and is described in this patent by Seq ID 554. p2A2 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2A2 is induced by a factor of 2.13 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro- inflammatory responses involving this factor.
The Oxford BioMedica clone p2K3 represents an EST. The protein sequence encoded by p2K3 is described in this patent by Seq ID 555. The nucleotide sequence is represented in the public sequence databases by the accession AI339140 and is described in this patent by Seq LD 556. p2K3 is down-regulated by greater than 2-fold by Epas. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2K3 was changed in expression -1.47, -2.38 and - 1.49 fold in the three diseased patients compared to the control group. This indicates that p2K3 plays a role in the process of atherogenesis. The Oxford BioMedica clone p2K10 represents an EST. The protein sequence encoded by p2K10 is described in this patent by Seq ID 557. The nucleotide sequence is represented in the public sequence databases by the accession AI268607 and is described in this patent by Seq LD 558. p2K10 is down-regulated by greater than 2-fold by Hif. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2K10 is induced by a factor of 3.33 at 6hr and 1.65 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. p2K10 is expressed at lower levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2K10 was changed in expression -2.38, -2.63 and -2.22 fold in the three diseased patients compared to the control group. This indicates that p2K10 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2K15 represents an EST. The protein sequence encoded by p2K15 is described in this patent by Seq ID 559. The nucleotide sequence is represented in the public sequence databases by the accession AI206099 and is described in this patent by Seq ID 560. p2K15 is down-regulated by greater than 2-fold by Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. Th2 cytokines, typified by Interleukin-4 and Interleukin- 13, are characteristic of a biased immune response resulting in strong humoral component, and these cytokines typically produce antagonising effects to the Thl cytokines more commonly associated with macrophage-mediated inflammation such as in rheumatoid arthritis or chronic occlusive pulmonary disease. p2K15 is repressed by a factor of 2 in response to IL-13 and 3.33 in response to IL-4, indicating a negative role in Th2 immune responses. p2K15 is suppressed by a factor of 6.67 in response to Interferon Gamma and Lipopolysaccharide as found during bacterial infections, which indicates a negative role in macrophage activation and pro-inflammatory responses involving these factors. The superoxide radical is a potent pro-inflammatory stimulus frequently associated with ischemic conditions. p2K15 is suppressed by a factor of 2.13 in response to superoxide, indicating an anti-inflammatory function in ischaemia/reperfusion. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2K15 was changed in expression -1.59, 2.25 and 1.18 fold in the three diseased patients compared to the control group. This indicates that p2K15 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2K4 represents an EST (In Intron to LOC90967). The protein sequence encoded by p2K4 is described in this patent by Seq ID 561. The nucleotide sequence is represented in the public sequence databases by the accession AA019337 and is described in this patent by Seq ID 562. p2K4 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2K4 is induced by a factor of 2.05 at 6hr and 1.52 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. p2K4 is expressed at higher levels in tumor tissue of at least one patient, compared to adjacent normal tissue of the affected organ, indicating a role in the process of tumorigenesis. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, p2K4 was changed in expression -2.56, -1.52 and -1.67 fold in the three diseased patients compared to the control group. This indicates that p2K4 plays a role in the process of atherogenesis.
The Oxford BioMedica clone p2J20 represents an EST (In intron to LOC93147 ~1.7kb to nearest exon). The protein sequence encoded by p2J20 is described in this patent by Seq ED 563. The nucleotide sequence is represented in the public sequence databases by the accession BE550891 and is described in this patent by Seq ID 564. p2J20 is down- regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. p2J20 is induced by a factor of 2.71 at 6hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor.
The Oxford BioMedica clone plP22 represents an EST containing repetitive element. The protein sequence encoded by plP22 is described in this patent by Seq ID 565. The nucleotide sequence is represented in the public sequence databases by the accession
P1P22 and is described in this patent by Seq ID 566. plP22 is down-regulated by greater than 2-fold by both Hif and Epas. Cytokines are involved in cell-cell communication, and an abundance of certain types of cytokine is an important contributing factor to several disease states also characterised by hypoxia, such as rheumatoid arthritis and cancer. plP22 is induced by a factor of 5.57 at 48hr in response to the pro-inflammatory cytokine Interleukin- 12, indicating a positive role in pro-inflammatory responses involving this factor. In a comparison between the aortas of a group of three patients with atherosclerotic plaques to that of a group of two equivalent healthy donors, plP22 was changed in expression -1.82, -2.17 and -2.44 fold in the three diseased patients compared to the control group. This indicates that plP22 plays a role in the process of atherogenesis.
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SEQ ID NO : A
Nucleotide sequence of ires-GFP DNA fragment
CTAGAGTGTGATΓTTAAGGGCGAATTCTGCAGATATCCATCACACTGGCGGCCGCACTAGAGGAATTCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGC TTGGAATAAGGCCGGTGTGTGTTTGTCTATATGTGATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTA GGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAG GCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTT GTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTAGTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGAATCTGATCTGGGGCCTCGGTGCACATGCTTT ACATGTGTTTAGTCGAGGTTAAAAAAGCTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATGATACCATGGTGAGCAAGGGCGAGGAGCTGTTCA CCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTT CATC GCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTC TTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCΓΓCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGA ACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAA GAACGGCATCAAGGTGAACRTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTG CCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCA TGGACGAGCTGTACAAGTAAAGCGGCCGCGACT
SEQ ID NO-B
Nucleotide sequence of DMA fragment containing human HIF-ID protein coding sequence
CTAGCCCTAGAATCCGACCGATTCACCATGGAGGGCGCCGGCGGCGCGAACGACAAGAAAAAGATAAGTTCTGAACGTCGAAAAGAAAAGTCTCGAGATGCAGCCAGATCTC GGCGAAGTAAAGAATCTGAAGTTTTTTATGAGCTTGCTCATCAGTTGCCACTTCCACATAATGTGAGTTCGCATCTTGATAAGGCCTCTGTGATGAGGCTTACCATCAGCTA TTTGCGTGTGAGGAAACTTCTGGATGCTGGTGATTTGGATATTGAAGATGACATGAAAGCACAGATGAATTGCTTTTATTTGAAAGCCTTGGATGGTTTTGTTATGGTTCTC ACAGATGATGGTGACATGATTTACATTTCTGATAATGTGAACAAATACATGGGATTAACTCAGTTTGAACTAACTGGACACAGTGTGTTTGATTTTACTCATCCATGTGACC ATGAGGAAATGAGAGAAATGCTTACACACAGAAATGGCCT'IGTGAAAAAGGGTAAAGAACAAAACACACAGCGAAGCTTTTTTCTCAGAATGAAGTGTACCCTAACTAGCCG AGGAAGAACTATGAACATAAAGTCTGCAACATGGAAGGTA'ITGCACTGCACAGGCCACATTCACGTATATGATACCAACAGTAACCAACCTCAGTGTGGGTATAAGAAACCA CCTATGACCTGCTTGGTGCTGATTTGTGAACCCATTCCTCACCCATCAAATATTGAAATTCCTTTAGATAGCAAGACTTTCCTCAGTCGACACAGCCTGGATATGAAATTTT CTTATTGTGATGAAAGAATTACCGAATTGATGGGATATGAGCCAGAAGAACTTTTAGGCCGCTCAATTTATGAATATTATCATGCTTTGGACTCTGATCATCTGACCAAAAC TCATCATGATATGTTTACTAAAGGACAAGTCACCACAGGACAGTACAGGATGCTTGCCAAAAGAGGTGGATATGTCTGGGTTGAAACTCAAGCAACTGTCATATATAACACC AAGAATTCTCAACCACAGTGCATTGTATGTGTGAATTACGTTGTGAGTGGTATTATTCAGCACGACTTGATTTTCTCCCTTCAACAAACAGAATGTGTCCTTAAACCGGTTG AATCTTCAGATATGAAAATGACTCAGCTATTCACCAAAGTTGAATCAGAAGATACAAGTAGCCTCTTTGACAAACTTAAGAAGGAACCTGATGCTTTAACTTTGCTGGCCCC AGCCGCTGGAGACACAATCATATCTTTAGATTTTGGCAGCAACGACACAGAAACTGATGACCAGCAACTTGAGGAAGTACCATTATATAATGATGTAATGCTCCCCTCACCC AACGAAAAATTACAGAATATAAATTTGGCAATGTCTCCATTACCCACCGCTGAAACGCCAAAGCCACTTCGAAGTAGTGCTGACCCTGCACTCAATCAAGAAGTTGCATTAA AATTAGAACCAAATCCAGAGTCACTGGAACTTTCTTTTACCATGCCCCAGATTCAGGATCAGACACCTAGTCCTTCCGATGGAAGCACTAGACAAAGTTCACCTGAGCCTAA TAGTCCCAGTGAATATTGTTTTTATGTGGATAGTGATATGGTCAATGAATTCAAGTTGGAATTGGTAGAAAAACTTTTTGCTGAAGACACAGAAGCAAAGAACCCATTTTCT ACTCAGGACACAGATTTAGACTTGGAGATGTTAGCTCCCTATATCCCAATGGATGATGACTTCCAGTTACGTTCCTTCGATCAGTTGTCACCATTAGAAAGCAGTTCCGCAA GCCCTGAAAGCGCAAGTCCTCAAAGCACAGTTACAGTATTCCAGCAGACTCAAATACAAGAACCTACTGCTAATGCCACCACTACCACTGCCACCACTGATGAATTAAAAAC AGTGACAAAAGACCGTATGGAAGACATTAAAATATTGATTGCATCTCCATCTCCTACCCACATACATAAAGAAACTACTAGTGCCACATCATCACCATATAGAGATACTCAA AGTCGGACAGCCTCACCAAACAGAGCAGGAAAAGGAGTCATAGAACAGACAGAAAAATCTCATCCAAGAAGCCCTAACGTGTTATCTGTCGCTTTGAGTCAAAGAACTACAG TTCCTGAGGAAGAACTAAATCCAAAGATACTAGCTTTGCAGAATGCRCAGAGAAAGCGAAAAATGGAACATGATGGTTCACTTTTTCAAGCAGTAGGAATTGGAACATTATT ACAGCAGCCAGACGATCATGCAGCTACTACATCACTTTCTTGGAAACGTGTAAAAGGATGCAAATCTAGTGAACAGAATGGAATGGAGCAAAAGACAATTATTTTAATACCC TCTGATTTAGCATGTAGACTGCTGGGGCAATCAATGGATGAAAGTGGAΓΓACCACAGCTGACCAGTTATGATTGTGAAGTTAATGCTCCTATACAAGGCAGCAGAAACCTAC TGCAGGGTGAAGAATTACTCAGAGCTTTGGATCAAGTTAACTGAGCGGATCCGACGGGGATCCT
SEQ ID NO:C
Nucleotide sequence of DNA fragment containing human EPASl protein coding sequence
AGCTTGCATGCCTGCAGGTCGACTCTAGAGGATCCAGCGACAATGACAGCTGACAAGGAGAAGAAAAGGAGTAGCTCGGAGAGGAGGAAGGAGAAGTCCCGGGATGCTGX3C GGTGCCGGCGGAGCAAGGAGACGGAGGTGTTCTATGAGCTGGCCCATGAGCTGCCTCTGCCCCACAGTGTGAGCTCCCATCTGGACAAGGCCTCCATCATGCGACTGGAAAT CAGCTTCCTGCGAACACACAAGCTCCTCTCCTCAGTTTGCTCTGAAAACGAGTCCGAAGCCGAAGCTGACCAGCAGATGGACAACTTGTACCTGAAAGCCTTGGAGGGTTTC ATTGCCGTGGTGACCCAAGATGGCGACATGATCTTTCTGTCAGAAAACATCAGCAAGTTCATGGGACTTACACAGGTGGAGCTAACAGGACATAGTATCTTTGACTTCACTC ATCCCTGCGACCATGAGGAGATTCGTGAGAACCTGAGTCTCAAAAATGGCTCTGGTTTTGGGAAAAAAAGCAAAGACATGTCCACAGAGCGGGACTTCTTCATGAGGATGAA GTGCACGGTCACCAACAGAGGCCGTACTGTCAACCTCAAGTCAGCCACCTGGAAGGTCTTGCACTGCACGGGCCAGGTGAAAGTCTACAACAACTGCCCTCCTCACAATAGT CTGTGTGGCTACAAGGAGCCCCTGCTGTCCTGCCTCATCATCATGTGTGAACCAATCCAGCACCCATCCCACATGGACATCCCCCTGGATAGCAAGACCTTCCTGAGCCGCC ACAGCATGGACATGAAGTTCACCTACTGTGATGACAGAATCACAGAACTGATTGGTTACCACCCTGAGGAGCTGCTTGGCCGCTCAGCCTATGAATTCTACCATGCGCTAGA CTCCGAGAACATGACCAAGAGTCACCAGAACTTGTGCACCAAGGGTCAGGTAGTAAGTGGCCAGTACCGGATGCTCGCAAAGCATGGGGGCTACGTGTGGCTGGAGACCCAG GGGACGGTCATCTACAACCCTCGCAACCTGCAGCCCCAGTGCATCATGTGTGTCAACTACGTCCTGAGTGAGATTGAGAAGAATGACGTGGTGTTCTCCATGGACCAGACTG AATCCCTGTTCAAGCCCCACCTGATGGCCATGAACAGCATCTTTGATAGCAGTGGCAAGGGGGCTGTGTCTGAGAAGAGTAACTTCCTATTCACCAAGCTAAAGGAGGAGCC CGAGGAGCTGGCCCAGCTGGCTCCCACCCCAGGAGACGCCATCATCTCTCTGGATTTCGGGAATCAGAACTTCGAGGAGTCCTCAGCCTATGGCAAGGCCATCCTGCCCCCG AGCCAGCCATGGGCCACGGAGTTGAGGAGCCACAGCACCCAGAGCGAGGCTGGGAGCCTGCCTGCCTTCACCGTGCCCCAGGCAGCTGCCCCGGGCAGCACCACCCCCAGTG CCACCAGCAGCAGCAGCAGCTGCTCCACGCCCAATAGCCCTGAAGACTATTACACATCTTTGGATAACGACCTGAAGATTGAAGTGATTGAGAAGCTCTTCGCCATGGACAC AGAGGCCAAGGACCAATGCAGTACCCAGACGGATTTCAATGAGCTGGACTTGGAGACACTGGCACCCTATATCCCCATGGACGGGGAAGACTTCCAGCTAAGCCCCATCTGC CCCGAGGAGCGGCTCTTGGCGGAGAACCCACAGTCCACCCCCCAGCACTGCTTCAGTGCCATGACAAACATCTTCCAGCCACTGGCCCCTGTAGCCCCGCACAGTCCCTTCC TCCTGGACAAGTTTCAGCAGCAGCTGGAGAGCAAGAAGACAGAGCCCGAGCACCGGCCCATGTCCTCCATCTTCTTTGATGCCGGAAGCAAAGCATCCCTGCCACCGTGCTG TGGCCAGGCCAGCACCCCTCTCTCTTCCATGGGGGGCAGATCCAATACCCAGTGGCCCCCAGATCCACCATTACATTTTGGGCCCACAAAGTGGGCCGTCGGGGATCAGCGC ACAGAGTTCTTGGGAGCAGCGCCGTTGGGGCCCCCTGTCTCTCCACCCCATGTCTCCACCTTCAAGACAAGGTCTGCAAAGGGTTTTGGGGCTCGAGGCCCAGACGTGCTGA GTCCGGCCATGGTAGCCCTCTCCAACAAGCTGAAGCTGAAGCGACAGCTGGAGTATGAAGAGCAAGCCTTCCAGGACCTGAGCGGGGGGGACCCACCTGGTGGCAGCACCTC ACATTTGATGTGGAAACGGATGAAGAACCTCAGGGGTGGGAGCTGCCCTTTGATGCCGGACAAGCCACTGAGCGCAAATGTACCCAATGATAAGTTCACCCAAAACCCCATG AGGGGCCTGGGCCATCCCCTGAGACATCTGCCGCTGCCACAGCCTCCATCTGCCATCAGTCCCGGGGAGAACAGCAAGAGCAGGTTCCCCCCACAGTGCTACGCCACCCAGΓ ACCAGGACTACAGCCTGTCGTCAGCCCACAAGGTGTCAGGCATGGCAAGCCGGCTGCTCGGGCCCTCATTTGAGTCCTACCTGCTGCCCGAACTGACCAGATATGACTGTGA GGTGAACGTGCCCGTGCTGGGAAGCTCCACGCTCCTGCAAGGAGGGGACCTCCTCAGAGCCCTGGACCAGGCCACCTGAGCCAGGCCTTCTACCTGGGCAGCACCTCTGCCC ACGCCGAGCCCTATGCAGTCTCGGCCGCAAGCTATCAGATCTGCCGGTCTCCCTATAGTGAGTCGTATTAATTTCGATAAGCCAGGTT
1
MHDAFEPVPILEKLPLQIDCLAAWEEWLLVGTKQGHLLLYRIRKDVGCN FEVTLEKSNKNFSKKIQQIHWSQFKILVSLLENNIYVHDL TFQQITTVSKAKGAS FTCD QHTETGEEV RMCVAVKKKLQ YFWKDREFHE QGDFSVPDVPKSMAWCENSICVGFKRDYYLIRVDGKGSIKELFPTGKQLEP VAPLADGKVAVGQDD TVVLNEEGIC
TQKCALN TDI PVAMEHQPPYI IAVLPRYVEIRTFEPRLLVQSIELQRPRFITSGGSNI IYVASNHFV R I PVPMATQIQQ QDKQFEIiA QliAEMKDDSDSEKQQQIHH
IKNLYAFNLFCQKRFDESMQVFAKLGTDPTHV G YPDLLPTDYRKQLQYPNPLPV SGAELEKAHI-A IDYLTQKRSQLVKK NDSDHQSSTSPLMEGTPTIKSKKKLLQI
IDTTL KCYLHTNVALVAPL R ENNHCHIEESEHVLKKAHKYSELI I YEKKG HEKALQV VTX5SK ANSP KGHERTVQY )HLGTENLH IFSYSVW^RDFPEDGLK
IFTEDLPEVES PRDRVLGF IENFKG AI PYLEHI IHVWEETGSRFHNCLIQLYCEKVQGLMKEYLLSFPAGKTPVPAGEEEGE GEYRQK LMFLEISSYYDPGR ICDF
PFDGLLEERA LGPJ4GKHEQALFIYVHILKDTR AEEYCHKHYDRNKIX3NKDVY S LP WLSPPSIHCLGPIKLELLEPKAN QAALQV ELHHSK DTTKALNL PANT
QINDIRIF EKVLEENAQKK FNQV N HAEF R QEERI HQQ KCI ITEEKVC^WCKKKIGNSAFARYPNGW HYFCSKEVNPADT
2
GGGGTTCCTGGCCGGATCCCGGTCTACCCTTAGCCCAGACTCGTTCCGGACCCCAGCCCGGCCCGGAACACTCTGGGCGAGACGGCGGTGGCAACTCTCCCCTTGCCGCCAΓ GCACGACGCTTTCGAGCCAGTGCCGATCCTAGAAAAGCTGCCTCTGCAAATCGACTGTCTGGCTGCCTGGGGTGAGCCGAGGGGCCGCGGGGCCGAGGCGGAGTCAGCACAG GAGCGGTCCX3GATCTTTTCTGAGGCCGGGGAAGTGGACAGGCGTCCATCCGTGTGGGCTTCGGTTGGATGCTACACGAGAGGGGCTTAGGATGAGAGAAGGCAGAGAGATGA CCACCGGCTATAGACATCGATGTCTGTGGGGCTACTTGGGTGATCCCAGTGATCCAGTCATTTAGGGGAGTTCCCCTTGCTTTTGCTCTCTGTGCAGAGTGGGAGGATGAGC TTTCCTTTTTAGTTGTGCTCAGCTTTGGCCCATTTTGATTCCCACGAAGACTTCATTTTAGAGGGTCAAAGCAGTAAGAAGTTCTCAGCCTGCCAGGGGCTTGAAGTTGTCC AGATGTTTGTGTTGTTTTCTAGATGAAAGTCAACCCTGGTTTTGGGGGCATTGAACAAGTTAACACCATATGCTTTT'ITTTCCCCTTAGTGATCATTCGTTCATTTCTCATT CCTGTAGGGAACTCATGTAGTTAGCTAACCTTTGAATCTAGCCAAGCGGTTGATTACCTTATATCCAAAGTGTCCAAGT'IACCTAACTGTAGGCGGAAGAGTTTCCAGACTG TCTTGAAACCTAACCCATAAAAACTAGCATAGTCCTTTTGGGATTGACTAGTGCAGAAGGCCGGGACAGACATCTCTTGTGTGCTCTGAAATACAAATGAAGGTTTCAGGGA TAACGGTGAACATTGTGCTCTTATCCGTGAGTGACTGGTTTGATACCAGCCGCCAAAGACCAAGGAAATCATTTCTAACTTTCCTCTTAATGTTTAGGTCCTAGAAATCAAG GACCATAAAAAGATGATTCAGATCCCTTAATCAGATCTTATACTGAGCTAGATAGGTAACCATGATGGGCCTTATGGAATCTTGGTGGTGTCTGATACCATGTGCGTCAGCT GTTCACAGTGTCACCGAGTCATCCTTGCAGAGTTCTTGATQACTTCTTCTGTAGGGTTCTTTCACGAAGAATTTTCATGT'IAATGTGCACCCTTCCTCCTTTAGCAGCTCTG GGTCTCTTTAAAATCATACCTCCACAGTAAGCAGTTCTAGTCCTTTGGGTTAAGAGGAGAATCCTACTTCCTCCAGACATCTCAAGAAAACCAATTTCTGTCATTAAATGCT CTCATTAAACATTTAAATAGAGGAGGAGAAAAAGTTTTTAAATGAAAGACCTGACACTGCATGAAAGGATTAATTCCCCCATTGCTTCATCAGATATACTTATTAGGTGGCT ACACG SCCATTCTCTTTGCTTGGGACAGTAATACAATGATGAATAAGAAACAGTGCCTGTGCTCCTAGGACACACACTGGGGGACAAATACACGTGAACAGATTATAATAC TAGAGACATATGCTGCCTATTATTGCAACATGGATGAGGGGGTACCCAACTCAGCTAAGGACATATGTTTCTGAAAGGGATTAATGCAGCTGTGGCTACACTTGACTTAGCT CGTCAGAATCCTTGACTCTGATCTCCTGTTGGACCATTAGCACATAGTGCTCCTAGACTCTCACCAACTCCACTTTGTCACAGTAAAGATTCCTTGCACCTGTGGTTTTCAG GAACACAGTTTTGAAACAATAGGTAGCTTTTGGCCTTCCTTGATCACCCACCGAACAGGAGAAATGCTCTTTGGTTCCTAAGGTGCTTAGGTACATATTAGGTTACAAGAGG CCATTAACTGCCTCCTGCTTCAAAAGTGCTTTATTTCCAGATTTGAGCAGCAGTAATTATTGCTCTTTCTAGTCATTACCCCTTTTTAACTACATTGTGCCTTTGGATGGAA AGTTCGTCCAGGAACTTCCAGAGGCAGGTCACACAGGGCCAAATAGTATTTGAGGTGTAAATGTCTTAGAGACAACATACTCTGTCTCCTGGGAAATAGAAATCAGGAGAGA ACATGATGAGGATGATTTCTTTCTAAACTCCAAAGTTGTATAATCCTGCTGCCTTTTCAGCATCTTCATTTGGATGTCCAGTAGCATAGCCAAAACCGTTCTTGATTCCTCT CCCCTCAAACATGCCTGTCCTCCTGTATCTTACGTCTCAGCAAGTGGCATTTCTATTTACCTCTTTGACTAAAGCCAAAAGCTTTGGAATCGTTCTTGACTTCTTTCATTCT GTTTTACACTGTATCCCATCTATCAGCAAATCTTGTGTGTTCTACCCCTAGAATAAATCTGAAATCCAGTCATTTCTCTCTATCTTGATGATTACTACTCTTGAAGGCACCA TCATCTGTCACCTGAATTACTGTAGTAGTCTTCTCATTGATCACCCTATATTTGCCAGTGTGCCATTTTCAGTTTTTTGTCTACCAGGTAGAGTGAAACTTTGAAAACCTAA ATCTGATTCCATCCTCTACTCAAAACCCTCTCATGGTATCACATCACAACTAGAATAAGTTCCAAAGTTTTCACCCTGTCTGGCAACATCTGACATGATCAGGCCCTGATTT CTTCCCTGTCTTCTG GTACTTACCTCTCACTCCTTTCTGGTACCAGTCCCACACAGCCTTCTTTGTTCCATCAATGCACAAAGCACATACCCACCTCAGGGCCTTTACATT TGCTGTTTCCTTGGCCTGGCACTCACTTGCCTTTGTATATATGGTTCATTCCTCATTTCACTCAGTTCTCTGCTGAAATGTCACCCAAATCAGCAAAACCTTCCCTGTGTAT CCTATATAAAAGAGATTGCCACATCCACCAATGTGCTGTTTTCTTAGCCTTATCrTCTAATCATGGGTCACCATCTACTGTTATTTTATATATT'IAATTATTATTGCCTCTC TCACTCCACATTAGAATATAAGTTCCCTCAGGGCAGTATCTTTGTTTTCTGCATTGCTATATCTGCAGTACCTAAAACATTTCCTGACTCAATGGGTATTCATTAAATATAT ATTTAATGAATAATCTTAATATGAATAGTAATAGCTTGCAGTTGTTAAATGCTAATCTGTATTAGGCTTTTATAAAATAAGACTCCATTTTACAGAAGAAAGACCTAAGGCT TAGAAAATTTAAGAAATTTTTCCAAGGTCACATGICCTGTAAATCATGTCTGCTTCTAGAGCCTGGTTCTCAAACTTGAATGTATATTCAAAGCCTGTAAAAAATGCAGACT TCACATGTATATATGAGTATCTGTATGTCTATATATACATACATACCTATATTTTCCAGAGAAACAATGGAAAGATAAGTCAAAAATTACTAAAATGATGCCCATAGCAGAA GGGAGAAGAGAGGATAAAATGGACAATGATAGAAACTAGACTTTTCGTCGTTTTAGCTTTGGAACTACATGAATGTTTCATAAAAACAAATAAAATTTAATTTAATTTTATT TTATTTTATTTTATTTCATTATTATTTTTTGAGACTGAGTCTCGCTCTGTCGCCCAGGCTGAAGTGCAGTGGTGCAATCTCAGCTCACTGCAACCTCTGCCTCCCAGGTACA AGCCACTGTCGTGCCTCAGCCTCCCGAGTAGTTAGGATTACTGCCACCCACCACCATACCTGGCTTATTTTTGTAGTTTTAGTAGAGACGGGGTTTCGTCATGTTGGCCAGG CTGGTCTCAAACGCCTGACCTGAGGTGATCCGCCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACTTTGCCCAGCCAACAAGATTAAATTTTAAAATGTA AATTTCAGGGTACCACTTCAAAGCCATTGAATCTGAATCTCCATGTGCAGGGCCCAGGAATGTGCATTTTTAATAAGTCCAGGTGATTCTAATGCAGCTAATTGGGGGCTTA TGCCCAGATGAGAAGTACTGTTATTTGCCATGTTACCCAACGAAGGGAAGTGACTACTATCTTACTTATCTTTGTGGTCCCTGCAGTGGCCAGCATTGGGCCAGAAATGGAA TTTATTACATGAAGTTGGACTGCATTGCACTGTTGGAAGGAGCTCCATTAGGGTAATTATGAGCAATAGGGCCTAGCCCTCCTTCTCAGGAGGAATTAAGTCCAACCTTGTG GCTCAGGGTTAGGCCXJTCAGGAGTTTTTTAGGGCTGATACTGCTTTGCTTATGTG'IGCGTTTTGTGTTTGCTTAGTATGTCTCACTTTCTGTTGTGTGTTACTGTATTGAGT
CTCAGAAGGCACTGTCCATCCCATGCTGCGCGTGCTCTGCAGGCTTGTCATCCTCTGTGTTGTGCATGCACAGCTTTGTTAAATAACGTGTCCTAGAGAGTGGAGGACCCAA CATGGGACAGGTCCTCTGGCTAATGGCACATGTAATCAATCAGGTTGATTTAAAAGTTTACAGAGAATTTAATCCATCGGATTGATTCCCTTTTATGACCAGTAGAATAGAC
TCAAGTGGTTCTCCTGTCTCAGCCTCCCTAGTACCTGGGATTACAGGTGCTCACCAGCACACCTGGCTAATTTTTTTTTTTTTTTTGAGACAGAGTCCTGCCCCGTCACCCA GGCTGGAGTGCAGTGGTACGATCTCAGCTCACTGCAGCCICTCCCTCCGGGGTTCATGCAGTTCTCTTGCCTCAGTCTCCTGAGTAGCTGGGATTACAGGCACACACACCAC CATGCCTGGCTAATTTTTTTTGTATTTTTAGTAGAGATGGGTTTCCACTGTGTTGGCCAGACTGGTCTTGAACTCCTGACCTCAGGTGATCTGCCCGCCTTGGCCTTCCAAA GTGCTGGGATTACAGGCATGAGCCAACCACACTCGGCCTAATTTTTATATTTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTAGTCTCAAACTCCTGACCTCCAG TGATTCGCCCACTTCGGCCTCCGTGCCCGGCCCCTAGACATTTGACTTTTTAAAATGTTTTGTCATGTCTTAGTTTGGGTTCACAAGAAAAAAAAAAAGTAAATTAAAAAAT CTATTGGCAAGAAACATTTCAATAAAAATGGAAAATAGACTCTTGAATGTCATGTTTAGGAATTTGACTTCATATTTTGGTAGTGTAGCTTCACAGGATTTTTTAAGCCCCA GTGTGACAGCATCAGAGATCTGCTCTAAGATAACTGACAGCAAATGCGAGAGAATGCATGGAGTGAATGAGACCAGTTGAAGGTGTCACAGGGGTCCCCAGAGAGACTCTAT AGGAGGAGGCTGTCATGAGGTACCATTACAGGTAGAATTGATAGACCCTGGCCGACTTGGGAGGAAGCTGAGGCTATTAAAAAAGATAAAGAAAAGCAGGAACTGGCAGGGA TTTGGGGGACAGAGTGGAGAGAGAAGGATGGGGAAGATGATGAACATTATGTTGGCCTTTTGTTTTGGTTGTAGATTTTTATGTATGTTATGAGTGGATTTTTAAAAAATTT
CCACTTCATTTTATTTATATCTGAAATATCAGTGGGTGGCCTAAAAATCAACTTTAATATTGCTAAATTGCTTGATA'ICATGATATCTATAAAGTTCTAAATATAGTATCTT
TTACAAAACAAATATTGCAAAATGAATTCTTTTATTTTTTCATGTTCTGCTGCAGCATAAATCTCCAGCCTTCATTAGAGCTGCTGTTATTTCTGATTTCAACATTTTTTTT GTGTGTGACCTGCCTTTCCTTTAAGACCCCAAATCAAAGAAAATAGAATCACTCTGTTTTTCTGGATGACTAAGAACATCATCCTGGAGAAATACTATTGATCCTTTGGATA AGGAATGTAGGTGCTGACCTGTTTTTATAAATATAACTACTGCCATTCAGACAACCTTTGGCTGACACCCATTTTTTTTGACATGGGTGCCTTAGTAAGTACATCACAGCAT GTGGTTGGGAATCAAGACAAATTGGGGTTGGGATCCCAACTCTGCTGCTTGCCACATGTGTGACTCTGGAAAAGTTATATATTCCCTAGGCCTCAACTTCCTCATCTATAAA ATGGGGATTTGAAAAAAGGACTTACTTCAAGGGATAGTTGTGAGGATTAGTGAAATAACAGATGCGTTTAGCA'ITTCCTGGAACACAATACATGCTCAATAAAAGTTATCTA TTTGTACCATTATCCAAGATTTTATTTTACAGAGGTCAAGAATCAAGAGAGTTTATGAAAGGAATGAGTGACCTTTATGTTATCAAAAAGCTAAGGAAGTATCTGTACATGC TTACCTTCCTTGAATGATGTAATATGGGTCTGTCAGGGTAATTATTTAAACTCTTTCTGAGCCTCTTTTTACCTAGACCAGTGCCTCCCAAAATGTGGTCCTTGAACCACCA GCATCAGCATCATCTGGGAAGTTGTTAGAAATGAAAATTCCTGGGCCTACTTTTAAACCTACTAAATCAGATGCTCCGGGGTAGAGCCTAGCATTCTGTATTTTAACAAACT CTCAAATAATTGTGATACACTAAAGTTTAAGAACCACTAGCCTAGACCATCTTTTAAAATGTACAATTTGGCTGGGCACAGTCGCTCACCCCTGTAATCCCAACACTTTGGG AAGCTGAAGGGGCATTGCTTGCGGTCAAGAGTTGGAGACCAGATTGGGCAATATTG GAGCCCTCATCTCTATAAACATTTTTTAAAAAATAGCTGAACGTGGTGGTGCATG CCTGTATTTCTCGCCACTCAGGAGGCTGAGGTGGGAGGATCACTTGAGCTAGGGAGGTGGAGGCTGCAATGAGCCATGATCACACCACTGCTCTCTAGCCTGGGCAACAGAG TAGAACCCTATCTTAAAAAAATAAAAGTTAAAAAAAAGTGTACAATTAAATGGTTTTTAGTACATTCACAGAGTTATGCAACTATCAGCACAAIAAATTTTAGAACATATTC ATCACTTTCAGAAGAAACTCAGTACCCATTAGTATTTACTTTCTATTTTCCCCCAAGCCCACCAGCCCTGGGCAACCGCTAATCTTTCTACCTCTGTGGATTTGCCTACTCT GGACATTTCATATAAATGGAATCACGTGGCCTTTTGTCTGGCTTCCTTCAGTTAGCATCATGTTTTTAGGTTCATCTGTGTTGTAGCATATATCCATACTTCCTTTCTTTTC ATTGTTAGCTAATATTCCGTTATATAGACATGCCACATTTTGTTTATCCGTTCATCAGTTGGTGGACATTTGGTTTGTTTCCATCTTTTAGCTATTACAGATAATACTGCTG TGAACATTTGTGTACAAGTTTTTGTGTAGAATATGTTTTCATTTCTGTTGGGTGTGTAACCAGGAGTGGAATTGCTGGGTCCCAGGGTAACTCTGTTTAGCCTTTTGAGGAG CTGCTAGACTTTTCCAAAGTGGCTCTCCCATT'ITACATTCCTGCCAGCAGTGTATGAGGATTCTAATTTCTTTATA'ITCTCATCAACACTTGTTATTAAATATTTTCTACTA GACTATCTTTTGAGATAATGAATTCTGTAAGCTTATTATGTTACGTCATTTATTTTCCTGAAAGTAAAAGCAT'ITAAAGGATGCCTCTTAGCTATTATTGCTGAGGTTGGAT ACCTGGTTTCACATTTGTACTTCCATTTTGTGATTTTATAAACTTTCATCATATTCTTTTTAGCAGAATTTAAAAATATATATCTGAAGATATATATCTTAATAAAAGTATA TATAACAAAAAATAAAAATCATAATAATTTAATCTTAAAAATACAAAGCCCTTCTATCTTTTTTATTAGTTTAACATTAAAACAATTGAGCCAGGACATTTTTATCCTCTGA TATGTCTAGCCTAGTAATTATTCAATAAATGTGTTTTTAAATGGTTGATTTTCAAACATGAGTATAAACATTTCTTAGCTTTGCAAAACACCTCCTATCAAAAGCAACTCAT TTTCTTGACACATTGATTTCTGATTACAAGCCCCAGCTAAAAAAATAGGGTTATACTCAAGCTGATTGACCTTTCTCAAAGCTGGTTTTTTTTTGTTTTTGTTTTTGTTTTG TTTTGTTTTTCCAGAGGAATGGCTTCTTGTGGGAACCAAACAAGGACATCTTCTTCTCTATAGGATTCGGAAGGACGTTGGTAAGTGCACATTGCTCATGCAAAAAAATAAG TTTTAATAGTCAGCTAGTATACAACTGTGAAATCAGTTATTCCTGGACCATTAAAAGAGAGATTGAAGGTTAGAGGGAGCACGGTGGGAAAATGGGGAGAAGACTTGAGAAT GCCTAGGGTTTTTCTCCTCCAAATTGTATTGCCCTACCTGCATTTGGGAGGTGAGGATGAATTGCTGGTTTACTTATTACTGAATTACTTATTACTGGTAGTGAGTCTCTAA GAAAAGAGGAGGTGGTΓGTTTTCCTCCTCTTTTCTTTGAGACTCACTACCAATAATAAGAAATACTACTAATGGGCATAAGCTTCCTGTATATATGGTGTGGTGGTAGGAAA AAAAATTAGGCAACATCGATTTAAAATATCTTGTTGGCTTATGAGGGGTAGAACAAGAAGAGAGGACCAGGGTTTGCCTTCATGTGCACTTCCCCCTGGCTGCGTGACCGTG AGCAAGTTCTTTCCAACATCAGTTTTCTATAAACTCTCTGCCCCACAAAGTTGTTGGGGTGGATGCAATAATAGGCTCGAAGAAACTGTGAAAACTAAAGTTCTAATCAAAT GTGACTGTCAGTAATGTAGAGTAATAACTAAAGTATTTGAAATGTATTCTGTTAAAGAGTGTTTTTTATTGGGGCAGAAAGTACCTCACTGCCCTTCCTTGTTTTCGTTTCT GTGCTCTCTTTATGGAGAATAGATGTGTTTAGGTATTATGCCCTGGAGCCACTCTACAGAAATCTGCAGTTAATTTCATACCCTTCAATATAATATATATTTCTCTGGTAAA TAGCTTAAGAGATAGCTTAAGATAAATAGAGCTCTCT GTGGAACCTGGAGCAAGGGTAACACTGGGGGAAAAAGCACCTTACTAGTGCACTCGGGAAAGAGAAGATATCCT GGTCAGTTTCTGCAGCAGGGTAAGAAAAGAAACCAGAGAACAAAATAGATAATTTATTTCATTTCTAAGTTTTTCAACTGTCCTCTAAATCAGGGTCAGCAAACTTGTTCTG AAAAGGTCCAAAGAATAAATATTTTAGGCTTTGCAGTGTTGTTACTACTTAACTCTGCCTTTGTAACATGAAAGCAGCTGTAGGCAATATGTAATGAATAGGTATGGCTATG TTCCAATAAAACTTTATTTACAAAAACATGCAAAGGCCTCAGTTAGGCCCTGGAGCAGTACATTGTTGATCTTTGTTTTAATGTTTTAAATTTTTAATTCTCATGGCCTGTG AAGTGGCTCATGCCTATAATCCCAGCACTTTGGGAGACTGAAGTAGGAGGAATGATTGAGGCCAGGAGTTCGAGGCCAGCCTGGGCAACATGGCAACACCCTGTCTACAAAA AATTAGCTGGATGTGGTGGCACGTGCTTATAATTCCAGCTGCTCTGGAGGCTGAGGTGAGAGGATCGCTTGAGCCCAGGAGGTTGAGGCTGCAGTGAGCTATGATCACACCA TTGCTCTCCAGCCTCAGCAACAGACTTTGTCTCAAAAAAAAATTTCTTTTTTTAGTTCTCGGAGCCAAAATATTTGCGT'RCTGTGATATTTGCCTGGTCTATAATTTTAAAA TTAAGCTCACATTTTAATTTTAAAGCTAAAAATGCTTATCTTATTCAGCATTCAACAATTGTTTTTTGACTCTCTGCTTTGCTTTCACATGTAAGTGGTGATCAGAAATTGA AAACAAGACTTTATAAATGAAGTCTCAACACAGTATAGACCTGAACTGGTAATATTAGTGTTAATCTGGCTTGGAACCCTGGTGGCGACTATTCCTTGCCCTATGATCATTT TATCATGTCACCTTTGACAAATTAGTTAATGT"ICCTGGGCCTTGGTTTCGCCATAGGTAGATTAAATATAGACAATTAGGAAATCAAATTCTGATTTGAAACTTTTCTTCAA GAAATGCCATTTTTCCCTATACTCTTGGTGAACAGTTTAGTTCTGGCCCAGATCTGGCCTGATGTGGGCCAGAAATAGACCTGGGCCCGTGTGAATTAGTTCTAGGGTTAAT TTGGTTTCCAGATTTGAGATATTTCAAGCCTAAATAGGTCTTTGGGTAGACTGTCTTTCTGAGGAAAGGGAGGGGATAATAGGGTCAAGAAAAGACTAGGGGTAGGGATCGT AGGCTCTGATCTGATCTGAGTCATTTCCCTGGAGCTCAGTTGAGCCAGTGACATTTTTATCCTCTGATATGTCTAGCCTAGTAATTATTCAATAAATGTGTTTTTAACTGGT TGATTCTAAAATATGAGTATAAACATTCCTCAATAGACATCTCTAGGCTTCATTCTGCTCCTTTATTTTTTGAGACAGGGTCTTGCTGTGTCGCCTAGGCTGGAGTGTAGTG GCGCTATCTTGGCTCACTGCAGCCTCAACCTCCTGGGTTCAAGCCATCCTCCCACCTCAGCCTCCCAGGTAGATGGGACCACAGGCACACACCACTATGCCCAACCCATTTΓ TGTATCTTTTTTTTTTTAGCATTACTTAGATT'ITTTCTTTTTTTTTTTTTAGGTTTTTTTTTCCACTCTTTTTAATTATACTTTAAGTTCTAGGGTACAAGTGCACAACGTG CAGGTTTGTTACATATGTATACATGTGCCATGITGGTGTGCTGCACCCATTAACTCGTCATTTACGTTAGGTATATCTCCTAATGCTTTCCCTCCCCCCTCCCCCCACCCCA CGACAGGCCCCCAGTGTGTGATGTTCCCCTTCCTGTGTCCAAGTGTTCTCATTGTTCAATTCCCACCTATGAGTGAGAACATGCAGTGTTTGGTTTTTTTGTCCTTGCAATA GTTTGCTGAGAATGATGGTTTCCAGCTTCATCCATGTCCCTACAAAGGACATGAACTCATCCTTTTTTATGGCTGCATAGTATTCCATGGTGTATATGTGCCACATTTTCTΓ AATCCAGTCTATCATTGATGGACATTTGGGTTGGTTCCAAGTCTTTGCTCTTGTGAACAGTGCTGCATTAAACATACG'IGTGCATGTGTCTTTATACTAGCATGATCTATAA TCCTTTGGGTATATACTCAGTAATGGGATGGCTGGGTCAACTGGTATTTCTAGTTCTAGATCCTTGAGGAATTGCCACACTGTCTTCCACAATGGTTGAACTAGTTTACAGR CCCACCAACAGTGTAAAAGCGTTCCTGTTTCTCTACATCCTCTCCAGCACCTGTTGTTTCC GACTTTTTAATGATCGCCATTCTAACTGGTGTGAGATGGTATCTCATTGR GGTTTTGATTTGCATTTCTCTGATGGCCAGTGATGATGATGATGAGCATTTTTTCATGTGTCTGTTGGCTGCATAAATGTCTTCTTTTGAGAAGTGTCTGTTCATATCCTTΓ GCCTACTTTTTGATGGGGTTGTTGGTTTTTTTCT'IGTAAGTTTGATTTCTTTGTAGATTCTAGATATTAGCCCTTTGTCAGATGAGTAGATTGCAAAAATGTTCTCCCATTC TGTAGGTTGCCTGTTCACTCTGATGGTAGTTTCTTTTGCTGTGCAGAAGCTCTTTAGTTTAATTAGATCCCATTTGTCAATTTTGGCTTTTGTTGCCATTGCTTTTGGTGTΓ TTAGACATGAAGTCCTTGCCCATGCCTGTGTCCTGAATGGTATTGCCTAGGTTTTCTTCTAGGGTTTTTATGGTTTTAGGTCTAACATTTAAGTCTTTAATCCATCTTGAAT TAATTTTTGTATAAGGTGTAAGGAAGGGATCCAGTTTCAGCTTTCTACATATGCCTAGCCAGTTTTCCGAGCACCATTTATTAAATAGGGAATCCTTTCCCCATTTCTTGTT TTTGTCAGGTTTGTCAAAGATCAGATGGTTGTAGATGTGTGGTATTATTTTTGAGGCCTCTGTTCTGTTCCATTTGTCTCTATCTCTGTTTTGGTTCCAGTACCATGCTGTT TTGGTTACTGTAGCCTTGTAGTATAGTTTGAAGTCAGGCAGCGTGACGCCTCCAGCTTTGTTCTTTTTGCTTAGGATCGACTTGGCAATGCAGGCTCTTTTTTGGTTTCATA TGAACTTTAAAGTAGTTTTTTCCAATTCTGTGAAGACAGTCATTGGTAGCTTGATGAGGATGGCATTGAATCTCTAAATTACCTTGGGCAGTATGGCCATTTTCACAATATG ATTCTTCCTATCCATGATCATGGAATGTTCTTCCATTTGTTTGTGTCCTCTTTTATTTCGTTGAGCAGTGGTTTGTAGTTCTCCTTGAAGAGGTTCTTCACATCCCTTGTAA GTTGGATTCCTAGGTATTTTATTCTCTTTGAAGCAATTGTGAATGGGAGTTCACTCATGATTTGGCTCTCTGTTTGTCTGTTATTGGTGTATAAGAATGCTTGTGGTTTTTG CACATTGATTTTGTATCCTGAGACTTTGCTGAAGTTGCTTATCAGCTTAAGGAGATTITGGGCTGAGCCATTTTTGTATCTTTTGTAGTGATGGGGTTTCGCCAGATTGCCC AGGCTGGACTTGAATTCCTGGGCTCAAGTGATCTGCCCACCTCAGCCTCCCAAAGTTCCGGGACTACAGATGCGTGCCATCATGCCCAGTTAATTTTTGTACTATTTTAGAG ACAGGGTTTCACCATGTTGGCCAGGCTGGTCTGGAATTCCTGACCTCAAGTGATCCGCCCGCCTCGACCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGTGCCCAGC CCAGTCTACTCTTATTTTGAACTGAGAGGGCTTAGATTTGTTCATGTCTGAGGCCTTTACAACTCTAGGTTTATTTCAGTCATGCTGTCATCCTAGAGCAGTGTTCTGAAAA TGTGGTCTCTAGACCCCTGGGGATCCTCAAGATCCTTTCAGAGGACCTACAAGGACAAAACCAAGTTTGCAGAAACACTAAAACATTTCGTTTTTTGTTTTTTTTTTTTTΓC ACTGTATTGACATTTACAATGATGGTGCAAAAGGAATGGTAATTAAAACTGGTTAGCACCTGAACACAAATCAGAACAGTAGTACCTAACTTCAAATAGAGATTTTTTTAAA AAAACGAAAAAAACAGTGGTACCAAGCTGTACTGATGGTCATTGTGTAATTCTCACCATGTGCTCACAGTGGGTTTTGTTTGTTTGΓTTTTTTGAGATGGTCTCATTCTGΓC ACTCAGACTAGAGTGCAGTGGCGCAATCATGACTCACTGCAACCTATAACTCCTAGGCTCAGGCGATCCTCCCGCCTCAGCCTCTCAAGCAGCTAGGACTACCGGCACACAC CAGCATGCCCAGATAGTTTTTTCACTTCTTGTAAAGATGAGTTGTCTCTTCTTGCCCAGGGTGGCCCCAAACTCCTTGCCTCAAGTGATGGGTTTTATTTATTTATTTTTΓC TTTTCTTTTTTTTGAGACGGAATTTCACACTTGTCTTCTAAGCTGGAATGCAATGGCATAATCTCGGCTCACTGCAACCTCCCCCTCCCAGGTTCAAGCAATTCTCATGCCΓ CAGCCTCCTGAGTAACTGGGATTACAGGCGCCCACCACCATGCCTGGCTAATTTTTGTATTTTCAGTAGAGACAGGATTTCACCATATTGGCCAGTCTGGTCTTTAACTCCΓ GACCTCΔGGTGATCTACACCTGGGAGGTTTCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAACCACCACACCTGGCCAGTTTGTTTTTGTTTTTGTTTTTTTTTAAAG CTAGTTTCACTTAAAAGTGTTCTTGGTTAGGCAGTACAAGTTATTTTTATTGTATTTTGACTTTTGGCAACACATCTTTTTAGTAARCTCATATGATATAATGGGAAGTACA CATAAAGCACTTCTGCTGTGTGCTAGGGTGTGAAGTCCGATAGCTGTCTCAAGGGAAAAATGCTTATGTGATTGAGTTACGAGCTAAACTGGCTACTTTTTTCAGGGAGTAR TATTTTTGTTTGAAAGAATGACAGGTTGTGGTTT'ITTCAGACCATTTAGATATTTGGCATTTTTTTTTTTTTTTTTATGAACAAAGGGAATCTGTTACTTTAAGGTAAACAA CTGGCAGTATTTGTTGTGAATGATAAAGTTAGAGCTTTTAAGAAAAAAAATAGAATTATGGAAAACTTGTGTTCACTCCCCTGAGTGTGACAGCTTCTCCATAATTAAAGAR TTTTTCTGATGAGATTGGGGGTGATAATAATGAGTGTCATTTTTTAACATCCTATAATGAAATGTAGGTCTGGATTGGAAAATCTGCATAACTCAGTGAACCAGTATTTTCC AAATGACTAATGCATGAGTTTTAAAATCACGTATGAGTAAAAAATACATTCAAAGTGTAAGGTAGACCAATGTTTTTTTACGTAACAGAAAATGAAAAGTTCATTGACAGGR GTGAGATTTCGCTTTACAAGAAATTACATTTGTTAAGTGTTGGTGTAGTATCAAAGAAGAATCTGAAAAATCTATTAAAGTACTTTTCCCTTTTCAACTATGTTATCTATAT GAGGACAGATTTTTTGTCATATACTTCAACCAAAACAAATTAAATTATCAAAACAGATTAAATGCAGAAGCAGATGTGGGTTCTTACTTATGGGGTTATTATTGTTATTTTT AAATACATATATGTTTTTAAATGTATGTATTTAAATTTCTAACATAAATATTCATGTATATAACCCCCAAAAAAGTTCTTTGAGGTCCTCAGTAATTTTTAAGATTATCAAG ATTTTGAGACAAAAAAGTTTAAGAATCTCTGCCTTAGAAAATTCTGTTTGTAAAGAGAATTATAGGCCGGGGGCAGTGGCTCACTCCTGTAATCCCAGCACTTTGGAAGGCC GAGGTGGGTGGATCACCTGAGGTCGAGAGTTCAAGGCCAGCCTGGCCAACATGGTGAAACCCTGTCTCTACTAAAAATACAAAAATTAGCCGGGCATGGTGGCACATGCCTG TAATCCCAGCTACTCCAGAGGCTGAGGGCACGAGAATTGCTTGAACCCGGGAGGTGGATGTTGCAGTGAGCTGAGATTGCACTACTGCACTCCGGCCTGGGCAACAGAATGA GACTCTGTCTCAAAAAAAAACAAAACAAAACAAAACAAAAAAATAAGAAAAGAGAAGTATTAAATGCAATAATAGGACGCTTTCAAGTGTAGGAAGTGTCTGAATTGTTTTT TTTTCTCATGAAATGTAACAGCAGAATACCAGGGCACACTCCCTGCAACTTTAGGGCCCTTTCTTCATCCCCTCTGCTGAGGGACACATGGAAGAAGTAAGACCAGCTTTGG TGGCATGAGTTCTTATGGCTGCCCCAAAGAGTCTCCCTGATTTCCAGAGGGCAAGGGCAGAGCTAGCTGTGGGGAACAACTCAGGTCAGCAGTGCGAGCATCCTGTCCATGA AGTAGAAGGCAGGTAGCAGGGCGTGGGTTCAGAGCACAGGCTTTAGAGTCAGCCTGGGTTTGCTTGTAGGCTCCCTCACTGGCTGTTACCTAACTGCTTTACCCCTCATGCC CCTCAAATATGAGCTTGGAATAATAATACCTACTTCTTGGGAGTAGTTGTGAGTTTACAGAAAAAAATATATATAAATTTTTAAACCCCGAACCCAGTATGTAGTTATTGCT TCATGATAGCTGCTCTGATGATGATGATGATAATTATTCTCTTTTTGACTCATTGGTGACTTTTGAGGCTGAATATTTTTGTCATCCCCAGCAAGGCTGAATTCACATGTTT TTATGGTATATAACTTTCTTCCCCTTTTTTGTAACAGTGCCAGCAGATGTAGCATCACCTGAAAGCGGCAGTAAGTGTAGACGCATTGAATTGCTTTAGCTCTGGAGATGGG TTTGAGTGTTTGCTCTGTCTCCGTGATACAGAACTTAGTTAGAATAGTTGCTGGAAATTAGTTGGTCTAGATCTAAGGATGCTTTGGGCTGGGTTTCATGGCTTGGGCTCTT ATATTTGACTGTTACTTTTTACACCCTTCCTTGTGGAACACTTTGCCAAGGTACTGATTTTGCAAGATAAGATCTTCAGACTCACGAGTACCTTGCCGCTTCAGTGAACTTT GTGTGATCCTTICTGCTGATGCCGAGTGAAGGTGCATGAAACGCTCTGCTCTAAAATTAGAGTTGAAAGCATCTTATAGTGCTTGTAAGAGAGCTGGCTATTTAGATCTCΓG ΆTTTTTAGTCTTTCAGGAACTTCCAAAGATTTATATAGGAGAGCAGTATGGAGCAGTATTTTTCTAGTAGTGGTTTTTCTATGTATCCCTGTATTTGGAACTACCAGTGTTT ATTTGTTTTCCATAGGTTGCAACAGATTTGAAGTGACACTAGAGAAATCCAATAAGAACTTCTCCAAAAAGATTCAGCAGGTAAGCAGTGATGGCAGTCCTTACAAGAATAT TTGACTTACATGAGACCCTGTCAGACTAGAACTTTGGTAATGTTATTTATTAACTCTGAATCCTCTTCTCTTTGACCTTCTATTTATGCAGGAGTGTCTGCTCATATATCAT GTGCCTGAGATCCTCTCTCACAAGCAGAAATGATAATCACAGAAATTATAGTGCCCAGAAAAATCAGTGAGATCCCTGTAACTGGATAGGCTCCGTGGTCCCTTTTTATTAC
TGTTATTGAATGAACATTTGCTAAACCTTGTCAGAAATGTTTAATTGGGTCTCATGAT'ITCCTATTTTCCAGATCCATGTGGTTTCCCAGTTTAAGATTCTGGTCAGCTTGT TAGGTAAGAAAAGGAGTTGCATTTGTATCCTGTGTCTAACAAGAAAAGATATGACCTAATTAATCCTTTCATGGTTAATTTGATAGTGGTTACTTAACAATGAACTGACGTG TTCCAAACCTGGTATAACAGGGTACATGGTTAATAAAGGCAGCAGCATCCTCCATAGACTCGAACTCTTCTCTCCAAGGAGTCTCACTTTATTCATTCATTCGTTCATTGAT CAAATATTTATTGAGCCTATTCTATGCAAAGTCTGGACTAGACATTCGGGATACCAAGTTCAGTGAGACATAGTTGCTATCTTTGAGACTTACATTCTGATTATGAAGACTA AATGACAGGAAGTAATCACGATACAATGTGGTAAGTTACAGTGAAAATTTATAAAAAGTGTTGTGGAATCTTGGTAATGGGAGGGACTATATTGTCTAGTAGATAACTAGAC TTTCAGTAGGAAAAGAGGCCAGCAGCGTATCACAAACACAGGGAACAACTAGAACAAAGGCCTTGAGATGTGGCAGTTTGTGGCAAATTGTTTATTGTGGCCAGACTAAGGA TATGTGGTGGAGATTGGCAGGATATCAGGTAAGAGACAGAGCAGGGCTACACTGTTGAGGCCCTCATGTGAAAAACCATGGTTTCATAGAAAGCAGCCAGTOAGGCCTTTTC TGGACATGCAGGGGACTAGCAGCTGATCTCACACTTTGCGCTGTTGACCCTGGGGCCCAAAGAGTAAAATCATGTTAAATGTTGTTCCTGGGTCCACAGATAAACATCTGAG GTAACTTAATCTTCATGACTAAAACTAGATATGAGGCCCAGGTAAAATGATTATTT GATTGCTTTGCTAGGAAAGAAATCATTGCCATGGGTTAGTACAAAATGCACAGGG
GATTTCCCTTTTCTAATTGGAGCCTCCTAATGTGAGTAGCTTTGAAAGCCATTTCTTGTATAAATACTGCATCATAATATTTCAGACTTGAAATGGACAGAGTATAAGAGTG CTTTGGACTGGGTGCAGTGGCTCACACCAGTAATCCCAGCACTTTGGGAGGCTAAGGCAGGAGGATTGCTTGAGTCCAGGAGTTTGAGACCAGCCTGGGCAACACAGGGAGA CCTCATCTCCACAAAAAATAAACAAAATTAGCCAGGTGTGGTGGTGCATGCCTGTAGTCCTAGCTACTCAGGAGGCTGAGGTAGGAGGATCACTTGAGTCTCAAGGAGGTTA AGGCTGTAGTGAGCTGAGATCATGCCCCTTTTGTTGATGCACTCTAGCCTGGGCAACAGAGTGAGACCGTGCCTCAAAAAAAAAAAAAAAAAAAAAAAAAAGAGTGTTTTGG
CTGCAACTTCTGACCTCCTGGGTCAAGGGATTCTCCTGCTTCAACCCCCTGAGTAGCTGGGATTACAGGCACCCAC ACCATACCCAGCTGATTTTTGTATTTTTAGTAGAG ACAGGGTTTCAC GTGTTACCCAGGCTGGTCTCAAACTCTTGACCTCAAGTGATCTGCCTGTCTCAGCCTCCCAAAGTGCTGGGATGACAGGTGTGAGCCACCATGCCGGGC CAAGCTCAAATGTTTAAGGAAGAAAATATCCAAGTTTAGAAGACCAAGTGACCTCTTAAATGCTTTGTACTGGTTATAGGTGAGAATGAATCATCCTAGTGAAACTGAAGGG ACATCTTCAACCAACATCTGCCATTTGCTTCTTCTAGATGTTAACACAGTTACTTTTTTTGCCTCGATAGTGGCTATGCTAGAGAATTATGATCATTGATCCTGATGTTAΓA CCTCCTCCCAAACAGAAAATAACATTTATGTCCATGACCTATTGACATTTCAACAAATCACTACGGTTTCAAAGGCAAAGGGAGCATCACTGTTTACTTGTGACCTCCAGGT AAGTTTACCCAAGATGAAATTTGGCTTTATGCTTTAATCAATACAGTCTTTCCTACATCATTCCTACCATTAGATGGGAAGAATGACACTGATGATCCATACCCAACAGAGA CTCCAAAGATTATTTATTTATTTATTTTTTTCCTGAGATGGAGTCTTGTTCTGTCGCCCAGGCTAGAGTGTAGTGGCACGATCTCGGCTCACTGCAACCCCTGCCTCTCGGG
TGGCCAGGCTAGTCTCGAACTCCTGACCTTAGGTGACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCACCCGGCCCAAAGAGAATATTTAATTGTATTA GAGAAATTTCTCTGTTGGTGCATAGTGTGAAGTTGAAGCGTTTGCATTCCCTGTGCGTGGGTTAATGAGAATCTAATACTATTGGCAAGAGGCAGCTAACCGAGGACAAAAA CTCTCGTCCTGGACAAACCATTGTTGGGAAAGCAAGACTGTAACAATATCATGAAGATAATTATAAGACATTAAATGGAGTCTTGTTCTAAACAGATCACTGAGGTCTTTGΓ CATTAGGGACTTTTCATTGTTCAGAAAAGATATCGCTCTTTATTTTTGCCAATTTATCATTCTTTTATTCTTCAGAATCTGCCTCACCCCTCTCTCTACTCAACTTACCATT TTTAGCATTTATGTTCTACATTGACACTGCATCATTTTATGCTTAGGAATACTCTTTTCCTTGCTCTTTAAAGGCTTAAAAGTGGGCTTGATGTCACTGGCACATGGTCAC CCTTAACCCAGCATGCATTGACAGCCAGGAGCAAGAAACATTTAAGAGCAAAAAGGAGGGAGGAGTTATATAGGGGAAGGACTGCCCCAGGATTTTCTCCTCTGAATTGTGA ATGTCCATGTGATTTGCTGGTGCTGTGGTCTTTGGCTGGCAACCCTTCGGGAGGAAGTGTTCCTCAGTCACTTGTTTCTTAGCGCATCTTAGAGAATGGTGTTCTGCTCAGC TTTCCTGGCAGGATGACTGTGTTACAGGGAATTTTCAGAGTAGTAGCAATTTCAAGGTAGACAATCTCTAATTTAGTTATCACTCAGTTAGAGAGAGTCATTGTATTTΓCAT TTGCTCTGCATGTCTCCTCCCAGCACACAGAGACCGGTGAGGAGGTGTTACGGATGTGTGTGGCAGTAAAAAAGAAGCTGCAGCTCTATTTCTGGAAGGACAGGGAATTTCA TGAATTGCAGGTAAGTCCACTGTTCCTTGGTCCATGGTTGGGTGGGAGCTGCTGCAGTGGCTCGGTTCTAGTGAAGTTCAGGACTCCAGTCTTGTCATTCTACGCAAATGAA TACTCTGGTATGAAGTGCATGAGAGCTTGTTGATGCCTACTTGTAATATGATTCTACAGTGTTTTTATAGATTGGTTTATTTCAAAGTGGGTTTTCACCTTTTCCAAATGTA CTTTGTCCAGTTCATGGACTTGTATTTTTATTAAGGGTAGTTTCCTGGCCTTGTGCCTGTAGAATTGTGCCCGATGAGGGTGAGGGTTGTTTTGCAGAATGGAGGTTGCAGA ATAACAGGAAAGTCATGATTTTTTAAAAAAATATTTATTTCATTCAGATCCTTGCTCTCTTTTTTCAGGGGGACTTTAGTGTGCCAGATGTGCCCAAGTCCATGGCGTGGTG TGAAAATTCTATCTGTGTGGGTTTCAAGAGAGACTACTACCTAATAAGGGTAAAATCTTATTATTTTGCAAATATCATTAGTTTATCTTGGGGAAGATGATTATCTGCTCCA AACTCCAGGTCAAGCGACCACTTTAAGTAGAGCTTTTGGCATAACAGGATTTGTTATTTGTATGTGTAGTTATCATTCATGCTCAGCATTTTTCACAAATAGGATATCTTTG TAACTTAAGTCAGTCCAAGAGTCAACGCTCAGTTCTTTACGTAATGATGATCCACAGTGTGTATTTTACTATTGGGACAGATAATGAAGGCTGTTTGCCTCTGTCCAGTGGA TCATCATGGACTGCTATCCTAAGGCTTCAGTGCTTAGGAATTTTAAACTAATTTTAGTATAAACTTAAGTATTTTTAAGACTTTGAGTTTCCTCTCCTGCCGTCAAATCTTT TTGTATGTTTGTACTAAAAGTGATTCTCACTATTT'ITTTAAATTTCAAAAGCCACGTGTTTTTACACGTGTTTATTACAGAAAATATAGATAAGGAGATAAAGGAAGTGCAA ATCAACCATAGTCCCCCCACTCAGAAATAGTCACTGCCAACTTCTTGGTATATGAACTTCCATCCTATTGGTAAAAATACTATGCTATACAATTGTTTTATGACC GTGTTT TCTCTTAACGTAAGTTGTAAATATCCATGACGTTG'ITTTTCTCCAATATGCATACTATATGTAGAAAAGATTGACACACTGTTCGTTTCATTGAATAATCTAAATCTCTTAG CTTCACACCCCT GTAATTCAGACATGGCAATTCTAGAAGCCTCTCTCTCTACCTTCCACTGGGTGAGCTCTTCATTGGTTATTTTATTTTATTTGAGACAGGGTACCCCTC TGTCACCCAGGCGGGAGTGCAGTGGCAGGATCTTGGCTCACTGCAGCCTCCGTCTCCTGGGCTCAAGCAGTCCTCCCACCTCAGCCTCCCAGGTAGCCCAGATGCCTACCAC CATGCTCAGCTAATTTTTGTATTTTTTTTTTTTTTGTATTTTTGTAGAGATGGGGTCACAATATGTTGCATAGGCTGGTCTTAAACTCCTGGGCTCAAGCAGCCCTCCTGCC TCAGCCTCCCAAAGTGCTGAGATTACAGCCACCATGCCTGGCCCCATTGTTATCTTGTTAATATATTTGTTCCATCTTTGTGTCATTTGAATATCCTGATTTTATCAGCATC AGAGTTGCAGACTCCTGGAGGΔGTCACTGCTGTGCCACTGΔCTCAATAGCAAGTAGGCCTACAGATGGTGAGAGAGCGCACAAGGAATAAGGGAACTGAGCAAAAGCTGGAC TTAAGGCTCTCAGTTCTCTGACTGCCTTGGATGCTGACATCACCTTCAGGGTGGGAAACCTTGCTTTAGGACCAGGCTATTCAGAAATTACTTATTTACATACAGTAAAATT TATTCTTTTTGGTGTACAGTTCTGTGTTTTGACAAATGCTTAGATTTATGTGACTAATGCCACAATCGAGATTCACAACACTACCATCACCCCCCAAAATTCCCTCAΓATTG AAGTCAGCCTCTCCTTCTGTTCCTAGACCTCTGGTAACCACTCATCTGTTCTTCATCTCCTATAGCTTTGCCTTTTCCAGAATGTCATATAAATTGAATGACACAATATGTA GGCTTTTGAGTCTGGCTTCTTTCACTTAGCAGAATGCACTGGAGATTTATCCATGTTGTTGTGTGTGTTAATAGTTTATTCTTTCTCATGGCTGAATAGTAGTCTATGGCAA GGTGTTTGTTTATCCATTCATCAGTTGATGGACAAAGTTGATTTTGGCCAGGCGCGGTGGCTCACACCTTTAATCCCAGCACTTTGGGAGGCCGTGGCGGGTGGATCACGAG GTCAGGAGATTGAGACCATCCTGGCTAACACGGTGAAACCCCATCTCTACTAAAAATACAAAAAAAAAAATTAGCCTGGCGTGGTGGCACACGCCTGTAGTTCCAGCTACTC AGGAGGCTGAGGCAGGAGGATTGTTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCTGAGATTGTGCCACTGCACTCCAGCCTGGGCGACAGAGCAAGACTGTCTCCAAAAAA AAAAAAAAAAAAAGTTGTTTTCAATTTTTAGCAATTTTGAATAAGCATCTAAGACATTTGCATACAAGCGTTTGTGTAAACATACATTGGCATTCCTGGGCAAATGCCTGGG AATGGGATTGCTGGGGCATATGGTAAGTGTATCTTTAAGGGGCATATGGCAAGTGTATCTTAAACTTTGTAAGAAACCAACAAACAAAACAGCTGCACCATTTTGCATTCCC ACCAGCAGTGAATGTGAGTTCTAGTTGCTCTGCATTCTTGCCAGCACCTGGCATTGTCAGTTGCCAGGCTAGATGCTTTCCTTTGCATTAGAGAACGGGTTTTACATTGTGA TAACAACGGTTATTATAATAAACTCTGTAACATTTTCTTATGTCAAACAAGGAATATTATTGGCTTCTCTAGGTTTCGGGTTCTATCTGGATTTTTCCTGTGTTCTTACCTC TGGCTGGGGAATGCTAGGTGACTCACTCTGTTTCT'ICCTATAGGTGGATGGAAAGGGGTCCATCAAAGAGCTCTTTCCAACAGGAAAACAGCTGGAGCCCTTAGTTACACCT CTGGCAGATGGAAAAGTGGCTGTGGGCCAGGATGATCTCACCGTGGTACTCAATGAGGAAGGGATCTGCACACAGAAATGTGCCCTGAACTGGACGGACATACCAGTGGCCA TGGGTGAGACCAACAGTAGCTGCTGTTTCCCACTTTGGGTTGAGGTTGTGTGCCATTCCTGCAGAACGGAGTCCCATTCGTAGCTTTAGCAGACTGGTTTACGTTGTGTCAT TCACTTTCAGTTCCCCTTCTTATAAGTAGATGACATTTTAGGGTCATTAAAAATGGGATAGTCTAGTTCTTGCAAGAAGCTGAGTTTTACTCCAGAGGGGGAAAACATATAA ACAGAAATGTTTATTTTAGGAAGTGATTATCTACTGCTATCTTTTACTTCTTAGTTTTTTTCTTCCTCCTTTTTTTAAGAGTTTTGATTGTGTCCTCTGCCAAATAGACTAC ATTTGGAAATTAGTGGAAATTCCTTGTGTATTCCTATAGTATGAGTAATTCCATATTGAAGGGTTTTTGATATAGTAATTCCATGTTGAAGGGTTTTTCTATTGTTGCTTTT
CAGCTCTCCACAATGGAATTGCCTGGAAGCATATAACCACTCTTGCCCCATTTTATTTTCAGTCGGAAGAGTGAGCATTACTAAAATAGTTACTGCTGTGAAGTGGGACGTA CTGACATGCTTTCTGTCTTTAAAGACCCCTGTCTCTGGAGACAAGGGTTACAGTCTTGGATAAAGAGACAAAACAAGGCACTGCTTAAGGTGTTAAATTGGATGAGTTAAAA TTCAGTAGTTCAGAGAAAGGGAAGTTTGTTGTTTAATTAGGAAGAAGTTTCATTACATAGGTAAGACTGAACTATGGACTAGGTCAGGCAGGGAGTTTGGAACCTGGCTTGA AGAAAAATTTCCATTCAATCTAGGCAGAAAGCCCAATAAATGAGTAGAAGTCCAAAGAAAGACATGCCGATTTGGGAGAGGGTATTACAGAGCCTGACTTGATACAGGTGGT CTGAATTACAGAGCAGTGAAATAGGGCCAGTTGGTAGATGTCCGTGAGAAGGTCTGGGAGGCCAGTAGATTCCTGAATGGTAGAATGTCTTGATAAAAGCATCATGTTCTGG CCGGGCACAGTGGCTCACGCCTGTAATCCTAGCACTTTGGGAGGCTGAGGCAGGCAGATTGCCTAAGCTCAGGAGTTCACAATCAGCCTGGGCAACATGGTGAAACCCCGTC TCAAACACGAAAAAAAAAAAAAACTAGCTGAGTGTGGCAGTGTGTGCCTGTGGTCCCAGCTACTTGGGAAGTTGAGGCAGGAGAACTGCTTGAAGGGAGGGGGAAGTTGCGG TGAGCCGAGATTGTGCCACTGCACTCCAGCGTGGGTGACAGAGCAAGACTCCCGCCTCAAAAAAAAAAACAAAAAACACATCATGTTCTAGGGTGATTGTTCTGGTTGTGGT TAGAGATAAGTAGACTAGAAGGAAGAGAAATCAAAAGGTCAGTATTTTAAAAGGCCCAGGATTATGGATAGTCACAAGT'ITGAGGGGCTTATGGAGCTTTATGAGAGGCTTT CCCGATGTTCTAGGCGACCTTGTTTTCCCTTCAGAAGAGGAACTTTGGTAGATGAGTTTAAGAGGCATGTAAAAGTCAAGCGTGTTTCTGATTTCCCAGGATGAGAGTTCCT
GTCTTCCAACCTTCGTTAGTGCCTGGGGCCTTCATCAGTGCTTCTCAAAACCATGTCTGTGTCTTACTGCTGAAGAAAG'ITTTGAGGCACTTGCCCTGTGAGGTCTCCTTTG
ACCCACAGGCAGGATTAGTCACTTCTTGGTGCTTCCCTAACCCTTTCAGGTATCTCTGTCACAGCAACTTGTCACACGTGAGCGATCTGTCTCCTCTGTTCCTGTAGGAGCT CTGTGAGGTCTGGATGCATGTCTTGATCCACTTTGAGTCCTTACTACATAGTACAGTGCCTGAAACATCAGAGCGTGTAAGAAAATGCTTGCTGAATAATTGCATCATTATC CTGGTCAGTCATTATTTATATGCCTGCTGTACACCAGCCAGTCTCCCAACTTTTGGAGATATAAAGAGATCCAGACCATCTCTATTGTCAACAAAAGATATGACAACCAAAG GGGTTTCTGTTATAGATTACCTTTTTAATTAAATGAGAACGTATTCAAGTGGGACAGATTTTAAAAGGAGAAAGAAATTTTACATATGTTATACAAGTTAGCACTAAAGAAA ATTGTACTAACTTTTCAAAATGAGGCCAGCATAAAAATAAAATAAAAAATTCAATATAAAACAATATGCTTTTAATTTCATTTTTCTGGTAAGATGAAAAATATCAGTATAA TAGCAGTAGCGTTCAAAATGATAGAAATATAACTTAGTTCTCAAGTTACTCATTTCTGAGTTCCCTCATAGCTTTGAAATTTTATTGTACTATTCATTGATAGTATAAATTG CAAATATAATAGGAAAAACTTTTTATCAGAAAATGGATAATTAAACTAGTGCAGCGACTCATGCCTGTAATCCCAGCACATTGGGAGGCTGAGGCAGGAGGACTGCTTGAGC CCAGGAGT TGAGACCAGCCTGGGCAACATAGTGAGACCCTGTCTCTACAAAAAATACATTTAAGAAATTAGCTGGGCATCGTGCTGTACGCATATATTCCCAGGACTTGGG TGGCTGAGGTGGGAGGATTGCTTGAGCCTGGGAGATGGAGGCGGCAGTAAGCCGTGATCACACCACTCACTGCATTCCAGCCGGGCCTATAGAGAGAGACTCTGTCTCAAAA
AAAAAAAAGGATAATTAGAAATATTAGCAAATTAGACACACTAAGAAATTATT'ITTATGAATATATATTTTGAAGTTAAATTTCTATGTGGTAATTATGCATCTAGTGGTTT GCTTTTTACTAATTTTTTTACTTTTAAAAACATTTTTATTTTTAAATGTAAAAAACACATAACATACAATTTACCACCTGAACCATTTTTAAGTGTACAGTTAAGTGGTATT ACGTATGTTAACATTGTGGTACAATAGATCTTCAGAACTTTTTTATGTTGCAAAACTGAAACTCTATACCCATTAACAACTCCTCAGTTCTTCTCCCTCCAGTCCCTGAAGC
CACCATTCTCCTRTCTGCTTCTATGAATTTGACATCTTCTAGATACCTCATATAAGGGAAATCATACAGTATTTGTCTTTCTGTGACTGCCTTGTTTAATTTAGCATAATGT CCTCAAGGTTCATGCCTTCCTTTTTAAGGCTGAACCTTAAAAAGGTAATATATATTCCACTTAAAAAGGTAATAAAATAATTACTTAAAAAAGTAATAATATTCCACTGTGT GTATATACCACATTTTGTTTATCCATCCGTTCGTGGATACTTGGGTTACTTTCACCATTGGCTGCTGTGAATAATGCTGCTACGAACATGTGTGTGCAAATATCTCCTTGAA ATCCTGATTTTCAACTGTTTTGAATATGTACCCAGAAATGAGATTCCTGGACCATATGGTGATTCTATTTTTAATTTTCTGAGGAACCACCATACTGTTTTCCATAGCGGCC GCACCATTTTACAGTCCCACCAACAGTGCGCAAGGGTTCCAATTTTTCCATATTCTTGTCAACACTTGTTATTTTCATTTTTTTAATAGTAGCCATCCTAAAGGCGTATGAG GTGATATCTCAC GTAGTTCTTTACGGATTCTTGATATAGCACAGAATATAGTCATAGAAAATATTTCTATTATCTCTAAGTTAGTGAAATTATGTTTCATATAGTATACAA ACAATAAATTTATCTTACAGTTCAGTGTAAGGTAAAGCAGATCCTTATTCAGTCTTGTTCTGAGATTTGTGTTTTTAAAGATATGTTTTGTGTTGCTTATTTTCTAAATTCC CTCCATTTATGTTAAATCTCCTTCACCATACAACTTCTCAAATATTGGAAGACTTGATTTGCAATGATTTTATGGTTTTGTCAGTCTGCTTTTTGCATGCTGACTTCTTTAG CACTGTGTGGAATTGTTCTGCTTCATCCAGCATTTTAAGCTTTGGACTGTCACATGCTTGTCAAAAAGTACAGAAAAATATAGTGGATATATTAAAAGTTATTTTCAAAAGA GAGAGGAAGAGTGAAGAAAAGGAGTATAACCCAAIAATTTGTACTGGATCAGAAGGGTAAATTTGGGGTCATGGATAGATGAATGAAAGGTTTTTTTTTAGATATAATAGAG GAAAACAATTTTAAGACTCGACAGCAAGTATCAAATAGAAATGCCTTCACTGAGAAGTCCATCCAGCCACCTTCTCTGTGTACCATTAAGCCATGTCTTAGTTCATTTGTGC AGCTATAACAGAATACCACAGACTAGGTAATTTATAAAAACCAGAAATTTGTTTCCTCACAGTTTTGGAGACTTGGAAGTCCCAGATCAGGGTGCCGGCATCTGGTGTCTGG TAAGGGCCTTCTTGATGCTCCTTCACATGGTGGAAGGAGAAGGGTAAGAGAAAGATGAGCTCTGCATTCTCACATGGCAGAAGAGAGAGAACCCACTCCACAAGCCETTTTT ATAGTGCATTAATCTATTGATGAGGCTGGAGCCTCACCACCTAAACACCTCCCATTAGGCCCCACCTCCCAACACTTTTGCACTGAGGATTAAGTGTCCAATGCATAAGTTG GGGAGGGAATAAAAATAGCCAAACCATAGCAGCCATCAGGTGGAGCATCACACCTTTTCTCTGTGAAAATCTCTAGCAGAAACAACATTGGCTAGAAATGTGGAACTCTTCC CTTAGAGTAATTTTAGGGAAAACAGAATTTGCCTTCCCCCTACCTTTCTTTTTTATTTCTTTTTTTTTTATTTTTTATTTTATTTATTTATTTATTTATTTATTTATTTATT TATTTATTTATTTATTGAGATGGAGTCTTGCTCTGTCGCCCAGGCTGGAGTGCAGTGGTGCATCTCGGCTCACTGCAAGCTCCGTCTTCCAGGTTCACGCCATTCTCCTGCC TCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCTGCCACCACGCCCGGCTAATTTTTTTGTATTTTTTTTTTTTAGTAGAGACAGGGTTTCACCATGTTAGCCAGGATGGTC TCGATCTCCTGACCTCGTGATCCACCTGCCICAGCCTCCCAAAGTGCTAGGATTACAGGCGTGAGCCACTGCACCCGGCCTTTCCCCCTCCCGCCACTTTTCTAAGAGAATG AAAGAAGAGGTTCTGTTACCTGGTTCTCCCACTGATGCATTGTTATGGGCAGCTGCAACTGGCCTTTGTCTGGCCTGGCTTTGTGACTGATGAAAAAGGAGCAAGTGAAACT TTTATCCAGTTCTTTGGGGAATAAGGCAGGAGTGGGATCAGGTGACTGTCAGCACAGCTGATGTGTCTTTTTTGTGCAAGAGATTTCTCTGATCATAACTCAAGCAAAGCAA
TCTTCCCACCTCAGCCTCCTGAGTAGCTGGGACTACAGGTGTGCACCACCACACCTGACTAATTTTTTAATAAATGTTTTTGTTGAGGCAGTGTCTCACTAAGATGCCTAGG TCGGTCTCAAACTTCCGGCCTACGTGACCTTCCCACCTCAACCTCTCAAGTTGCTGGGATTACAGGCCAATTTTTTTTTTCTTTCTTTCTGAATCACAGTGTAAGATCCTGG CTTGATATTTGACTAGGGGACTTTTTGGAGATCCAITTAAATGTATCTTAGAA'IGGGCAGCTGAAACACTCCATAAACCCAAAGCCTTAGACCGGAACAACTGCTGTGTATG TTCTCTTTCACAGAGCACCAGCCTCCCTACATCATTGCAGTGTTGCCTCGATATGTTGAGATCCGAACATTTGAACCGAGGCTTCTGGTCCAAAGCATTGAATTGCAAAGGC CCCGTTTCATTACCTCAGGAGGGTAAGGAATTTCTTTTTTTGCTATGGCTGTATATTATCCCAAAGTTGTAAAGTCACCTGTGTCATCACAAAGCCTGTGATCTTTTGCTAA TATTCTTACTCTTGCTTCCAGATCAAACATTATCTATGTGGCCAGCAATCATT'ITGTTTGGAGACTCATCCCTGTCCCCATGGCAACCCAAATCCAACAACTTCTCCAGGAC AAGCAGTTTGAATTGGCTCTGCAGCTCGCAGTAAGTCTTGTTCCTGACTAGTCTTCCTTCCTTATTGTTCTTGAAAGTAGGTGATTTGGGTTTCAATGTTCATATTTATTTR GGGTTAGTAGAATAAGCACATAGCTGAAAGTCCAGGGCCTTGAATACTAGGTCTGACTCCACCGTAAAATATCTATGTAACTCTAAGTGAGTTTACTTTTTCACTTTATCTG TCAAATGTAGAATGAATATCAATTCTAGTAATAGTACCTTGTAGAATTAAGGTGAGAGTCCGGGAGCAGTGGCTCACGCCTGTAATCCCAGCATTTTGGGAGGCCAAGGCGA GCAGATCACCTGAGGTCAGGAGTTCGAGACCAGCTTGGCCAACATGACAAAACCCTGTCTCCACTAAAAATACAAAAATTAGCTGGGCATGGTGGCAGGAACCTGTAATCCC AGCCACTCAGGAAGCTGAGGCAGGAGAATTGCTTGAACCCAGGAGGTAGAGGTTGCGGTGAGCCAAGATCATGCCACTGCACTCCAGCTTGGGTGACATAGCGAGACTCTGT CTCAAAAAACAAAAAAAAAAATTAATGGGAGAATAAAATAATTTAATATATTGTATGGTCATGAAAAATTAAAGATAATGGAGACATTAAAGTTTAGTAGCAATCATAAATA TACTGTTATAGTAAAGTTGAATGCAACAACTAGAGGACCCCTCAAAATTCCTTTCCACAGTAGACTCCTATGTTTGGATAAGTAGGCTTTCTTTTGATATTCTGAAACΓACΓ TCAAGTTGTTGTATTCAGCCAGGCGGCAGTCTTATATTTATGATGCTTACTGTAATGTTTGCAAGGGATCTTGTTCACAGCAAAATAGTGACCACCTCTTGTTCCAATGTTG ATGTCAGAGTCTGTGTCTTGTTCTTTTAAACATCGTCAGTGATGATTATTGTCATCTGTAGGGGGTGGATTTGCTTTTAGGAAACAACCAAAAGTCATTCTGAGCCTAACCT AGTTGTTAAACCAGATATTGCTACTTTATGTATTTGGGGGTTTTTTGAGGTTTTTTTTTTTTTTTTTTTTTTTTTTTAAAACAGGGTCTCACTCTGTCACCCAGACTGGAGT GCAGTGATGCAGTCTTGGCTCACTGCAGTCTTGACCTCCTGGTCTCAAGTGATCAGCCCACCTCAGCCTCCTGTGTTGCTGGGACCACAAGCATGTACCACCACACCCAGCT AATTTGTTTATTTTTTGTAGAGACAGGGTCTCACTTTGTTGCCCAGGCTGGTCTTAAACTCCTGAGCTCAAGTGATCCTCCTGTCTCAGCCTCCCAAAGTGCTGGGATTATA GATGTGAACTACTATGCCCAGCCTCAGATAGTGATACTTTAAAGAAGAGATGTTTATGAAGATAATAGTAATAAAACTGAATTTCTAGAGTATCCTGTAAACTATTTCTAAA AGGAAAGCACTTTTTTAGAATGCAGATACTTTAAGTTACCTATGGTGGCTACTCGTGAAGAACATTTACTTTGGACATATATGTTCTGGATTTAAAATAAAAATCTGATCTT AATAGTAAGACATAGTTAATAT CCATAAAGATGATTGCTTTCTTAGAGCACTGAATTTCAGCATCTTACTGTTTTTTTTTCTACTCATGCATTGTCCTATATTATTTTATT TTCATTTTTAAAAATAATACAGTGAATACCCATGAACTCAC
3 ETNNSFQELATKNKNR RRI EVQNS HPGSGEEKAFQFYNSCMDTLAIEAAGTGPLRQVIEELGGWRISGKWTSLNFNRT RLLMSQYGHFPFFRAYLGPHPASPHTPVIQ
FFHPσYPRAVNPG AGSIM HELLJ^IFYQLLLPGGCI ACD^raA QEAHLCLKRHY AFP PS TεF IDεL FLENAADVσG AIA QAYSKR RHHGETVLPS DLSPQQI FFRSYAQVMCRKPSPQDSHDTHSPPHLRVHGPLSSTPAFARYFRCARGΔLLNPSSRCQLW
4
GGGAGGAGAAGCCTGGGTGCCCCCCACTGATAAGCAGGCTCCACCCAGAGGCCAGTCCTGTGTGTCTGGGGACAAGGCGAAAGAGCAGCAGAAGTGCCCCTTCTCCAGGATC
AAGGAACTGGGGCGGGGGGTGTTTCCTGGACCCCAGTCCTCCGAATCAGCTCCTAGAGTGGAACCAGGAAGGATTCTGGAGCCACAGAAGATAGACAGATGGAAGGTGGGGA
CCAAAGTGAGGAAGAGCCGAGGGAACGCAGCCAGGCAGGTGGAATGGGAACTCTCTGGAGCCAAGAGAGCACTCCAGAAGAGAGGCTGCCCGTGGAAGGGAGCAGGCCATGG
GCAGTGGCCAGGCGGGTGCTGACAGCTATCCTGATTTTGGGCCTGCTCCTTTGTTTTTCTGTGCTTTTGTTCTACAACTTCCAGAACTGTGGCCCTCGCCCCTGTGAGACAT
CTGTGTGTTTGGATCTCCGGGATCATTACCTGGCCTCTGGGAACACAAGTGTGGCCCCCTGCACCGACTTCTTCAGCTTTGCCTGTGGAAGGGCCAAAGAGACCAATAATTC
TTTTCAGGAGCTTGCCACAAAGAACAAAAACCGACTTCGGAGAATACTGGAGGTCCAGAATTCCTGGCACCCAGGCTCIGGGGAGGAGAAAGCCTTCCAGTTCTACAACTCC
TGCATGGATACACTTGCCATTGAAGCTGCAGGGACTGGTCCCCTCAGACAAGTTATTGAGGAGCTTGGAGGCTGGCGCATCTCTGGTAAATGGACTTCCTTAAACTTTAACC
GAACGCTGAGACTTCTGATGAGTCAGTATGGCCATTTCCCTTTCTTCAGAGCCTACCTAGGACCTCATCCTGCCTCTCCACACACACCAGTCATCCAGATAGACCAGCCAGA
GTTTGATGTTCCCCTCAAGCAAGATCAAGAACAGAAGATCTATGCCCΛGATCTTTCGGGAATACCTGACTTACCTGAATCAGCTGGGAACCTTGCTGGGAGGAGACCCAAGC
AAGGTGCAAGAACACTCTTCCTTGTCAATCTCCATCACTTCACGGCTGTTCCAGTTTCTGAGGCCCCTGGAGCAGCGGCGGGCACAGGGCAAGCTCTTCCAGATGGTCACTA
TCGACCAGCTCAAGGAAATGGCCCCCGCCATCGACTGGTTGTCCTGCTTGCAAGCGACATTCACACCGATGTCCCTGAGCCCTTCTCAGTCCCTCGTGGTCCATGACGTGGA
ATATTTGAAAAACATGTCACAACTGGTGGAGGAGATGCTGCTAAAGCAGAGGGACTTTCTGCAGAGCCACATGATCTTAGGGCTGGTGGTGACCCTTTCTCCAGCCCTGGAC
AGTCAATTCCAGGAGGCACGCAGAAAGCTCAGCCAGAAACTGCX3GGAACTGACAGAGCAACCACCCATGCCTGCCCGCCCACGATGGATGAAGTGCGTGGAGGAGACAGGCA
CGTTCTTCGAGCCCAGGCTGGCGGCTTTGTTTGTTCGTGAGGCCTTTGGCCCGAGCACCCGAAGTGCTGCCATGAAATTATTCACTGCGATCCGGGATGCCCTCATCACTCG
CCTCAGAAACCTTCCCTGGATGAATGAGGAGACCCAGAACATGGCCCAGGACAAGGTTGCTCAACTGCAGGTGGAGATGGGGGCTTCAGAATGGGCCCTGAAGCCAGAGCTG
GCCCGACAAGAATACAACGATATACAGCTTGGATCGAGCTTCCTGCAGTCTGTCCTGAGCTGTGTCCGGTCCCTCCGAGCTAGAATTGTCCAGAGCTTCTTGCAGCCTCACC
CCCAACACAGGTGGAAGGTGTCCCCTTGGGACGTCAATGCTTACTATTCGGTATCTGACCATGTGGTAGTCTTTCCAGCTGGACTCCTCCAACCCCCATTCTTCCACCCTGG
CTATCCCAGAGCCGTGAACTTTGGCGCTGCTGGCAGCATCATGGCCCACGAGCTGTTGCACATCTTCTACCAGCTCTTACTGCCTGGGGGCTGCCTCGCCTGTGACAACCAT
GCCCTCCAGGAAGCTCACCTGTGCCTGAAGCGCCATTATGCTGCCTTTCCATTACCTAGCAGAACCTCCTTCAATGACTCCCTCACATTCTTAGAGAATGCTGCAGACGTTG
GGGGGCTAGCCATCGCGCTGCAGGCATACAGCAAGAGGCTGTTACGGCACCATGGGGAGACTGTCCTGCCCAGCCTGGACCTCAGCCCCCAGCAGATCTTCTTTCGAAGCTA
TGCCCAGGTGATGTGTAGGAAGCCCAGCCCCCAGGACTCTCACGACACTCACAGCCCICCACACCTCCGAGTCCACGGGCCCCTCAGCAGCACCCCAGCCTTTGCCAGGTAT
TTCCGCTGTGCACGTGGTGCTCTCTTGAACCCCTCCAGCCGCTGCCAGCTCTGGTAACTTGGTTACCAAAGATGCCACAGCACAGAAATATCGACCAACACCTCCCTGGTCA
CATCCATGGAATCAGAGCAAGATTTCCTTTCTGCTTCTGTTCCAAAAATAAAAGCTGGCACTTGGCTTCCGCTTGTCTCTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
5
MVQLIAP EVM NEAADLKP A SRR ECSGGIMAHYSPDLLGPEMESRYFAQVGLEHLASSSPPAFGFLKCLDYSISVLCSATSLAMLEDNPKVSK ATGDWMLTLKPKSI TVPVEIPSSPLDDTPPEDSIPL.VFPELDQQLQP PPCHDSEESMEVFKQHCQIAEEYHEVKKEIT LEQRKKELIAKLDQAEKEKVDAAELVREFEALTEENRTLRLAQSQC VEQLEKLRIQYQKROGSS
S
CCGAGAGCGAGGGAGGGCTGTGAGGACTGCCAGCACGCTGTCACCTCTCAATAGCAGCCCAAACAGATTAAGACATGGGAGGTGAAAGACAACTTGAGTGGTTAAATTACTG
TCATGCAAAGCGACTAGATGGTTCAGCTGATTGCACCTTTAGAAGTTATGTGGAACGAGGCAGCAGATCTTAAGCCCCTTGCTCTGTCACGCAGGCTGGAATGCAGTGGTGG
AATCATGGCTCACTACAGCCCTGACCTCCTGGGCCCAGAGATGGAGTCTCGCTATTTTGCCCAGGTTGGTCTTGAACACCTGGCTTCAAGCAGTCCTCCTGCTTTTGGCTTC
TTGAAGTGCTTGGATTACAGTATTTCAGTTTTATGCTCTGCAACAAGTTTGGCCATGT GGAGGACAATCCAAAGGTCAGCAAGTTGGCTACTGGCGATTGGATGCTCACTC
TGAAGCCAAAGTCTAT ACTGTGCCCGTGGAAATCCCCAGCTCCCCTCTGGATGATACACCCCCTGAAGACTCCAT'rCCTTTGGTCTTTCCAGAATTAGACCAGCAGCTACA
GCCCCTGCCGCCTTGTCATGACTCCGAGGAATCCATGGAGGTGTTCAAACAGCACTGCCAAATAGCAGAAGAATACCATGAGGTCAAAAAGGAAATCACCCTGCTTGAGCAA
AGGAAGAAGGAGCTCATTGCCAAGTTAGATCAGGCAGAAAAGGAGAAGGTGGATGCTGCTGAGCTGGTTCGGGAATTCGAGGCTCTGACGGAGGAGAATCGGACGTTGAGGT
TGGCCCAGTCTCAATGTGTGGAACAACTGGAGAAACTTCGAATACAGTATCAGAAGAGGCAGGGCTCGTCCTAACT'ITAAATTTTTCAGTGTGAGCATACGAGGCTGATGAC
TGCCCTGTGCTGGCCAAAAGATTTTTATTTTAAATGAATAGTGAGTCAGATCTA'ITGCTTCTCTGTATTACCCACATGACAACTGTCTATAATGAGTTTACTGCTTGCCAGC
TTCTAGCT GAGAGAAGGGATATTTTAAATGAGATCATTAACGTGAAACTATTACTAGTATATGTTTTTGGAGATCAGAATTCTTTTCCAAAGATATATGTTT TTTCTTTT TTAGGAAGATATGATCATGCTGTACAACAGGGTAGAAAATGATAAAAATAGACTATTGACTGACCCAGCTAAGAATCGTGGGCTGAGCAGAGTTAAACCATGGGACAAACCC ATAACATGTTCACCATAGTTTCACGTATGTGTATTTTTAAATTTCATGCCTTTAATATTTCAAATATGCTCAAATTTAAACTGTCAGAAACTTCTGTGCATGTATTTATATT TGCCAGAGTATAAACTTTTATACTCTGATTTTTATCCTTCAATGATTGATTATACTAAGAATAAATGGTCACATATCCTAAAAGCTTCTTCATGAAATTATTAGCAGAAACC ATGTTTGTAACCAAAGCACATTTGCCAATGCTAACTGGCTGTTGTAATAATAAACAGATAAGGCTGCATTTGCTTCATGCCATGTGACCTCACAGTAAACATCTCTGCCTTT GCCTGTGTGTGTTCTGGGGGAGGGGGGACATGGAAAAATATTGTTTGGACATTACTTGGGTGAGTGCCCATGAAAACATCAGTGAACTTGTAACTATTGTTTTGTTTTGGAR TTAAGGAGATGTTTTAGATCAGTAACAGCTAATAGGAATATGCGAGTAAATTCAGAATTGAAACAATTTCTCCTTGTTCTACCTATCACCACATTTTCTCAAATTGAACTCΓ
TTGTTATATGTCCATTTCTATTCATGTAACTTCTTTTTCATTAAACATGGATCAAAACTGA
7
MGNTTSDRVSGERHGAKAARSEGAGGHAPGKEHKIMVGSTDDPSVFS PDSKLPGDKEFVSWOQD EDSVKPTQQARPTVIR SEGGKEVFISGSFNNWSTKIP IKSH DF VAIIJD PEGEHQYKFFVDGQΪΓVHDPSEPVVTSQ GTINNLIHVKKSDFEVFDA KLDSNESSETSCRD SSSPPGPYGQEMYAFRSEERFKSPPILPPHLLQVI NKDTNIS CDPA LPEPNHVMLNH YALSIKDSVMV SATHRYKKKYVTTLLYKPI
8
ATGGGAAACACCACCAGCGACCGGGTGTCCGGGGAGCGCCACGGCGCCAAGGCTGCACGCTCCGAGGGCGCAGGCGGCCATGCCCCGGGGAAGGAGCACAAGATCATGGTGG GGAGTACGGACGACCCCAGCGTGTTCAGCCTCCCTGACTCCAAGCTCCCTGGGGACAAAGAGTTTGTATCATGGCAGCAGGATTTGGAGGACTCCGTAAAGCCCACACAGCA GGCCCGGCCCACTGTTATCCGCTGGTCTGAAGGAGGCAAGGAGGTCTTCATCTCTGGGTCTTTCAACAATTGGAGCACCAAGATTCCACTGATTAAGAGCCATAATGACTΓT GTTGCCATCCTGGACCTCCCTGAGGGAGAGCACCAATACAAGTTCTTTGTGGATGGACAGTGGGTTCATGATCCATCAGAGCCTGTGGTTACCAGTCAGCTTGGCACAATRA ACAATTTGATCCAIGTCAAGAAATCTGATTTTGAGGTGTTCGATGCTTTAAAGTTAGATTCTATGGAAAGTTCTGAGACATCTTGTAGAGACCTTTCCAGCTCACCCCCAGG GCCTTATGGTCAAGAAATGTATGCGTTTCGATCTGAGGAAAGATTCAAΔTCCCCACCCATCCTTCCTCCTCATCTACTTCAAGTTATTCTTAACAAAGACACTAATATTTCΓ TGTGACCCAGCCTTACTCCCTGAGCCCAACCATGTTATGCTGAACCATCTCTATGCATTGTCCATTAAGGACAGTGTGATGGTCCTTAGCGCAACCCATCGCTACAAGAAGA AGTATGTTACTACTCTGCTATACAAGCCCATTTGA
9
MEALMARGALTGPLRA CL GCL SHAAAAPSPIIKFPGDVAPKTDKELAVQYLNTFYGCPKESCNLFVLKDT KKMQKFFG PQTGDLDQNTIETMRKPRCGNPDVANYNF FPRKPK DKNQITYRIIGYTPD DPETVDDAFARAFQVWSDVTPLRFSRIHDGEADIMINFGR EHGDGYPFDGKDGLLAHAFAPGTGVGGDSHFDDDEL TLGEGQWRVK YGNADGEYCKFPFLFNGKEYNSCTDTGRSDGFL CSTTYNFEKDGKYGFCPHEALFTMGGNAEGQPCKFPFRFQGTSYDSCTTEGRTDGYR CGTTEDYDRDKKYGFCPETA MSTVGGNSEGAPCVFPFTF GNKYESCTSAGRSDGKMWCATTANYDDDRK GFCPDQGYSLF VAAHEFGHAMGLEHSQDPGALMAPIYTYTKNFRLSQDDIKGIQE YGAS FDIDLGTGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGP VATFWPELPEKIDAVYEAPQEEKAVFFAGNEYWIYSASTLERGYPKP ΓSLG LPPDVQRVDAAFNWSKNKKTYIFAGDKF RYNEVKKKMDPGFPK IADAW AIPDN DAWD QGGGHSYFFKGAYYLKLENQS KSVKFGSIKSDWLGC
10 GTTTCCGCTGCATCCAGACTTCCTCAGGCGGTGGCTGGAGGCTGCGCATCTGGGGCTTTAAACATACAAAGGGATTGCCAGGACCTGCGGCGGCGGCGGCGGCGGCGGGGG CTGGGGCGCGGGGGCCGGACCATGAGCCGCTGAGCCGGGCAAACCCCAGGCCACCGAGCCAGCGGACCCTCGGAGCGCAGCCCTGCGCCGCGGACCAGGCTCCAACCAGGCG GCGAGGCGGCCACACGCACCGAGCCAGCGACCCCCGGGCGACGCGCGGGGCCAGGGAGCGCTACGATGGAGGCGCTAATGGCCCGGGGCGCGCTCACGGGTCCCCTGAGGGC GCTCTGTCTCCTGGGCTGCCTGCTGAGCCACGCCGCCGCCGCGCCGTCGCCCATCATCAAGTTCCCCGGCGATGTCGCCCCCAAAACGGACAAAGAGTTGGCAGTGCAATAC CTGAACACCTTCTATGGCTGCCCCAAGGAGAGCTGCAACCTGTTTGTGCTGAAGGACACACTAAAGAAGATGCAGAAGTTCTTTGGACTGCCCCAGACAGGTGATCTTGACC AGAATACCATCGAGACCATGCGGAAGCCACGCTGCGGCAACCCAGATGTGGCCAACTACAACTTCTTCCCTCGCAAGCCCAAGTGGGACAAGAACCAGATCACATACAGGAT CATTGGCTACACACCTGATCTGGACCCAGAGACAGTGGATGATGCCTTTGCTCGTGCCTTCCAAGTCTGGAGCGATGTGACCCCACTGCGGTTTTCTCGAATCCATGATGGA GAGGCAGACATCATGATCAACTTTGGCCGCTGGGAGCATGGCGATGGATACCCCTTTGACGGTAAGGACGGACTCCTGGCTCATGCCTTCGCCCCAGGCACTGGTGTTGGGG GAGACTCCCATTTTGATGACGATGAGCTATGGACCTTGGGAGAAGGCCAAGTGGTCCGTGTGAAGTATGGCAACGCCGATGGGGAGTACTGCAAGTTCCCCTTCTTGTTCAA TGGCAAGGAGTACAACAGCTGCACTGATACTGGCCGCAGCGATGGCTTCCTCTGGTGCTCCACCACCTACAACTTTGAGAAGGATGGCAAGTACGGCTTCTGTCCCCATGAA GCCCTGTTCACCATGGGCGGCAACGCTGAAGGACAGCCCTGCAAGTTTCCATTCCGCTTCCAGGGCACATCCTATGACAGCTGCACCACTGAGGGCCGCACGGATGGCTACC GCTGGTGCGGCACCACTGAGGACTACGACCGCGACAAGAAGTATGGCTTCTGCCCTGAGACCGCCATGTCCACTGTTGGTGGGAACTCAGAAGGTGCCCCCTGTGTCTTCCC CTTCACTTTCCTGGGCAACAAATATGAGAGCTGCACCAGCGCCGGCCGCAGTGACGGAAAGATGTGGTGTGCGACCACAGCCAACTACGATGACGACCGCAAGTGGGGCTTC TGCCCTGACCAAGGGTACAGCCTGTTCCTCGTGGCAGCCCACGAGTTTGGCCACGCCATGGGGCTGGAGCACTCCCAAGACCCTGGGGCCCTGATGGCACCCATTTACACCT ACACCAAGAACTTCCGTCTGTCCCAGGATGACATCAAGGGCATTCAGGAGCTCTATGGGGCCTCTCCTGACATTGACCTTGGCACCGGCCCCACCCCCACACTGGGCCCTGT CACTCCTGAGATCTGCAAACAGGACATTGTATTTGATGGCATCGCTCAGATCCGTGGTGAGATCTTCTTCTTCAAGGACCGGTTCATTTGGCGGACTGTGACGCCACGTGAC AAGCCCATGGGGCCCCTGCTGGTGGCCACATTCTGGCCTGAGCTCCCGGAAAAGATTGATGCGGTATACGAGGCCCCACAGGAGGAGAAGGCTGTGTTCTTTGCAGGGAATG AATACTGGATCTACTCAGCCAGCACCCTGGAGCGAGGGTACCCCAAGCCACTGACCAGCCTGGGACTGCCCCCTGATGTCCAGCGAGTGGATGCCGCCTTTAACTGGAGCAA AAACAAGAAGACATACATCTTTGCTGGAGACAAATTCTGGAGATACAATGAGGTGAAGAAGAAAATGGATCCTGGCTTTCCCAAGCTCATCGCAGATGCCTGGAATGCCATC CCCJGATAACCTGGATGCCGTCGTGGACCTGCAGGGCGGCGGTCACAGCTACTTCTTCAAGGGTGCCTATTACCTGAAGCTGGAGAACCAAAGTCTGAAGAGCGTGAAGTΓTG GAAGCATCAAATCCGACTGGCTAGGCTGCTGAGCTGGCCCTGGCTCCCACAGGCCCTTCCTCTCCACTGCCTTCGATACACCGGGCCTGGAGAACTAGAGAAGGACCCGGAG GGGCCTGGCAGCCGTGCCTTCAGCTCTACAGCTAATCAGCATTCTCACTCCTACCTGGTAATTTAAGATTCCAGAGAGTGGCTCCTCCCGGTGCCCAAGAATAGATGCTGAC TGTACTCCTCCCAGGCGCCCCTTCCCCCTCCAATCCCACCAACCCTCAGAGCCACCCCTAAAGAGATCCTTTGATATTTTCAACGCAGCCCTGCTTTGGGCTGCCCTGGTGC TGCCACACTTCAGGCTCTTCTCCTTTCACAACCTTCTGTGGCTCACAGAACCCTTGGAGCCAATGGAGACTGTCTCAAGAGGGCACTGGTGGCCCGACAGCCTGGCACAGGG CAGTGGGACAGGGCATGGCCAGGTGGCCACTCCAGACCCCTGGCTTTTCACTGCTGGCTGCCTTAGAACCTTTCTTACATTAGCAGTTTGCTTTGTATGCACTTTGTTTTTT
CTGTTCACTCTACTTAGCATGTCCCTACCGAGTCTCTTCTCCACTGGATGGAGGAAAACCAAGCCGTGGCTTCCCGCTCAGCCCTCCCTGCCCCTCCCITCAACCATTCCCC ATGGGAAATGTCAACAAGTATGAATAAAGACACCTACIGAGTGGC
11
MRGLGLWL GAMM PAIAPSRP ALMEQYEVVLPRR PGPRVRRALPSHL,G HPERVSYVLGATGHNFT H RKNRD GSGYTETYTAANGSEVTEQPRGQDHC YQGHVE GYPDSAASLSTCAGLRGFFCVGSDLHLIEPLDEGGEGGRHAVYQAEHL QTAGTCGVSDDS GS GPRTAAVFRPRPGDSLPSRETRYVELYWVDNAEFQM GSEAAVRH RVLEVVNHVDKLYQKLNFRVV VGLEIKNSQDRFHVSPDPSVTLENLLT QARQRTRRHLHDNVQLITGVDFTGTTVGFARVSAMCSHSSGAVNQDHSKNPVGVACTMAHEM GH^ILG^ΩHDEN QGCRCQERFEAGRCIMAGSIGSSFP NFSDCSQAYLESFLER QS C NAPD SH VGGPVCGN FVE GEQCDCGP EDCRN CCNSTTCQLAEGAQC AHGTCCQECKVKPAGELCRPKKD CD EEFCDGRHPECPEDAFQENGTPCSGGYCYNGACPTLAQQCQAFWGPGGQAAEESCFSYDILPGCKASRYRADNCGVLQC GGQQP LXSRAICIVDVCHA TTEDGTAYEPVPEGTRCGPEKVCWKGRCQDLHVYRSSNCSAQCHNHGVCNHKQECHCHAGWAPPHCAKLLTEVHAASGSLPVLVΛΛALVLI-AVVLVTL AGIIVYRKARSRI SRNVAPKTTMGRSNPLFHQAASRVPAKGGAPAPSRGPQELVPTTHPGQPARHPASSVALKRPPPAPPVTVSSPPFPVPVYTRQAPKQVIKPTFAPPVP PVKPGAGAANPGPAEGAVGPKVALKPPIQRKQGAGAPTAP
12
GACCCGGCCATGCGCGGCCTCGGGCTCTGGCIGCTGGGCGCGATGATGCTGCCTGCGATTGCCCCCAGCCGGCCCTGGGCCCTCATGGAGCAGTATGAGGTCGTGTTGCCGC GGCGTCTGCCAGGCCCCCGAGTCCGCCGAGCTCTGCCCTCCCACTTGGGCCTGCACCCAGAGAGGGTGAGCTACGTCCTTGGGGCCACAGGGCACAACTTCACCCTCCACCT GCGGAAGAACAGGGACCIGCTGGGTTCCGGCTACACAGAGACCTATACGGCTGCCAATGGCTCCGAGGTGACGGAGCAGCCTCGCGGGCAGGACCACTGCTTATACCAGGGC CACGTAGAGGGGTACCCGGACTCAGCCGCCAGCCTCAGCACCTGTGCCGGCCTCAGGGGTTTCTTCCAGGTGGGGTCAGACCTGCACCTGATCGAGCCCC GGATGAAGGTG GCGAGGGCGGACGGCACGCCGTGTACCAGGCTGAGCACCTGCTGCAGACGGCCGGGACCTGCGGGGTCAGCGACGACAGCCTGGGCAGCCTCCTGGGACCCCGGACGGCAGC CGTCTTCAGGCCTCGGCXrCGGGGACTCTCTGCCATCCCGAGAGACCCGCTACGTGGAGCTGTATGTGGTCGTGGACAATGCAGAGTTCCAGATGCTGGGGAGCGAAGCAGCC GTGCGTCATCGGGTGCTGGAGGTGGTGAATCACGTGGACAAGCTATATCAGAAACTCAACTTCCGTGTGGTCCTGGTGGGCCTGGAGATTTGGAATAGTCAGGACAGGTTCC ACGTCAGCCCCGACCCCAGTGTCACACTGGAGAACCTCCTGACCTGGCAGGCACGGCAACGGACACGGCGGCACCTGCATGACAACGTACAGCTCATCACGGGTGTCGACTT CACCGGGACTACTGTGGGGTTTGCCAGGGTGTCCGCCATGTGCTCCCACAGCTCAGGGGCTGTGAACCAGGACCACAGCAAGAACCCCGTGGGCGTGGCCTGCACCATGGCC CATGAGATGGGCCACAACCTGGGCATGGACCATGATGAGAACGTCCAGGGCTGCCGCTGCCAGGAACGCTTCGAGGCCGGCCGCTGCATCATGGCAGGCAGCATTGGCTCCA GTTTCCCCAGGATGTTCAGTGACTGCAGCCAGGCCTACCTGGAGAGCTTTTTGGAGCGGCCGCAGTCGGTGTGCCTCGCCAACGCCCCTGACCTCAGCCACCTGGTGGGCGG CCCCGTGTGTGGGAACCTGTTTGTGGAGCGTGGGGAGCAGTGCGACTGCGGCCCCCCCGAGGACTGCCGGAACCGCTGCTGCAACTCTACCACCTGCCAGCTGGCTGAGGGG GCCCAGTGTGCGCACGGTACCTGCTGCCAGGAGTGCAAGGTGAAGCCGGCTGGIGAGCTGTGCCGTCCCAAGAAGGACATGTGTGACCTCGAGGAGTTCTGTGACGGCCGGC ACCCTGAGTGCCCGGAAGACGCCTTCCAGGAGAACGGCACGCCCTGCTCCGGGGGCTACTGCTACAACGGGGCCTGTCCCACACTGGCCCAGCAGTGCCAGGCCTTCTGGGG GCCAGGTGGGCAGGCTGCCGAGGAGTCCTGCTTCTCCTATGACATCCTACCAGGCTGCAAGGCCAGCCGGTACAGGGCTGACATGTGTGGCGTTCTGCAGTGCAAGGGTGGG CAGCAGCCCCTGGGGCGTGCCATCTGCATCGTGGATGTGTGCCACGCGCTCACCACAGAGGATGGCACTGCGTATGAACCAGTGCCCGAGGGCACCCGGTGTGGACCAGAGA AGGTTTGCTGGAAAGGACGTTGCCAGGACTTACACGTTTACAGATCCAGCAACIGCTCTGCCCAGTGCCACAACCATGGGGTGTGCAACCACAAGCAGGAGTGCCACTGCCA CGCGGGCTGGGCCCCGCCCCACTGCGCGAAGCTGCTGACTGAGGTGCACGCAGCGTCCGGGAGCCTCCCCGTCCTCGTGGTGGTGGTTCTGGTGCTCCTGGCAGTTGTGCTG GTCACCCTGGCAGGCATCATCGTCTACCGCAAAGCCCGGAGCCGCATCCTGAGCAGGAACGTGGCTCCCAAGACCACAATGGGGCGCTCCAACCCCCTGTTCCACCAGGCTG CCAGCCGCGTGCCGGCCAAGGGCGGGGCTCCAGCCCCATCCAGGGGCCCCCAAGAGCTGGTCCCCACCACCCACCCGGGCCAGCCCGCCCGACACCCGGCCTCCTCGGTGGC TCTGAAGAGGCCGCCCCCTGCTCCTCCGGTCACTGTGTCCAGCCCACCCTTCCCAGTTCCTGTCTACACCCGGCAGGCACCAAAGCAGGTCATCAAGCCAACGTTCGCACCC CCAGTGCCCCCAGTCAAACCCGGGGCTGGTGCGGCCAACCCTGGTCCAGCTGAGGGTGCTGTTGGCCCAAAGGTTGCCCTGAAGCCCCCCATCCAGAGGAAGCAAGGAGCCG GAGCTCCCACAGCACCCTAGGGGGGCACCTGCGCCTGTGTGGAAATTTGGAGAAGTTGCGGCAGAGAAGCCATGCGTTCCAGCCTTCCACGGTCCAGCTAGTGCCGCTCAGC CCTAGACCCTGACTTTGCAGGCTCAGCTGCTGTTCTAACCTCAGTAATGCATCTACCTGAGAGGCTCCTGCTGTCCACGCCCTCAGCCAATTCCTTCTCCCCGCCTTGGCCA CGTGTAGCCCCAGCTGTCTGCAGGCACCAGGCTGGGATGAGCTGTGTGCTTGCGGGTGCGTGTGTGTGTACGTGTCTCCAGGTGGCCGCTGGTCTCCCGCTGTGTTCAGGAG GCCACATATACAGCCCCTCCCAGCCACACCTGCCCCTGCTCTGGGGCCTGCTGAGCCGGCTGCCCTGGGCACCCGGTTCCAGGCAGCACAGACGTGGGGCATCCCCAGAAAG ACTCCATCCCAGGACCAGGTTCCCCTCCGTGCTCTTCGAGAGGGTGTCAGTGAGCAGACTGCACCCCAAGCTCCCGACTCCAGGTCCCCTGATCTTGGGCCTGTTTCCCATG GGATTCAAGAGGGACAGCCCCAGCTTTGTGTGTGTTTAAGCTTAGGAATGCCCTTTATGGAAAGGGCTATGTGGGAGAGTCAGCTATCTTGTCTGGTTTTCTTGAGACCTCA GATGTGTGTTCAGCAGGGCTGAAAGCTTTTATTCTTTAATAATGAGAAATGTATATTTTACTAATAAATTATTGACCGAGTTCTGTAGATTCTTGTTAGA
13
MKLVSVA MY GSLAF GADTAR DVASEFRKK W K ALSRGKRELR SSSYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARIRVKRΎRQSNNNFQGLRSFGCR FGTCTVQ AHQIYQFTDKDKDNVAPRSKISPQGYGRRRRRSLPEAGPGRTLVSSKPQAHGAPAPPSGSAPHF
14
GAATTCAGGTCCGCTCAGGTGACTCCTTCCAGGAAGAGTCCTTAAATAACTTCCGCGCGGCCATTTCTTCCCCAGGTGCAATGTCCACTGTTGAGTCCCGAGAGTGAAAAGG CAGCTAAGCCAGCAGTGCGCGGCCCAGACAGACCACTCTGGGCAAGGTCCGCGCGACCCACTGCCCAGCCGCCTTTGCACCGGAGCTCAGAGCCATATGGCAGAGTAGGAAG GAAGCTTAAAGGTCTGCTGGGGACCGGCTCTAAGATGGGGACTCGAGAGATGGGACATGACTCGCCCACCTTCACACAGCGAATTGCCGGGAGGTGAGGACTAGAAGCCTGT TTGGCTAGTGGTCTCGCACCTTTGGCCTCTCCGTCGAGTCGCTGGGCTTCAGGACATTCGATTAGAGGAGTGGTTAGTAGGACCCCAGAAACCCACAAGCACGAAGCAGGAA GCCCCGTGGCTTAGCCTTTCCTTCCCAGTTTGGCCCCCAGGAGAGAAGTAAGAAAGAGAAGAAGCTGTGATGAAAGAGCACAAACGGGTTACAAACGTGTCTAGCGTGATTC ATCATGAACAGGCACAAATTCTTTGGGCGGGGGCTAGGACTCTCCTTTGCCCCTTGAGAAGTTGGTGACCCCAGCCTAGAGGAATCCACGCCGCGCCCCAGTCGGCCGTGCT AGCGTGTCGGGCCGAGTAGGGACTCTGCTGCTTCCTACCTGCAGGGTGACTTCCCCTCTCTGCAGATACCTCCCCTCTCTGAGCTTGAATTTTCTACCTGCTGAAATGGGAA AAGGAATGTTACCTTCCTTGCCTGACTCAAGGGTGGCTGTGAAGCTCAAAGTAGACTGGGATGTGGCCGTGCTTGGTAAACTGTAAAATGATTAGCATACGTGAAGCGTTAG TGTGCTCCCTGGCAGTCAGTCCTCACGTTTACGATGGATTAATGAAGGCAGCCAGGCACAATCTCAGGTTATGACCTTATAAGGCATAATAGGATTACAAGGAGGCAAAATG AAACAGTATATTTCCTCCTAATTTTGGTTATTCCTATGTTTCCAAATAGAAATGAAAATTCTGAAATTTCAGATAATTCCCCCCTCCAAATCCCAATTCTCAATTTAGCTTT TCTGAGCCTTGTCCCTACCGTGAAATCTTACTAGCTCACCCCGAAACGCCGGGGTCTTGGTCCTCTGGGGGACIAGTGAGTCCTGCTCCTCTCGGCTTTGCTCCGTCCCTEC CCCGGCCCCTCCGCGGGAGTCTGGGGTCGCGGCCCGGTCAGGCGCCAAGCCGGCAGGGGGCGCGGTCCACTTGAGGCCACAGCTCCCCAGGTCCAGGGCTCGGGCCATCCGC GCTGTCCCTTCCGCGGGCTCTTGCTGTTCTTCGCCAGGAGGCTTTGCACTCCGGGCCGCATGGGTCCTGGATAAGGACCTCAAGAGGTTGTAGTGGCGCCCCTTCGCTCCGG CGTACTGTCTGAACCCTGTGCCCAAAGAGGGCTGTGCAGTTCCTGCACCAACCGCCTGGAGCCCATACCTAAGCCTCTGGGCACGAGGGACCTCCTCTCCCCCGCTCCCCCC TCCCCCCATCCCAACTCCAGCCCCAAAGGAAGCAATGCGCGCGTCCGAGAGCAGGAGCGCGCGTGGCTGAGGAAAGAAAGGGAAGGCAACCGGGCAGCCCAGGCCCCGCCCC GCCGCTCCCCCACCCGTGCGCTTATAAAGCACAGGAACCAGAGCTGGCCACTCAGTGGTTTCTTGGTGACACTGGATAGAACAGCTCAAGCCTTGCCACTTCGGGCTTCTCA CTGCAGCTGGGCTTGGACTTCGGAGTTTTGCCATTGCCAGTGGGACGTCTGAGACTTTCTCCTTCAAGTACTTGGCAGATCACTCTCTTAGCAGGTAGGTGCCGCAGACCCT GCGGGTTAAGAGGTGGGGTGGGGGGCAGTGCTTGCCAAGGCCCTAAACTGGGAGCGCTGGGTGAGGGGAACAACCCACTTTGGAGGGTTCTCTGAGAGATAGATACACCCCA TATCCTGGGCCCAGCTCGTSCACACAGCTGGAGGTCCAGAGACCCAGTCCCCTCTGCTCCGTCAGCCAAGTTCCAAGAAGTTGAGCAGAGACCCTCTGGGAGCCTGGCGGGG TGCAGCGGCCTCCCCTGCGGGGCCTGTCACCCGGCCGGCGCGTGCAAACGCTCTGGGCCTCTCTGCGCGGAGGGAGATAAGCGTCTGAGCCAGGGAAAGCGCGGGCTAAACC CGCCTCGCCGGGGCCCCTGCCCGCCCTCCGTGCCCCGCCCGGGCGGTGCAGCTGGCCCGGGTGCTCACGCTCGACTCTCTTTCTTCTTTTCCAGGGTCTGCGCTTCGCAGCC GGGATGAAGCTGGTTTCCGTCGCCCTGATGTACCTGGGTTCGCTCGCCTTCCTAGGCGCTGACACCGCTCGGTTGGATGTCGCGTCGGAGTTTCGAAAGAAGTGAGTCCGGG CAGCGCCTTCCCCCTTGCTGGTACCTGGCAGGCAAGGGGAACTGACCGTTGGTCCCGAAGGTCTAGAAGTGAATGGGAGCAGGGACAGGCCTGGGCGTCACCTGAACGCACG CGAATCGGGTCTGCTTGTGTTTTCCAGGTGGAATAAGTGGGCTCTGAGTCGTGGGAAGAGGGAACTGCGGATGTCCAGCAGCTACCCCACCGGGCTCGCTGACGTGAAGGCC GGGCCTGCCCAGACCCTTATTCGGCCCCAGGACATGAAGGGTGCCTCTCGAAGCCCCGAAGACAGGTAACTACGCCCTGTGCTGTCCAGGGACGGGAGGGAAGGAAGGTGTG CGGGAGGAGTTCTCTGTCTCCACTCCCCTGGCCCGGGGGATCGTCGGGGCTGGACCGCAGCTCAGATGGCGCGAGCAGTTTCCAGCTCCCTCTGGCTCTAGAATGGCTCCCG TTCCCGGTGTTGGGGCCAAAGCTCTGCTTGATGGGGTCTCAAGTTGCCTTTCTTCCCCCTCCCCCCGCCCGCAGCAGTCCGGATGCCGCCCGCATCCGAGTCAAGCGCTACC GCCAGAGCATGAACAACRTCCAGGGCCTCCGGAGCTTTGGCTGCCGCTTCGGGACGTGCACGGTGCAGAAGCTGGCACACCAGATCTACCAGTTCACAGATAAGGACAAGGA CAACGTCGCCCCCAGGAGCAAGATCAGCCCCCAGGGCTACGGCCGCCGGCGCCGGCGCTCCCTGCCCGAGGCCGGCCCGGGTCGGACTCTGGTGTCTTCTAAGCCACAAGCA CACGGGGCTCCAGCCCCCCCGAGTGGAAGTGCTCCCCACTTTCTTTAGGATTTAGGCGCCCATGGTACAAGGAATAGTCGCGCAAGCATCCCGCTGGTGCCTCCCGGGACGA AGGACTTCCCGAGCGGTGΓGGGGΔCCGGGCTCTGACAGCCCTGCGGAGACCCTGAGTCCGGGAGGCACCGTCCGGCGGCGAGCTCTGGCTTTGCAAGGGCCCCTCCTTCTGG GGGCTTCGCTTCCTTAGCCTTGCTCAGGTGCAAGTGCCCCAGGGGGCGGGGTGCAGAAGAATCCGAGTGTTTGCCAGGCTTAAGGAGAGGAGAAACTGAGAAATGAATGCTG AGACCCCCGGAGCAGGGGΓCTGAGCCACAGCCGTGCTCGCCCACAAACTGATTTCTCACGGCGTGTCACCCCACCAGGGCGCAAGCCTCACTATTACTTGAACTTTCCAAAA CCTAAAGAGGAAAAGTGCAATGCGTGTTGTACATACAGAGGTAACTATCAATATTTAAGTTTGTTGCTGTCAAGAT'RTTTTTTGTAACTTCAAATATAGAGATATTTTTGTA CGTTATATATTGTATTAAGGGCATTTTAAAAGCAATTATATTGTCCTCCCCTATTTTAAGACGTGAATGTCTCAGCGAGGTGTAAAGTTGTTCGCCGCGTGGAATGTGAGTG TGTTTGTGTGCATGAAAGAGAAAGACTGATTACCTCCTGTGTGGAAGAAGGAAACACCGAGTCTCTGTATAATCTATTTACATAAAATGGGTGATATGCGAACAGCAAACCA ATAAACTGTCTCAATGCΓGATTCATCTCTCGGCTCGGCTCTCACGTCTAGGAGGGAGGTGCCTGGTCCGGCCGCCCAGGAGCCTTGGGGTCCCGCCGCCGGGCTTGGGAAGG TGGGACAGCGGCGCGTGCAAGTGCTGGCCCTACTCTGAGCGGGCTGAGCTGTCACGAGCTCTGTTCTCTGTGTGGGGCGCGCAGAACACGTGTCCTGGGTGCGAATCAGGGC TTCGCGGAGACGCCCGAGGRCACCGCCTGGCGTGGCGGCCGGCGGGGGGTGGGTAGGGGGAGCCCTAGTGGGTTGGCGAGCCTGGACTCTCGGGTTGCGCAACGGAGTCCTA GATTTATAGGGTTGCTCACAGAACCCGGCGCGAAAGCGAGCTTCGAAGAGTTGGGGTGGTCTCTGAGGCCTTCTAAGAGAGGCGTTCCCCCTGCCTGCCGCGGTTGTTAAAG TTCCAAGCCGCCCTAGCAAΓGCGTGGGGACACCTCCGGAAAACCCAGTAΔCCCCTAGTAACCCCGGGTCTGCCCGGGCCTGAGCGCCCGCGGGCCGCTGGCTCATGGGCGAG GCTGTAGCGCCCC
15
MRDPVSSQYSSFLFWRMPIPΞLDLSELEGLGLSDTATYKVKDSSVGKMIGQATAADQEKNPEGDGL EYSTFNF RAPIASIHSFE DL
16
AGTCAGCACGGGGGTGCΓGGAAGAGATCGGGAATAATAGCGCAGACCAATGAGCCTAGGGAGATGCTTTCATCGTCTCTCCTTCCCTCAAGTGT'ICTGGAACCTATCATTTG ANTTAGCCGAGTCAGGCAGGAGGGGGCGGGGAATCCTTCCGCCCTTCTTAGGAGGGGCTGCATTGCAGGGGGAGAGTGAACTGACAGACTCAGTCACTGAAGAGGGAAAAGG AGTGAGAAGACAAAGCCGTCAAAGCCCCAACAGCTTTGTATTTCTCCAGCCCGGCCGGCAGACCCCGGAGCTCCCGAGGCACTCCCTCCATCTTTGGAACGCGCCAGTAATT GAATTGATAACAGGAAGCTATGAGGGACCCTGTGAGTAGCCAGTACAGTTCCTTTCTTTTCTGGAGGATGCCCATCCCAGAACTGGATCTGTCGGAGCTGGAAGGCCTGGGT CTGTCAGATACAGCCACCTACAAGGTCAAAGACAGCAGCGTTGGCAAAATGATCGGGCAAGCAACTGCAGCAGACCAGGAGAAAAACCCTGAAGGTGATGGCCTCCTTGAGT ACAGCACCTTCAACTTCΓGGAGAGCTCCCATTGCCAGCATCCACTCCTTCGAACTGGACTTGCTCTAAGGCCAAGACTTCTCTCTCCCATCACCTTGCCCTCATTGTCTTCC CTCTCAAGCCCCTTCCTTTCCACTCCTTTCCCATT TAATCTTGTTCTCTCCCTACTGTGTTGGTGGTGCTGATGAATCTGCCAGAGTTGAGTTCTATGTATTTATTTATCT ATCTGTCTACTCCATTTCRCTCAAAAGCCCTCAAGTCACAAAGTAAATGGTTCAAGCAATGGAGTACTGGGTCACAGGGATTCCTCCTTTCCCCCCCAAATATTAACTCCAG AAACTAGGCCTGACTGGGGACACCCTGAGAGTAGTATAGTAGTGCAAAATGGAAGACTGATTTTTGACTCTATTATAATCAGCTTCAGAGATTCCTTAAACCTTCCTAATTT CCΓGCTCCAGGGCAGTGAAACACAAATATTTCTTCAAGGGGIΏATGAAAACCTCXSGAAGTTTTAATTTGAGGTTATCTGCTACGAAACAGTATTTCTAAAAGGCTAAAGTGA
AGGGAAAATAATTGAARCATRTTAGAAGTAGCTAATTTCTTTTCTCAAAAGAGTGTCCCTTCTTCACACCTACTCACTTTACAACTT GCTCCTAACTGTGGGTTGAAAACT CTAGCTAAAGAAAGTTARCAAARCTTAACATGCATTCCTACTATTATGATAGTTTTTAAGGTTTCAATTCAATCTTCTGAACGGCATAAGTCCTATTTTAGCCTTACCTCCT GCATTTGCAATACGTAAΓACΓGATCAGTGGGCACΛGTTCTTCAGCTACATTGAGACCCTGAAATGAACAATTATATTCTGACTCGACATCTTGTCCCCAATCCTTCCAAAAA TAΓΓGATGGTGATTTGTGCΓACCATTTACTCGTTTATTTAATAAAGACATTCAATTCCCA 17
MNLHSG REYTLTSA KDSRFPPMTRDELPRLFCSVSL TNFEDVCDYLDWEVGVHGIRIEFINEKGSKRTATYLPEVAKEQGWDHIQTIDSL RKGGYKAPITNEFRKTIK TRYRSEKMTLSYAEY AHRQHHHFQNGIGHPLPPYNHYS
18
CCCACTGTTTGTAACATGGAAGATTGGTCGAGACAAAAGATTACGTGGATGCATAGGTACTTTTTCTGCCATGAATTTGCATTCAGGACTCAGGGAGTACACACTTACCAGT GCCCTTAAAGATAGCCGTTTTCCCCCAATGACAAGGGATGAGCTGCCACGGCTTTTCTGCTCAGTGTCTCTGCTCACTAACTTTGAAGATGTCTGTGATTATTTGGACTGGG AGGTGGGTGTACATGGCATTAGAATAGAATTCATCAATGAAAAAGGATCAAAACGCACCGCCACCTACCTACCGGAGGTTGCAAAGGAGCAAGGATGGGACCATATACAGAC CATAGACTCCTTATTGAGGAAAGGAGGATACAAAGCTCCGATTACTAATGAATTCAGGAAAACCATAAAACTGACCAGGTATCGTAGTGAAAAGATGACCCTGAGCTATGCΓ GAATACCTTGCTCATCGCCAGCATCATCATTTCCAAAATGGCATTGGGCATCCCCTTCCGCCTITACAACCATTATTCCTGACACTGAGCCGCACAACCAGTCACTGGGCCTC TCTGCAGACCTCTTCCCAGGAGACCCTACACCTTCTTGGTCTAGCTATCTCTTTTACTGTACCATTTTATGATGATAGTTTCCGTTGCCATGGTGAAGCTTCGACATCGTCA ACTAAGATCATCATGGTAACGGGTAGAAAAATGGCATTTGTTAAGATCCTGTTTTATTATTTTAGATCGTTGATTTTTTTTTTGCAGCATATATAATTTTGGGTTTTTTTTT CCTTATAATATTATGTAGAATTTTGCTTTGCTGTCTCAGTCAGGTTTCTGTTTTTCTGTCCTCCTTGCCTTTCTTCCCGTTTTGCTTCCTGTTTTCCTTCTTCCTTCCCGTT TTCCTTCTTCCTTCCCTGCCTCCCTTCCTTTGACTGTGGATGGAAGAAAGTGTGCAGTTTTTAGGGATTTTACTTAGGTTCGTCTTTAGTTTTCCTCAGTAAGATAGTTGTT TTTTGATACCTGAGTTTGGGATTAATTCATATCAAATTCAGGTATTTGTATATTACTCTTGATTTTTGTCTGAAATTCACTTTGCTATGACAGCCTAGTAGTTGGGTCTTCA CTCCTTAAGTATATGT"ITTTCCCATGGTGAAAATACATGAACTTTAGTTCTAGTAGTGAGCATTCAAAGGTCCGTGATAGGGCTTGTCACAGAGAGAGAGAAATCATTTATC CCTATTGTGCTGGTTATCATAGAAGAGACTGCCTCACCACTTTATAGAACCAATTTGCAAACTAAAACACTGTTTGGAGAAGGTACAAACTACCTTTCAAAAAGGCTACAGG AAACATTTTATGAGCAGCAAATATTAGGAAGAGAGCAGATACAGAATTTAGTGCCTTTGAGAAGAATATAATTAAGTGGAATTAAGAGGGGTTAGAAAAAAGGCAATTTAGA AAAATATTCTTGTAAAACTTTATTGTTTCTATATGTGAAACAGAAGATTAGACAAATTCCTTACTCTTAAGTATTTTTTTAAGCTGAAAAAAAATTATTTTGAGCAAATAAC CAATAAGAGACATTTGTCTATTTTATATTAATTTAAATTTGTTAGCTCTAGGTTTCAATAAGTCATGATTGGCTAGAATCCATTTTAGCTACCATCTAAAGATATGGTAAAG ATAATTTAGTAAAACAAAAGTTCATATTTGCCATGATTTCAGATATGTTTGTCATGGGGACAATATTAGAGTTTTAGAGATACTATAAAATAGCTTGAATTTCTTTCTGCAC TACATACTTTTGATAGAAACACATTTACTACATTGATAAGATGTTATGTCACACCTGTGAAAATGGAGTTGGCATTCAGATATGCTATAGTTAGAGCCCAGCTCATCTGCAA GTATAGTCTTCCCATGATGCATACAAAGATAACTTACTGATGTCGATAGGAGGTCCATACATATATCCCCAGGAAAAATGACAGATTATTCTGGAGGAAGATGACCTTCATT TTATGGTTATGTGTGTGTGTCTGTGTGTCTTTGGAAAAATATATATAATTTTTTCAAATAGGAAGCCAACATATCAAGTGATGAATTAAAGTATGCTGCAGAATATATATTC TAAAACTACAAAAAAG'ICACTGAATATCAAAATGATACAGCTTATACATATAGTTACTG'IGACAAGTGACAGACTGCTAGTTCAGAATTCAAAAATCCTTTCCTAGTTTGTG AGATAATGGGCTAAATTCCTTCTGCCTGCCACTGGGGCAAAGCAAATTGCTTTAGTTTTTGATGAGAGTTCTTAGAAGTTTGTTGGTATTCCTTCATCCACAGCATCCATTG TTGAAATAACCATTTTCAGTTGTGATGCCTTAACTAAGAAGCCAATTGTTAGCCTGAAATGCAATCTTGGTAGCCAGTTTCAATGAAGCTAGAGATTAGTCAGAAAAAGTTA GCTGTTGGGCTTTAGAAAGGGATTTTGAGTCCTGTCATTTCTACTTGGGAGCATTTTGGAGCAGATTAGTCTTTCAGTATAAAAACAAGTGGCTACCTGATGGAAACTTTTC TTACCCTTATAGGGAAACTGAGCACAAGCTGAATGATATTGTCTGCTGCAAAAAAAAACAAAC
19
MRNRGQGLFRLRSRCFLHQS P GAGRRKG DVAEPGPSRCRSDSPAVAAWPAMASYPSGSGKPKAKYPFKKRASLQASTAAPEARGG GAPPLQSARSLPGPAPC KHFP DLRTS DGKCKEIAEELFTRSLAESE RSAPYEFPEESPIEQLEERRQRLERQISQDVKLEPDI LRAKQDFLKTDSDSDLQLYKEQGEGQGDRSLRERDVLEREFQRVTI
SGEEKCGVPFTDLLDAAKSVVRA FIREKY A SLQSPCPTTRRY QQLAEKPLETRTYEQGPDTPVSADAPVHPPALEQHPYEHCEPSTMPGDLGLGLRMVRGVVHVYTRR
EPDEHCSEVELPYPDLQEFVADVNVLMALI INGPIKSFCYRRLQYLSSKFQMHVLLNEMKELM
EQGREQTLREVFESMNLTAYD SVDTLDVHADRNTFHRFDKFNAKYNPIGESVLREIFIKTDNRVSGKYFAHI IKEVNSDLEESKYQNAELRLSIYGRSRDE DKIIARWAVM
HRVHSPN\ΠI LVQVPRLFDVYRTKGQIJWFQEMLENIFLPLFEATVHPASHPELHLFLEHVDGFDSVDDESKPENHVFNLESPLPEAWVΞEDNPPYAYYLYYTFANMAMLNH
LRRQRGFHTFVLRPHCGEAGPIHH VSAFM AENISHG LLRKAPVIIQYLYYLAQIGIAMSPLSNNS FLSYHRNPLPEYLSRG VSLSTDDP QFHFTKEPLMEEYSIAT
QVW LSSCDMCELARNSVLMSGFSHKVKSH LGPNYTKEGPEGNDIRRTNVPDIRVGYRYETLCQE ALITQAVQSEMLETIPEEAGITMSPGPQ
20
AAGGGCCGCAGAGCCTGGCGCGGAGCCGGCGAGATTTTGGTGGGGTCTCACCTGTTGCGTGACTCCCCCACAGTCCGGCCGCGGGAGTCCGACCCTGAATGCCCAGGGAGTG TTGAGAGAAATCTGGACGAGTTTCGGGTCCCGCTCCCTTGGGAGCACGTGGCCTACCAGCCTCTCGATTGCAGGGTTGαGTGGTCGCGACACCGGGGTCGCCTTGAGGCCAG TCCGGCTGCCGAGGTCTGCGGGAGTCCACCTCCGGCCAGCTGGCAATTTTGAAAGACTGCCTTACTTTCCCCATCTCAGTGCCAGGGCAGGGGCCCTTGGAGTGACTTGGCT GGGGTCTGTGGCCCGATCCCCCTGCCGTCCCTCAGGACCCGGGCTTTCTGCTGTACAGACTTCTCGTGGGCAGCCTCCCCTCGGAACTCGGGCATCATGGCCTCAGAGGCTC GGGGTGGTCTGGGGGCCCCTCCGCTGCAGTCTGCCCGATCCCTGCCGGGCCCCGCCCCCTGCCTCAAGCACTTCCCGCTCGACCTGCGCACGTCTATGGATGGCAAATGCAA GGAGATCGCCGAGGAGCTGTTCACCCGCTCACTGGCTGAGAGCGAGCTCCGTAGTGCCCCGTATGAGTTCCCCGAGGAGAGCCCCATTGAACAGCTGGAGGAGCGGCGGCAG CGGCTGGAGCGGCAGATCAGCCAGGATGTCAAGCTGGAGCCAGACATCCTGCTTCGGGCCAAGCAAGATTTCCTGAAGACGGACAGTGACTCGGACCTACAGCTCTACAAGG AACAGGGTGAGGGGCAGGGTGACCGGAGCCTGCGGGAGCGTGATGTGCTGGAACGGGAGTTTCAGCGGGTCACCATCTCTGGGGAGGAGAAGTGTGGGGTGCCGTTCACAGA CCTGCTGGATGCAGCCAAGAGTGTGGTGCGGGCGCTCTTCATCCGGGAGAAGTACATGGCCCTGTCCCTGCAGAGCTTCTGCCCCACCACCCGCCGCTACCTGCAGCAGCTG GCTGAAAAGCCTCTGGAGACCCGGACCTATGAACAGGGCCCCGACACCCCTGTGTCTGCTGATGCCCCGGTGCACCCCCCTGCGCTGAAGCAGCACCCGTATGAGCACTGTG AGCCAAGCACCATGCCTGGGGACCTGGGCTTGGGTCTGCGCATGGTGCGGGGTGTGGTGCACGTCTACACCCGCAGGGAACCCGACGAGCATTGCTCAGAGGTGGAGCTGCC ATACCCTGACCTGCAGGAATTTGTGGCTGACGTCAATGTGCTGATGaCCCTGATTATCAATGGCCCCATAAAGTCATTCTGCTACCGCCGGCTGCAGTACCTGAGCTCCAAG TTCCAGATGCATGTGCTACTCAATGAGATGAAGGAGCTGGCCGCCCAGAAGAAAGTGCCACACCGAGATTTCTACAACATCCGCAAGGTGGACACCCACGTCCATGCCTCGT CCTGCATGAACCAGAAGCATCTGCTGCGCTTCATCAAGCGGGCAATGAAGCGGCACCTGGAGGAGATCGTGCACGTGGAGCAGGGCCGTGAACAGACGCTGCGGGAGGTCTT TGAGAGCATGAATCTCACGGCCTACGACCTGAGTGTGGACACGCTGGATGTGCACGCGGACAGGAACACTTTCCATCGCTTTGACAAGTTTAATGCCAAATACAACCCTATT GGGGAGTCCGTCCTCCGAGAGATCTTCATCAAGACGGACAACAGGGTATCTGGGAAGTACTTTGCTCACATCATCAAGGAGGTGATGTCAGACCTGGAGGAGAGCAAATACC AGAATGCAGAGCTGCGGCTCTCCATTTACGGGCGCTCGAGGGATGAGTGGGACAAGCTGGCGCGCTGGGCCGTCATGCACCGCGTGCACTCCCCCAACGTGCGCTGGCTGGT GCAGGTGCCCCGCCTCTTTGATGTGTACCGTACCAAGGGCCAGCTGGCCAACTTCCAGGAGATGCTGGAGAACATCTTCCTGCCACTGTTCGAGGCCACTGTGCACCCTGCC AGCCACCCGGAACTGCATCTCTTCTTAGAGCACGTGGATGGTTTTGACAGCGTGGATGATGAGTCCAAGCCTGAAAACCATGTCTTCAACCTGGAGAGCCCCCTGCCTGAGG CGTGGGTGGAGGAGGACAACCCACCCTATGCCTACTACCTGTACTACACCTTTGCCAACATGGCCATGTTGAACCACCTGCGCAGGCAGAGGGGCTTCCACACGTTTGTGCT GAGGCCACACTGTGGGGAGGCTGGGCCCATCCACCACCTGGTGTCAGCCTTCATGCTGGCTGAGAACATTTCCCACGGGCTCCTTCTGCGCAAGGCCCCCGTCCTGCAGTAC CTGTACTACCTGGCCCAGATCGGCATCGCCATGTCTCCGCTCAGCAACAACAGCCTCTTCCTCAGCTATCACCGGAATCCGCTACCGGAGTACCTGTCCCGCGGCCTCATGG TCTCCCTGTCCACTGATGATCCCTTGCAGTTCCACTTCACCAAGGAGCCGCTGATGGAGGAGTACAGCATCGCCACCCAGGTGTGGAAGCTCAGCTCCTGCGATATGCGTGA GCTGGCCCGCAACAGCGTGCTCATGAGCGGCTTCTCGCACAAGGTAAAGAGCCACTGGCTGGGACCCAACTATACCAAGGAAGGCCCTGAGGGGAATGACATCCGCCGGACC AATGTGCCAGACATCCGCGTGGGCTACCGCTACGAGACCCTGTGCCAGGAGCTGGCGCTCATCACGCAGGCAGTCCAGAGTGAGATGCTGGAGACCATTCCAGAGGAGGCGG GTATCACCATGAGCCCAGGGCCTCAATGAGCCTGGTCCATGAAGTGCCCACCACATCGCAGCACTTTTACCACGTTTTGTCCTCAGACCCCGCCCATGCTGTGTGGTCTCTG CATGTCTCCATTCTTCTCTGTCTCTGTCTTGCATGTCTCCTACCATGTCACTGTCCCTGGGCCACCCAGTGAAAGCAAAGCCTGGGAATCTGCTCATTGTTGTTTGGGCTCA GGTATTGAGCCTGATGGCCCAGGTATTGAGGGCCTCCCCTGCTGGTGGCCCTGTCCTGGGATCCTCAGAAGCCTGACTGTCCTATGGGCTTCTCCAGTGTCCACAGGGGCTT GGGATGGTTGTGGGGGGCTGGCCCCTCTAGCCTTTCCGGTCCTTCCTGGGCAAATCTAAGCCTTGGCCAGGGCCGAAGTTTAGGCCCCTGTCTTGTTCATGTAGCCGAGGGG CAGGCGGGGGACCTCTACACCTCTGCTGTGGGCACGGGGCTGCTGAGGGTCTGTGGAACTCCAGCAGCTCTGCACTGGGTAGAGCTGGGCCTAGAGCTCAGTCACAGGCCTG GGCTTCCTGGCCTGAGTGGGTAGACGCAGGCGGCAGAGGTGCTGGACCACATCTCCGCCAAGTCACTGCCCAGCAGCCTTCTCCGTCCTGTCCCCAGCCCACGTGCTCCTTG GGTGTCAGCTTCCTGTGCCTCTGTGGGAGAGGGCAGCTGCCTTGTGTTATGTCTGGGGCCACAGTTGCTGCAAAGTCCTGGATCTGCCACTCAACCCCGGGAGTGGTGTTCC CAGTGTGGCTCCCAGAGCTTTGACCAGATTGTGATCCCAGCTGGCCCCTATGTTGTGTTCTGGACTGAGGCCTTTGCTGTGAACTGCAGTGTTTCATACGAACCATCTTTCC TAGTGCATGAGAAATAAAGATTATTTAAGTAAAAAAAAAAAAAAAAAAA
21
MSGAPTAGAAI »I CAATAV SAQGGPVQSKSPRFASraEMNV^^GLLQL^^
SRIQQLFHKVAQQQRHLEKQH RIQHLQSQFGLLDHKHLDHEVAKPARRKRLPEMAQPVDPAHNVSRLHR PRDCQELFQVGERQSG FEIQPQGSPPFLVNCKMTSDGGWT
VIQRRHDGSVDFNRPWEAYKAGFGDPHGEFW GLEKVHSITGDRNSRIiAVQLRD DGNAELLQFSVH GGEDTAYS Q TAPVAGQ GATTVPPSG SVPFST DQDHDLRR
DKNCAKSLSGGW FGTCSHSN NGQYFRSI PQQRQKLKKGIF KTWRGRYYP QATTM IQPMAAEAAS
22 GCGGATCCTCACACGACTGTGATCCGATTCTTTCCAGCGGCTTCTGCAACCAAGCGGGTCTTACCCCCGGTCCTCCGCGTCTCCAGTCCTCGCACCTGGAACCCCAACGTCC CCGAGAGTCCCCGAATCCCCGCTCCCAGGCTACCTAAGAGGATGAGCGGTGCTCCGACGGCCGGGGCAGCCCTGATGCTCTGCGCCGCCACCGCCGTGCTACTGAGCGCTCA GGGCGGACCCGTGCAGTCCAAGTCGCCGCGCTTTGCGTCCTGGGACGAGAΓGAATGTCCTGGCGCACGGACTCCTGCAGCTCGGCCAGGGGTGCGCGAACACCGGAGCGCAC CCGCAGTCAGCTGAGCGCGCTGGAGCGCGCCTGAGCGCGTGCGGGTCCGCCTGTCAGGGAACCGAGGGGTCCACCGACCTCCCGTTAGCCCCTGAGAGCCGGGTGGACCCTG AGGTCCTTCACAGCCTGCAGACACAACTCAAGGCTCAGAACAGCAGGATCCAGCAACTCTTCCACAAGGTGGCCCAGCAGCAGCGGCACCTGGAGAAGCAGCACCTGCGAAT TCAGCATCTGCAAAGCCAGTTTGGCCTCCTGGACCACAAGCACCTAGACCATGAGGTGGCCAAGCCTGCCCGAAGAAAGAGGCTGCCCGAGATGGCCCAGCCAGTTGACCCG GCTCACAATGTCAGCCGCCTGCACCGGCTGCCCAGGGATTGCCAGGAGCTGTTCCAGGTTGGGGAGAGGCAGAGTGGACTATTTGAAATCCAGCCTCAGGGGTCTCCGCCAT TTTTGGTGAACTGCAAGATGACCTCAGATGGAGGCTGGACAGTAATTCAGAGGCGCCACGATGGCTCAGTGGACTTCAACCGGCCCTGGGAAGCCTACAAGGCGGGGTTTGG GGATCCCCACGGCGAGTTCTGGCTGGGTCTGGAGAAGGTGCATAGCATCACGGGGGACCGCAACAGCCGCCTGGCCGTGCAGCTGCGGGACTGGGATGGCAACGCCGAGTTG CTGCAGTTCTCCGTGCACCTGGGTGGCGAGGACACGGCCTATAGCCTGCAGCTCACTGCACCCGTGGCCGGCCAGCTGGGCGCCACCACCGTCCCACCCAGCGGCCTCTCCG TACCCTTCTCCACTTGGGACCAGGATCACGACCTCCGCAGGGACAAGAACTGCGCCAAGAGCCTCTCTGGAGGCTGGTGGTTTGGCACCTECAGCCATTCCAACCTCAACGG CCAGTACTTCCGCTCCATCCCACAGCAGCGGCAGAAGCTTAAGAAGGGAATCTTCTGGAAGACCTGGCGGGGCCGCTACTACCCGCTGCAGGCCACCACCATGTTGATCCAG CCCATGGCAGCAGAGGCAGCCTCCTAGCGTCCTGGCTGGGCCTGGTCCCAGGCCCACGAAAGACGGTGACTCTTGGCTCTGCCCGAGGATGTGGCCAAGACCACGACTGGAG AAGCCCCCTTTCTGAGTGCAGGGGGGCTGCATGCGTTGCCTCCTGAGATCGAGGCTGCAGGATATGCTCAGACTCTAGAGGCGTGGACCAAGGGΒCATGGAGCTTCACTCCT TGCTGGCCAGGGAGTTGGGGACTCAGAGGGACCACTTGGGGCCAGCCAGACTGGCCTCAATGGCGGACTCAGTCACATTGACTGACGGGGACCAGGGCTTGTGTGGGTCGAG AGCGCCCTCATGGTGCTGGTGCTGTTGTGTGTAGGTCCCCTGGGGACACAAGCAGGCGCCAATGGTATCTGGGCGGAGCTCACAGAGTTCTTGGAATAAAAGCAACCTCAGA ACAAAAAAAAAAAAAAAAAAGCGGAGCTCACAGAGTTCTTGGAATAAAAGCAACCTCAGAACAAAAAA
23
HRCPKSAVTMRNEE L SNGTANKMNGA DHSDQPDPDAIKMFVGQIPRSWSEKE KELFEPYGAVYQINVLRDRSQNPPQSKGCCFVTFYTRKAA EAQNALHKIKTLPGM HHPIQMKPADSEKSNAVEDRKLFIGMVSKKCNENDIRVMFSPFGQIEECRILRGPDGLSRGCAFVTFSTRAMAQNAIKAMHQSQTMEGCSSPIWKFADTQKDKEQRRLQQQ LAQQMQQLNTATWGNLTGLGGLTPQYLAL QQATSSSNLGAFSGIQQMAGMNALQLQNLAT AAAAAAAQTSATSTNANP STTSSALGALTSPVAASTPNSTAGAAMNSLT SLGT QGLAGATVGL NINALAGMAA NGGLGATGLTNGTAGTMDA TQAYSGIQQYAAAALPT YSQSLLQQQSAAGSQKEGPEGANLFIYH PQEPGDQDILQ FMPFGN VISAKVFIDKQTNLSKCFGFVSYDNPVSAQAAIQAMNGFQIGMKR KVQ KRSKNDSKPY
24
CGACTGTGGCATTGATGTTTGAGCATACTTCTGAACTGGCTTTTGTTGAGACTATCAGTATAGAAGCATGCGCTGTCCCAAATCCGCTGTTACTATGAGAAATGAAGAGCTG CTTTTAAGTAACGGCACAGCCAACAAGATGAACGGAGCTTTGGATCACTCAGACCAACCAGACCCAGATGCCATTAAGATGTTTGTCGGACAGATCCCCCGGTCATGGTCGG AAAAGGAGCTGAAAΒAACTTTTTGAGCCTTACGGAGCCGTCTACCAGATCAACGTCCTCCGGGACCGGAGTCAGAACCCTCCGCAGAGTAAAGGTTGTTGTTTCGTAACATR TTATACAAGAAAAGCTGCACTTGAGGCCCAGAATGCACTGCACAATATTAAAACTTTACCTGGGATGCATCATCCCATTCAGATGAAACCTGCAGATAGTGAAAAGTCCAAC GCTGTGGAAGACAGAAAATTGTTCATAGGAATGGTTTCGAAGAAATGTAATGAGAACGACATCAGGGTGATGTTCTCTCCATTTGGCCAGATAGAAGAATGCCGGATCCTCC GGGGACCTGATGGGCTGAGTCGAGGCTGTGCGTTTGTCACATTTTCTACAAGGGCAATGGCACAGAATGCAATCAAAGCCATGCATCAGTCTCAGACCATGGAGGGCTGCTC TTCACCTATCGTGGTGAAGTTTGCTGACACTCAGAAGGACAAAGAGCAAAGGCGCCTCCAGCAGCAGCTCGCTCAGCAGATGCAGCAGCTCAACACTGCCACCTGGGGGAAC CTGACAGGGCTGGGCGGACTGACCCCACAGTATCTGGCGCTCCTGCAGCAGGCCACCTCCTCCAGCAACCTGGGTGCGTTCAGCGGCATTCAACAAATGGCAGGCATGAATG CTTTACAGTTGCAGAACCTGGCGACGCTGGCTGCTGCTGCAGCTGCGGCCCAGACCTCAGCCACCAGCACCAATGCAAACCCTCTCTCTACCACGAGCAGCGCCCTGGGAGC CCTCACGAGTCCCGTGGCTGCTTCAACCCCCAACTCCACTGCTGGTGCAGCCATGAACTCCTTGACCTCTCTTGGGACTCTGCAAGGACTGGCTGGAGCCACTGTTGGACTG AATAATATTAATGCACTAGCAGGTATGGCGGCTCTGAATGGAGGACTTGGCGCCACAGGCTTGACGAATGGCACGGCTGGCACCATGGACGCCCTCACCCAGGCCTACTCAG GAATTCAACAGTACGCAGCCGCCGCGCTGCCCACTCTGTACAGCCAGAGCCTGCTGCAGCAGCAGAGCGCTGCAGGCAGCCAGAAGGAAGGTCCAGAGGGGGCAAACCTCTT TATTTACCACCTTCCACAGGAATTTGGAGACCAGGACATTCTGCAGATGTΓCATGCCTTTTGGAAATGTTATCTCTGCTAAAGTCTTCATTGACAAACAGACCAATCTGAGC AAGTGCTTTGGTTTTGTTAGCTACGACAATCCAGTCTCTGCACAAGCTGCTATCCAAGCTATGAATGGCTTTCAGATCGGCATGAAACGCTTGAAGGTGCAGCTGAAGCGTT CCAAAAACGACAGCAAACCTTACTGATCCTAACCCCAGAGGCTCCCTGCTCTCATTTTAGCTTTCTTAGGGTAAGTCCCACGAGCCAGCCTGTCTCAACAGGGAAGGCAGAG GAGGACCACATTGCCAACTTTTACCAAGAGAGACGGTTATTTTTACAATAAGGCCTCCATGTCCCCACCCACTTCCCCTACCCAGTTTGCCATAATTAAAACTTGGGCTACT
TTGTTTCTATTGAGTAATTCCTCCTCCAGTTGTGCCACTGTATTCTCCTTTGTTTTGCGATTTGAATCTCCTTTTACCTTTTTTTTAATTTTTTTCATTTTTGCTTTTTTTT
AAAGAGAAGCATATACACAAATAAATGGCATCTTGAGAATTTAAAAGGCAAACAAACAAACGCTAATGTTGCAATTCTAACTCTGAAACCACTGGTGCCCCGAGAGCACTGC CTGGAGAATTCACCCCTCCTTGCCCGGCGCCCGCCCCCGGAGGGAGGGCCCGGTGCTTAGAGGTTAACTTGGTGGCCTAGGAGAGGGAGAAGCCAGGAGAAGCACTTACTCC AACCACACGTCTTTCCACTACATCGGCTTGTTTTACTAAGTAGGATTTTATTTTAGGGTTCAAAGAAACATGACATTTATTGGTCAAAATATTACACTGGTTGTCTATTTTG TTATTGTTTTATTTTAGTTTTTAGAAAGGATTAATGTACAAAAAGATTTAGAGATCTGTTTCTTAAAGCTACAGGGTTTAAAAAATAAAAATGAGTTGAAAATACTTGATGΓ TTCTTGAAAGATAAATTTAATAATAATAAATAAATACATAAATACATAAATAAAAAAGAAAGCCACAGGCCTGTAAATTTTATTTGTAAAAAAGCATTTCTATTTTTATACA AAATTTTTACTGCCTCAGAAATAATGGAAGTTATTTATTGCCTATTGTTAACTTATTGGGTACCTAAAGAGCAGTTCTCTGTCTAGCTAGAACCTTCTGAAGTAGTCTCTAG AGGAATTGTTCTAGGAATGGGCTTTTTTTCACCGTTGAACCCTAGACCTGAAGTTCATGCTTTATCCTCTCGTTGTTTGTATCTGTCΓGATTATTTTGTTTGTAACTTCCAΓ TATCTAGTTTACAGTTCAGTCGTCTGACTTTCCCCGTATGTCACATTTGTTGAAACTGGACCTTCTCCCCCTGTCCCTCACCCCAAAACACCCGGAATCCATCCCCTTTCGC TCTCTCCAGATGGATTCTCTTGGGGTTTCATTGTGCTG'TGGATAAGGAGTGTAAGAAATGCAAATTATGTGAATGGCTCGGAGACTCCCTAATGACCTAAGATTTGCATTAG TTTTTCTCCTGCACCCTTAAAAGTGATTTTGTTGCCGCTGCATAGATTCTGTGTAACTTTTTACTCTTCCTTGTTTTTTCCCTAGACATCTTCATGCCCGTTAGTTCATCGΓ TTGCCTAGCATGTCCCTGTGGCGTCTCAAAAAAAAGTTTCATCGTCCCGTCATTGTTTCTGATGTCTTTCTGACCTCACATCATATTTGGTTCTCCTACTGACCTTTGATCΓ AGTTTGACCTTTGAAATTTGCATGTGACCTCATCTAGCTATGAATTCTGGGAAGTCAATGTGAAAAACATTGCTGCATTCATGCAAGACTGAAATTTATTATTAGACAAAΓΓ CATTATAGAAAAAACCTGTGGCAAAAACGTTTCTTTCTTATTTTTTTTCTTTTCCTAAAACAGACTTGAAAGTATTATACAGGGATTGGCATTCTTCCCGGTCACTGGTAAC AATAGCAATATGTGTCCAGGGACACAGAATGTTGGTTTCTAACAGACTACTTCCAAAAACAGTTTGAGAAAAAAACTGTCTGATTTTAAGTCTCTAGAGGTCTGTAATAGTT TTTACATTTTTCAGGCAGTGTAAAGTTTTTTGATAAGGCCATTTTAGGTGGCTCACTTTCTCATTAAGATATATATATAGAACCACTTTTTGTAGATTAGTATAAGAAAAAT TTTACCCTGTTTTGGGGCAAATGCTACCTATTTGTGTCACCTTTTGCTGAACTCACAGTTAGACAATCCATGGTTTAATGCACATGAAATTACCTATATTTTATACTGTTT CAATGTACAGGAGAAAGGTTACTGTAAACTGTGTTATGTTGGTGCTTCTGTGAATTAAGTTGTGGTTTCATCATGAGTCTTAATGTTCTTTGTTGATAAGACAAGTTTAGAA TGGTTTACTTAATACAAAAAAAAAAAAAAGAATTTCAAAAAAAAAAGTTGTTTGCTTAAAAAAAATTTCATGTGAGGGAAAAAAAAAAAAACCTATTCCAGAATAAGTTTT GTGTTGGCTTGTGAAGCATTGATGTCATTTTTTTTAATTGTGGACTATTTAGATGTGTTTGTGTTCAGCAAAATGTGATCTGTTTTTTTCTTTTAAAGAAAAAAAGTGAAAA TATATAGTGCCAAATTCCAAAGGTACTTCCTTCCTAGAGCTTCAGTGTGTTTCTTGTGAGAAGTAATTTGATAACATGGGTATTTTATTATGTGTTTTGTATAAATCCCTAA TATTTAAAAAAAAAAACAAAACAAAAAAAGGTTACAAAGTTTGTTAACTTGCTATCCTGTGGTCTTGTTGCCTGAAATTGTTATTGTTTGTTATTTCTCTCTGATGTTTTTT GTAAGACATTGTATAAGTGCCCATGTCCCACTTTTTTAACCACTCCGCACATCAGTGCTGTGAAGGCAACCTCACCATGTATTTTCTTCATAATCTATGGAAACCTCTAAGG GAGAAAGTTTTGAACTTTTAACCCTTTCTACCCAGAGCTATCTGGAATGTTGATGACTTTTTATACTGTCATGATTTGAGTTTGTTTTGGGGTGTTTCCAATTTGGATTTT TTCCCTGCATCTATCCTCIAAGTTGTTTCGGTTTGACTACTTTGTTCTTTGGTTAAGATCCAAAAGAAAACAGAAAACAATTCCACGAGGCCAATCTAAAGGGAAAAAATC CTACACTACTTTTACTACTTTTGATTATTTCTCATTTTTGGGAAAAGAATTCCTAATGTGCTACTAGAATTCCTTCTTCAGTTTTAACGAGTAATTGGATAAACCCTGAGGG AAAACGGAGGTAGATTCAGCACCTAACAATCCTGTATGCTTTTGAGATCACGTTTAGTGCTATGTCCTAGTCTAGAATATTTTCATATACCTTGCAGTAAAACCACTTTGTG GCAGGACAGTCTCTTGAGGGGTT TGTTTCTGTTTCCTAAATACTCCTAAATAATATTTCTAATCAGCCATTATGCTGGGGCATCTCTGATCCCAGTAGGTACCTC GAATA ACCAGGTGTCTGGAGTTAGAAGCCCATAGCCCTTTCCCAGCCTTTTTGGTTTTTTTAATTGAACACATTTCATCTAAGTAAAGCTCAGTTCTTTATCACAATTTACTGACC AAATACCTAGCACCAGTTCCTGC GCCACTTTTTAAAGTGCCATATGACTTTCTACGAACAGGTACCTTGCTGTCTTGACAAATCCTAATGTCACGCCTACAGCCCCAACAC AAGCTCCAGTCTTCCTCTTCGGCATGCCCTGGAAGCTTCTTGGCCTCAGCTCCCCTTCCCCGCTCAGCACCCTGTTAGGATCAGTGTGTGTGGATGGGATAGCCCTGGGATG GAAAGGACTAGCCTCTACTGATGCAAAAAAACAAAAAGCAACACAAACGTTTCCTTCTTATAGCACATGCACTTCCTTACAATGACATGATTTGTATTATCCTCACATGTGT TTACTACTGCTGGGGCCTTCCTTCATCCTCTGAGGGCTATTTTGTACTTTCTGCAGCAATCAGCTTAATAACAACACTTATTGCACCTGTCTCTCTCTGAGAACACGGTGΓG CTCGACACGTACCACGTAACGTGGAAACACAAGAGCCCACCACTTGAATTTCTAAGACCATTTCATTCTGAAACTTCTTATCAATTACCTAAATCTCAACGAAAAACAATT ACTGAAGCCGACTCCCCTCCCCATCTCCCTCTCAACCTCAACCCACCTGCATGCATCTCCCCCAGAGGAAAACACTGAGGGTAGGGGACAGGGAGGCTCAGGACGCGCCCT CTGAATCGGAGTGTTTCTTCTTCACAAGTCACCAAGAGAGGACATGAGGGGGAAAGICCTTTTTTGCCCTTCTCCAAAAAATAACCTTCCACAGAGACAAACTGTCCTTCTA TCCACTTTTATCTTTTAATAAATATCAAAAGGAAAAAGCTGCAAGGGTGCAAAGGGCCTGTGCCAGAAGAAAACACACACAGGGAAACCGCTTTTTTTAATCAATTGTAΒAG AATAGTCATTTTTAATCTAAATTAGAGAATTGTGATACAATGGCAGTCCTCAAAGGCGTAACGAGTTCATCTTTCTTTCACCATAGGGGTTATAGTTGGCTTGTGCTACΓCT GGAATCATTTTACTGTTTGTTTTTATTATCTTAAGTGCTAATTAAAAAAAAAATAAAATTTTAAAAAAACCTGTAGTTTCATTACCTTTTTGAATAATGTCATACAAAAAAT GTATTTGTTTTTTTGTGCTGTGAGAATTGATGTTTGTAGATTAATAATCATTTTGTTTAGAATTACAAAATAGTTTTTAAATATTGTCTGAGAAAAGCCAAAGTTAATGCAA CTACAACTGATTGTACTTATGCATTTTGTACCAGTGGAACTTTTTATACTGGAGATTAAAAAAAAAATGGAAATTTTTGTGGCTTGCTCTGGTGGGCCCCTGACAATGACTG ATTTCAAGTTTGATTTCGGGTTGATTGATTGATTGATTGATAGAAAGAAAGTTGCTTTTCTTTTGAGAATTAAAAACTTTGGCTTGATTTCTTTTTTCCCTTTGCTTATATC TAGCATTAGAATTTTGTCTTAAAATAACAGCGGTAAGTTTCACTTTTTATTCTGTATTGTGCAGTTACACAATAAGGTAATTAGATTTAGAAGTACTCAGTCACTTTAAGΓG GATAAATGTATTAGTTAAAACTTTAGGGTTTGCTTTTTTGCTGTTTAGATCAAAGTTTTTTCTGATTCTTCTGTCCTCATTGTGAACATAACCGTGTAGTTGAAACAGTCAA ACTTATTTTTGTAATGTATGTTATTGTGTGATGCAGTTTTTTTGCTTCTGTCTCCAATATTAAACCATTTTCC
25 AEPSGAETRPPIRVTVKTPKDKEEIVICDRASVKEFKEEISRRFKAQQDQLVLIFAGKILKDGDT NQHGIKDGLTVHLVIKTPQKAQDPAAATASSPSTPDPASAPSTTP ASPATPAQPSTSGSASSDAGSGSRRSSGGGPSPGAGEGSPSATASILSGFGGILGLGSLG GΞANFME QQQMQRHVMSNPEMLSQI ENPLVQDMMSNPDLMRHMIMANPQ
MQQ MERNPEISHMIJSΠSPELMRQT ELARNFAIWQEMF-SIQDRA SN ESIPGGYNAL^
PPTSQAPGSGGEGTGGSGTSQVHPTVSNPFGINAASLGSG FNSPEMCALLCQISENPQ MQNVISAPYMRSMNQT AQNPDFAAQMMVNVP FAGNPQLQEQ RLQ PVFL QQMQNPES SILTNPRAMQA LQIQQGLQTLQTEAPGLVPSLGSFGISRTPAPSAGSNAGSTPEAPTSSPATPATSSPTGASSAQQQLMQQMIQLLAGSGNSQVQTPEVRFQ QQLEQLNSMGFINREANLQALIATGGDINAAIERLLGSQLΞ
26
CCCCAAGAGTAGTAGTAGTAGTAGTACCATACGATCGTACTGACCACCTGTCG'ITTACCCAGCCCTAGACATGCTGCTACTGCTATTCCATGGATCCTAGGTCACACCACCT TAAGCGCCGGCGCAGCTGCGGCCCGCCCGCCCCTCCTCCTCCTCGGCCCGCCCGACCGCCCGCCGGCCCACCGCCGCCGCCGTACCGCCTCGGCTCGCCCCGGCTCTGCTCC GGGGGGTAAGCCCAGTGGCAGTTCTGGGGGTTCCTGTTCCTCCTTTGCGGCGGCATGGCGGAGCCGAGCGGGGCCGAGACGAGGCCCCCCATTCGGGTCACCGTCAAGACCC CCAAGGACAAGGAGGAAATTGTGATCTGCGATCGAGCCTCGGTCAAGGAGTTCAAAGAGGAAATCTCCCGGAGGTTTAAGGCTCAGCAGGATCAGCTGGTCCTGATCTTCGC
AGGCAAGATCCTCAAGGATGGGGACACACTGAACCAGCACGGAATCAAGGACGSGCTCACTGTCCATCTGGTCATCAAGACCCCTCAGAAGGCTCAAGATCCAGCTGCTGCC ACTGCTTCTTCCCCCTCCACACCTGACCCTGCCTCAGCACCCTCCACCACGCCTGCTTCACCCGCCACCCCTGCCCAGCCCTCCACCTCTGGCAGTGCCTCTTCAGATGCTG GCAGTGGAAGCCGGAGGAGCAGTGGTGGGGGGCCCTCTCCGGGGGCTGGGGAGGGATCCCCCAGTGCTACTGCGTCCATACTCTCTGGCTTTGGGGGCATCCTGGGGCTGGG CAGCCTAGGCCTGGGCTCTGCCAACTTCATGGAGCTGCAGCAGCAGATGCAGCGGCACGTGATGTCCAATCCTGAGATGCTGTCACAGATCATGGAGAACCCCCTGGTCCAG GATATGATGTCTAACCCTGATCTGATGCGTCACATGATTATGGCCAACCCCCAGATGCAGCAGTTGATGGAGCGGAACCCTGAGATCAGCCACATGCTCAATAACCCTGAAC TCATGAGGCAGACAATGGAGCTTGCTCGGAATCCAGCCATGATGCAAGAGATGATGCGGAACCAGGACCGGGCCCTGAGCAACCTTGAGAGCATCCCTGGAGGGTATAATGC CCTCCGCCGCATGTACACGGACATCCAGGAGCCCATGTTCAGTGCTGCCCAGGAACAGTTTGGCAACAATCCCTTCTCTTCCCTGGCCGGGAACTCCGACAGCTCATCCTCC CAGCCTCTGCGGACTGAGAATCGAGAGCCCCTCCCTAACCCCTGGAGCCCCTCGCCCCCCACCTCCCAGGCCCCCGGGTCCGGTGGGGAGGGCACCGGAGGATCGGGGACCA GCCAGGTGCACCCGACAGTCTCGAACCCCTTTGGGATCAATGCGGCTAGCCTGGGGTCAGGGATGTTCAATAGCCCAGAAATGCAAGCCCTCCTCCAGCAGATCTCTGAGAA CCCCCAGCTGATGCAGAATGTGATCTCAGCACCCTACATGCGCAGCATGATGCAGACGCTTGCCCAGAACCCCGACTTTGCTGCTCAGATGATGGTGAATGTGCCGCTCTTC GCGGGGAACCCCCAACTGCAGGAGCAGCTCCGCCTGCAGCTCCCAGTCTTCCTGCAGCAGATGCAGAACCCAGAGTCACTCTCCATCCTTACCAATCCCCGAGCCATGCAGG CATTGCTGCAGATCCAGCAGGGACTACAGACCTTGCAGACCGAGGCCCCTGGGCTGGTACCCAGCCTTGGCTCCTTTGGGATATCCCGGACCCCAGCACCCTCAGCAGGCAG CAACGCAGGGTCTACGCCCGAGGCCCCCACTTCCTCACCAGCCACGCCAGCCACATCTTCTCCAACAGGGGCTTCCAGCGCCCAGCAGCAACTCATGCAGCAGATGATCCAG CTTTTGGCTGGAAGTGGAAACTCACAGGTGCAGACGCCAGAAGTGAGATTTCAGCAGCAGCTGGAGCAGCTCAACTCCATGGGCTTCATCAATCGTGAGGCTAACCTGCAGG CCCTGATTGCCACAGGAGGGGACATCAACGCAGCTATCGAGAGACTGCTGGGCTCCCAGCTCTCCTAATCCCTCGGCCCATGCCTCCTGCCTCTCCCCTCCCTCGATGTCAG CATTCGGTTCTTCTGTCAATCCTTACCCTCTGCAGCTTGTCCTCCCTTCCGTCTTCTCCCTCATCCTTTCCAAACAGCAGGGTGACTTTAGAGGCATGGGCTCCAACCCCTT
AGCTCTGTCTGAGAATTATGGTTTTACTGCTACG'ICTCTAACAGACTCTTCTCTCCTGGTCTCCTTGAGCAGTGCTACTTAAACAGTTTTCACAGTTTCATTGATTGACTCT ACCTCCTTGCCCCACACCACTTTTGCAATCTTTAAACTTTCAGTGGCTGTGCAGAGTCGAGGGAGGAACCAGCTCTCTGGTTTACTGGAACATAGTCTTCCATCTATACCAC TAGGGTTTTGTCTTATGTTTACTTTTGGTAACTCTCTTCCTTCTTTTTCTCCCTACCCCCCAACCCCTAGCCCAACCAATGCTAGAATTTCTTGCTCTGAAGGAGGAGCAGG TGAAACAGGTGGTAATT TCCTTCTCGGCCCCTATTCTGGTTCATTCAGCACTTTTTGGTGGGAACTGTTGGAAATTCCAGGGTAAGGAGGAAGATGCCTGTTCTCCCTGTC TGAAGAGGGAGATGAGACAGCTCTCTGGACAGGAATTAACAAACGCTGGAGCAGCCCAGAGGAAATTCGTGTGAAAGAGGAGGGAATGAGATTATTCGGAGGAAGGGAATGG GGGAGACAGCCTGAGTAAAAGGCTTGGAAGTTGGAATTAGCAGTGGGGAGCAGAAGCACTCATAGCTCTTTTAGGCAGAAGAATCCAGGC
27 GCFCAVPEEFYCEV L DESKLT TTQQQGIKKSTKGSWLDHVFHHVNLVEIDYFG RYCDRSHQTY LDPAKTLAEHKELINTGPPYTLYFGIKFYAEDPCKLKEEITR
VDPSGLSEEQLKEIPYTKIETQGDPIRITHSHSPK Y
28
GACATGGGCTGTTTCTGCGCTGTTCCGGAAGAA'ITTTACTGCGAAGTTTTGCTCCTGGATGAATCCAAGTTAACCCTTACCACCCAGCAGCAGGGCATCAAGAAGTCAACGA
AAGGTTCCGTTGTCCTTGACCACGTATTCCATCACGTAAACCTTGTGGAGATAGATTATTTTGGGCTACGTTACTGTGACAGAAGCCATCAGACGTATTGGCTGGATCCTGC
AAAAACCCTTGCTGAACACAAAGAACTGATCAACACTGGACCTCCATATACTTTGTATTTTGGTATTAAATTCTA'IGCTGAAGATCCATGTAAACTTAAAGAAGAAATAACC
AGATATCAGTTTTTCTTGCAGGTGAAGCAAGATGTCCTTCAGGGCCGTCTGCCCTGTCCCGTCAACACTGCTGCTCAGCTGGGAGCGTATGCCATCCAGTCGGAGCTTGGAG
ATTATGACCCATATAAACATACTGCAGGATATGIATCTGAGTACCGGTTTGTTCCTGATCAGAAGGAAGAACTTGAAGAAGCCATAGAAAGGATTCATAAAACTCTAATGGG
TCAGATTCCTTCTGAGGCTGAGCTGAATTACTTGAGGACTGCCAAATCCCTGGAGATGTATGGCGTTGACCTCCATCCCGTCTATGGAGAAAACAAGTCTGAGTATTTCTTA
GGATTAACTCCGGTTGGTGTTGTTGTGTACAAGAATAAAAAGCAAGTGGGGAAGTATTTCTGGCCTCGGATTACAAAGGTTCACTTCAAGGAGACTCAATTTGAACTCAGAG
TACTGGGAAAAGATTGTAACGAAACCTCATTCTTTTTTGAAGCTCGGAGTAAAACTGCTTGCAAGCACCTCTGGAAGTGCAGTGTGGAACATCATACATTTTTTAGAATGCC AGAAAATGAATCCAATTCACTGTCAAGAAAACTCAGCAAGTTTGGATCCATACGTTATAAGCACCGCTACAGTGGCAGGACAGCTTTGCAAATGAGCCGAGATCTTTCTATT CAGCTTCCCCGGCCTGATCAGAATGTGACAAGAAGTCGAAGCAAGACTTACCCTAAGCGAATAGCACAAACACAGCCAGCTGAATCAAACACCATCAGTAGGATAACTGCAA ACATGGAAAATGGAGAAAATGAAGGAACAATTAAAATTATTGCACCTTCACCAGTAAAAAGCTTTAAGAAAGCAAAGAATGAAAATAGCCCTGATACCCAAAGAAGCAAATC CCTCATGCACTCGTGGGAAGAAAATGGCCCCCAGAGTGGACTCTACAATTCTCCCAGTGATCGCACTAAGTCGCCAAAGTTCCCTTACACGCGTCGCCGAAACCCCTCCTGT GGAAGTGACAATGATTRRGTACAGCCTGTGAGGAGGAGGAAAGCCCATAACAGTGGTGAAGATTCAGATCTTAAGCAAAGGAGGAGGTCACGTTCACGCTGTAACACCAGCA GTGGTAGTGAATCAGAAAATTCTAATAGAGAACACCGGAAAAAGAGAAACAGAAIACGGCAGGAGAATGATATGGTTGATTCAGCGCCTCAGTGGGAAGCTGTATTAAGGAG ACAAAAGGAAAAAAACCAAGCCGACCCCAACAGCAGGCGATCCAGACACAGATCTCGTTCGAGAAGCCCCGATATCCAAGCAAAAGAAGAGTTATGGAAGCACATTCAAAAA GAACTTGTGGATCCATCCGGATTGTCCGAAGAACAATTAAAAGAGATTCCATACACTAAAATAGAGACACAAGGTGACCCAATCCGCATCACGCATTCTCATTCGCCAAAGC TTTAT AGTGCTTGACACAAGGTGACCCAATCCGCATCAGGCATTCTCATTCGCCACGAAGTTACCGCCAGTATCGCAGGTCCCAGTGTTCAGATGGGGAGCGATCAGTTCT CTCGGAAGTGAATTCAAAAACAGATCTTGTACCACCACTTCCGGTGACCCATTCTTCGGATGCTCAGGGTTCTGGGGATGCTACAGTTCATCAGAGAAGAAATGGGTCTAAA GATAGCCTGATGGAAGAAAAACCTCAGACATCTACAAACAACCTGGCTGGAAAACACACAGCAAAAACAATAAAAACTATACAAGCTTCCCGCCTCAAG
29
MPSQMEHAMETMMFTFHKFAGDKGY TKED RV MEKEFPGFLENQKDPLAVDKIMKDLDQCRDGKVGFQSFFSLIAGLTIACNDYFWHMKQKGKK
30
AGAATACACTCACAAGCCACTCCGCTGCTCGCCTCTCOGCCCCGCGTCCAGCTCGCCCAGCTCGCCCAGCGTCCGCCGCGCCTCGCCAAGGCTTCAACGGACCACACCAAAA GCCATCTCAAATGGAACACGCCATGGAAACCATGATGTTTACATTTCACAAATTCGCTGGGGATAAAGGCTACTTAACAAAGGAGGACCTGAGAGTACTCATGGAAAAGGA GTTCCCTGGATTTTTGGAAAATCAAAAAGACCCTCTGGCTGTGGACAAAATAATGAAGGACCTGGACCAGTGTAGAGATGGCAAAGTGGGCTTCCAGAGCTTCTTTTCCCTA ATTGCGGGCCTCACCATTGCATGCAATGACTATTTTGTAGTACACATGAAGCAGAAGGGAAAGAAGTAGGCAGAAATGAGCAGTTCGCTCCTCCCTGATAAGAGTTGTCCAA
GAAAGAAAAGTTAAATACCAGATAAGCTTTTGATTTT'IGTATTGTTTGCATCCCCTTGCCCTCAATAAATAAAGTTCTTTTTTAGTTCC
31 M) RQF MC SLCTAFA SKPTEKKDRVHHEPQLSDKVHNDAQSFDYDHDAFLGAEEAKTFDQLTPEESKERLGKIVSKIDGDKDGFλ TVDEL DWIKFAQ RWIYEDVERQ KGHDLNEDGLVS EEYKNATYGYV DDPDPDDGFNYKQMMVRDERRFK ADKDGDLIATKEEFTAFLHPEEYDYMKDIVVQETMEDIDKNADGFID EEYIGDMYSHDGNT DEPEWVKTEREQFVEFRDKNRDGKMDKEETKDWILPSDYDHAEAEARH λ YESDQNKDGKLTKEEIVDKYD FVGSQATDFGEA VRHDEF
32
GTGAGCGGCGGCCACGGCATCCTGTGCTGTGGGGGCTACGAGGAAAGATCTAATTATCATGGACCTGCGACAGTTTCTTATGTGCCTGTCCCTGTGCACAGCCTTTGCCTTG AGCAAACCCACAGAAAAGAAGGACCGTGTACATCATGAGCCTCAGCTCAGTGACAAGGTTCACAATGATGCTCAGAGTTTTGATTATGACCATGATGCCTTCTTGGGTGCTG AAGAAGCAAAGACCTTTGATCAGCTGACACCAGAAGAGAGCAAGGAAAGGCTTGGAAAGATTGTAAGTAAAATAGATGGCGACAAGGACGGGTTTGTCACTGTGGATGAGCT CAAAGACTGGATTAAATTTGCACAAAAGCGCTGGATTTACGAGGATGTAGAGCGACAGTGGAAGGGGCATGACCTCAATGAGGACGGCCTCGTTTCCTGGGAGGAGTATAAA AATGCCACCTACGGCTACGTTTTAGATGATCCAGATCCTGATGATGGATTTAACTATAAACAGATGATGGTTAGAGATGAGCGGAGGTTTAAAATGGCAGACAAGGATGGAG ACCTCATTGCCACCAAGGAGGAGTTCACAGCTTTCCTGCACCCTGAGGAGTATGACTACATGAAAGATATAGTAGTACAGGAAACAATGGAAGATATAGATAAGAATGCTGA TGGTTTCATTGATCTAGAAGAGTATATTGGTGACATGTACAGCCATGATGGGAATACTGATGAGCCAGAATGGGTAAAGACAGAGCGAGAGCAGTTTGTTGAGTTTCGGGAT AAGAACCGTGATGGGAAGATGGACAAGGAAGAGACCAAAGACTGGATCCTTCCCTCAGACTATGATCATGCAGAGGCAGAAGCCAGGCACCTGGTCTATGAATCAGACCAAA ACAAGGATGGCAAGCTTACCAAGGAGGAGATCGTTGACAAGTATGACTTATTTGTTGGCAGCCAGGCCACAGATTTTGGGGAGGCCTTAGTACGGCATGATGAGTTCTGAGC TGCGGAGGAACCCTCATTTCCTCAAAAGTAATTTATTTTTACAGCTTCTGGTTTCACATGAAATTGTTTGCGCTACTGAGACTGTTACTACAAACTTTTTAAGACATGAAAA GGCGTAATGAAAACCATCCCGTCCCCATTCCTCCTCCTCTCTGAGGGACTGGAGGGAAGCCGTGCTTCTGAGGAACAACTCTAATTAGTACACTTGTGTTTGTAGATTTACA CTTTGTATTATGTATTAACATGGCGTGTTTATTTTTGTATTTTTCTCTGGTTGGGAGTATGATATGAAGGATCAAGATCCTCCACTCACACATGTAGACAAACATTAGCTCT TTACTCTTTCTCAACCCCTTATATGATTTTAATAAT'ICTCACTTCACTAATTTTGTAAGCCTGAGATCAATAAGAAATGTTCAGGAGAGAGGAAAGAAAAAATATATATGCT CCACAATTTATATTTAGAGAGAGAACACTTAGTCTTGCCTGTCAAAAAGTCCAACATTTCATAGGTAGTAGGGGCCACATATTACATTCAGTTGCTATAGGTCCAGCAACTG AACCTGCCATTACCTGGGCAAGGAAAGATCCCTTTGCTCTAGGAAAGCTTGGCCCAAATTGATTTTCTTCTTTTTCCCCCTGTAGGACTGACTGTTGGCTAATTTTGTCAAG CACAGCTGTGGTGGGAAGAGTTAGGGCCAGTGTCTTGAAAATCAATCAAGTAGTGAATGTGATCTCTTTGCAGAGCTATAGATAGAAACAGCTGGAAAACTAAAGGAAAAAT ACAAATGTTTTCGGGGCATACATTTTTTTTCTGGGTGTGCATCTGTTGAAATGCTCAAGACTTAATTATTTGCCTTTTGAAATCAC GTAAATGCCCCCATCCGGTTCCTCT TCTTCCCAGGTGTGCCAAGGAATTAATCTTGGTTTCACIACAATTAAAATTCACTCCTTTCCAATCATGTCATTGAAAGTGCCTTTAACGAAAGAAATGGTCACTGAATGGG AATTCTCTTAAGAAACCCTGAGATTAAAAAAAGACTAT'ITGGATAACTTATAGGAAAGCCTAGAACCTCCCAGTAGAGTGGGGATTTTTTTCTTCTTCCCTTTCTCTTTTGG ACAATAGTTAAATTAGCAGTATTAGTTATGAGTTTGGTTGCAGTGTTCTTATCTTGTGGGCTGATTTCCAAAAACCACATGCTGCTGAATTTACCAGGGATCCTCATACCTC ACAATGCAAACCACTTACTACCAGGCCTTTTTCTGTGTCCACTGGAGAGCTTGAGCTCACACTCAAAGATCAGAGGACCTACAGAGAGGGCΓCTTTGGTTTGAGGACCATGG CTTACCTTTCCTGCCTTTGACCCATCACACCCCATTTCCTCCTCTTTCCCTCTCCCCGCTGCCAAAAAAAAAAAAAAGGAAACGTTTATCATGAATCAACAGGGTTTCAGTC CTTATCAAAGAGAGATGTGGAAAGAGCTAAAGAAACCACCCTTTGTTCCCAACTCCACTTTACCCATATTTTATGCAACACAAACACTGTCCTTTTGGGTCCCTTTCTTACA GATGGACCTCTTGAGAAGAATTATCGTATTCCACGTTTTTAGCCCTCAGGTTACCAAGATAAATATATGTATATATAACCTTTATTATTGCTATATCTTTGTGGATAATACA TTCAGGTGGTGCTGGGTGATTTATTATAATCTGAACCTAGGTATATCCTTTGGTCTTCCACAGTCATGTTGAGGTGGGCTCCCTGGTATGGTAAAAAGCCAGGTATAATGTA ACTTCACCCCAGCCTTTGTACTAAGCTCTTGATAGTGGATATACTCTTTTAAGTTTAGCCCCAATATAGGGTAATGGAAATTTCCTGCCCΓCTGGGTTCCCCATTTTTACTA TTAAGAAGACCAGTGATAATTTAATAATGCCACCAACTCTGGCTTAGTTAAGTGAGAGTGTGAACTGTGTGGCAAGAGAGCCTCACACCTCACTAGGTGCAGAGAGCCCAGG CCTTATGTTAAAATCATGCACTTGAAAAGCAAACCTTAATCTGCAAAGACAGCAGCAAGCATTATACGGTCATCTTGAATGATCCCTTTGAAATTTTTTTTTTGTTTGTTTG TTTAAATCAAGCCTGAGGCTGGTGAACAGTAGCTACACACCCATATTGTGTGTTCTGTGAATGCTAGCTCTCTTGAATTTGGATATTGGTTATTTTTTATAGAGTGTAAACC AAGTTTTATATTCTGCAATGCGAACAGGTACCTATCTGTTTCTAAATAAAACTGTTTACATTCAAAAA
33 SAEVPEAASAEEQKEMEDKVTSPEKAEEAKLKARYPHLGQKPGGSDF RKR QKGQKYFDSGDYNMA A MKNKQLPTAAPDKTEVTGDHIPTPQDLPQRKPS VASKLAβ
34
GGCACGAGCGCGGGCGGAGGCGGCCCGGCGGGCCCTGGGAGAGCTGGGACGGGCGGCGGCCGGGTGGCCTCGGCCACCCGCTAATTGCATCTTTTCCCGGCGTCTCGTCTGC AGAGGGAGCACTATGTCTGCGGAAGTCCCCGAGGCAGCCTCCGCGGAGGAGCAGAAGGAAATGGAAGATAAAGTGACTAGTCCAGAGAAAGCAGAAGAAGCAAAATTAAAAG CAAGATATCCTCATCTGGGACAAAAGCCTGGAGGTTCAGATTTCTTAAGGAAACGGTTGCAGAAAGGGCAAAAATATTTTGATTCTGGGGATTACAACATGGCTAAAGCAAA AATGAAGAACAAGCAACTTCCTACTGCAGCTCCGGATAAGACGGAGGTCACTGGTGACCACATTCCCACTCCGCAAGACCTTCCTCAACGGAAGCCGTCCCTTGTTGCTAGC
AAGCTGGCTGGCTGATTAAGAAGCTGAACTGCATGAA'ICTGCTAAATCTCATTATTTCTCCTTAATATGTTACTTATCTACTTTTTATTTCCTTTCATTCACTAGTCATTTG
AGACTGACAGCTTTGCAGGTAGCAGTAGTGTGTGCTGCTATTGTGGAATATACGTGTGTAGAGTTTTTGATTAGTTTAACAGTGCACTGGTGAAGAGGACATGTTAGAGCAA CATAAGTAAACTACTTGAAAATAGTTGTATATATTACCTAACTTCTAGTGTAGTACTGGTTCTAACAAGTAACAAGCAAGTTTTAAAATTTTAATGTTTTGGCTTTCATTAC TTCATCTTAATTATAGCTTTGTATGTTACTCTTATTTAATATAATCTCTATTGTATTGATTTCTTCTGTATTTACCTTTTGGATTTTGTAAAACAGAAGTTTAAGACCACAA GTTAGAAGAAAGGTCACATATTTCAAACACAACTAGATGGGGCTCTGAAAGATTTGTATCTCTGTGCTTGAACTTGAATGGCCTTAAACCTGTTTCAGCTTTAACAGTAGAA TTTTACTTGGGCAATATTTGCCCATTCTGGTGTAACTTATGTGACTCTAGTGCTTAACAGCTGCCGTTGAAGCTAATATTCAGTTCTGTANAGTTAGAATACCTTTTGTTGT TGAAGATGTGAATGAAGTATGCCATGTGCATTAACTGTTTGAATTCACTTTTGTGCCATTTTTGTAAAΓACAGTAGTTTTGCACAACCTCTCACAAATGTCTGTATTAATTT CACATACTTAAAAAGTAGATAATGTGCCAACCAGAAGCACAAGAGTTCCTACACAAAACTCTGTAAATCATTATAGCTTTTGTATAATAAGAGTAGTTTACAATCTCGGGCΓ TATAGAATACCAAACTGAAATCTTAGTTCAATCTGCCATAGACTTAAGCTTTTCATTTGTTACTAATAΓCCATGACATTCAGTGGCCTTGTGCAAATACGATATGTTGCTTA GGCATATCTTTTGTCCTATGCAGAACCTTTCATTTTGATTTTTATGAAAGTTGCAATTCATGTAATTTATATAAACTTTTTAAATGTAGAAACTTTTTACTTCCACACTCAG TTTTGGAGACCCTAGAATAAAAGGCTTCAATACTCTGCATTCCATGCCCTCTGCCACCTGCTTTTTTTTCCCCTTTGTTCTTTGACTCAAATGGTATTGAGCTGTTTGTTGΓ ATATGGAAGCATAGGTGTCTATATCCTTACTCTTTTATATAACACAATAATGGCGTTTTCCTTCTAATTTCTCAGTTGTTAACTTCTTTCTCTTTTTTTTTTAGGATAGGGC CTTGCTCTGTCACCTGAGCTCTAGTGCAGTAGTGCAATCACAGCTCACTGCAACCTTACTCCTAGGCTCAAGTTAACTATTCTTGATCCTTTATTATTACTAATATTCTACA ATTGTTTAAATAAAAGGAACTTTATAATGAAACGGTTCGGAATACTGGCTCAAGAACCTATGTCAAGATGAGCTGAATTTTGGTAAATTATTTTAGGAATTATGACAAGCTA ATTGAATTAGGCTTGTGACAATTAGAGTAATTTACATGACAGGTAAAACTCCTATTAAAAATGTTTAGATGTTTGCTTCTGTAGATGTCACTTTAGTAAAATACCAATTTAG TTTTACTTGTGGCTTATCTAGTTAGAACTTAGCAGACTTTACTGGGACAAGTTTACTGCTCTTGTAGGAGCTCCTCTCACAAGTAGTTGTAATGCTGTAGCATGATACTCAG GATCAGTAGCTTGAGATGTTACTATTTTTCTCTTCATCTTTGACTTGCAGAGAGCCTCCCGTTTTTGGATCCAGGCATCTTTTCTGAATCCTGGTTCCATCAGTATACCTGC TCTCCTATGACCCCAAATCATAGTCAATGGTGCCTCAAACATAGCACCTTAAGTTAAAGGCTGCCTAGTGCTCTGAGGAAAGCTTGCTGATTATCTTCCTGATCTACTCACC CCAAAAGGCAGAAAAGCAACACAGTCACTGCTGTGGTCATTTGTAATGTAAAGATCAGTTATATATATATATTTGTAATGAGAGCAAGTATATACTCATTATAGAATCAATT TAAGAAGTTTAAAATAACCCAGAGTAGAATTTCTATATCTAGTCTTGGTTTTTTTCATGAATATTTGCAAGTAATTACCATTAAATTCACACATGAAAGATTAATCTGAAAG ATCAGAGACCATGTTATTCCTGACCACGATAGAACTGCTCCTGTGGTTTGGGACAAGTAATAAAACAACTGCTTGAGTTTTGTTTGTAAAATACATAATTAATATTTGACCT ACCTCAAAATGTATTGAGGATCTGTGAAATGCTAAGTGCCCAAAATAAAATATTGCTGATTGTCTTTTTATTAAAAGTAAATTTCCTCATTAAGCCAACCTGCCTTCTGTAA GTCACAGTGCTTAAATCTCAGGATTTTTCATTAGGAGAGACCTGTCGTTAAGGATTTGTAGGTATAATTGCTTAGCCTCCATTATTGGTGCTTGGGATAGAGAGGTTTTAGA TTTTTGTTTTTTTTTTGTTCTGCCTCAAAGCTCAGTTTATTGAAGACATTTGTAAGCTATTGGATCATCACTTGAATCAAGATTTTGACTAGTGAGCTTAATTGTCCATΓTC TTACAATTTCAAAGTTACAGTCTCAGAAATGGTTAATTTTAATAACTGTCCTATCATAAATTAATGTTGGAATAAATTGAAGTTGTTGATAAATACTTCATGAAAACTAAAG TCTGAAATAAATTACTTGTTTTATGTCCAATAGCTACTACATTTGATAGAACAGTTTTGAGGAACATTTCATTCTTGAACGCAGCATCTGACATGGTTCTCAGCAAGTTGGA TAGTAAGGATTATTGGCTTGTTTCGATGAGTGGAAGCGGCATGTTTGTAGCATACAAGTTATTCAATAATCTTGTGCTGATGACCTAAAAATATGTCTTAACTATTCATCA GGAAAGCCTGGTGAAGCCTTTACTTGTTACTACTTCAACAGTTGGAATTAGTTGTCTTTTTACTTGATGAAACAAAACTATACCTCTGAATATTTATGGATACTTTTTACT AAATCAGGCTTGTGTTCTTAATCCAAATTAGTAAAGTTTTATGGAAGCTGAAATGTAATACAGTAGTCTCCCCTTATCTGTAAGAGATACATTCCAAGACCCCTAGTGGATG CCTGAAACCTCAGATAGTACTGAACCCTTTATCAACTATGTTTTTTCAGTCTGACAACCAAGGCGGCTACTAAGTGACTAAGGGGCAGGTAGTATACAGTGTGGATAAGCAG GACAAAGGGGTGATTCACATCCCAGGCAGGACAGAGCAGGAGATCATGAGATTTCATCACTCAGGATGGCTTGTGATTTATTTTATTTTATTCTTTTTTTTTTTTGAGATGG AGTCTCACTCTTGCCCAGGCTGGAGTGCAGTGGTGCGATCTTGGCTCACTGCAACCTCTGCCTCCTGGGTTCAAGCAGTTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGATT CAGGCGTCCGCCACCATGCCCAGCCAATTTTTGTACTTTTAGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCAGGTGATCCACTCGCCT
CGGCCTCCCAAAGTGCTGGGATTATAGGCATGCGCCACCATGCCCGGCCGGCTTATGAT'ITAAAACATGAATTGTTTATTTCTGGAATTTTCCACATAATATTTTTGGACCA
AGGTTGCCTCAGGTAACAAACTACAGAAAGTGAAATTGCAGATAAAGGGGATTACTGCTCCTCTGCTCTAAAATTGGTGTTTGGGTGATCAGAAGCAGGTAGCCAATGGGAA GAGCACTTCTGAGTGATAACTAAAGCAGTTTGGTGGCCTTTTCACATTCTCCAATGTTCAAACATATTTTCCACTTTCCATTTTCTCTTTCACCTCATTTTGCCTCTCTATC CCCCATCCCTGCTTATITCTTAAGCCCATTGATGGCACTCATTAAATTGTATTTAGGGCTAATGAGTCATTGTTCCTTAATATCGTTTTCAATATGCCACAATTTAGGACAC ATTTAAAATTTTTTAAAACAATATCCTAATCAATATTΏACTAATTTGAGCCACATTCCCAACTCTAACTCAGCACACACTGCCAGTCTTCCCCAATATCTGTCTCCTCTCAA TTCCCCACCACACCTTATAAAATTGTAATCAAAGATATCTCACTCTGTCATTGTTAATCTAAGAATAAAAACACTGACTTTAATACGGTTTTACTAAGTTTCAACCTTCTAA TTAGGTAGGCCTCTAGGTATTCTGCAGATCACTGCTGGTCTTGATAGCCATTAATATATGTTTGTATTATGTTATTTTTCAACTAAATCGCAGTTGGAAAAAAAACATATTT AATATTATGCCCTTGGATCTGTTACTGCATCACTAGCACTTGTGATGCAATAGAACACTTCGCCTGTACTGAAAGGGCCAAGAGTAAATGCCTTGTTT GTTTTTTTGTTTT GTTTTGTTTTGCTTTTTGTTAAAACATGTCTATAGAGTTGGCAGTTAATGCTGAATTTGTCAAATACCCCTTCCAAAATTATACTTGTATTTAAAAAATAAATGGATCTACC TAAAAAAAAAAAAAAAAAA
35
PU^HMMANMHGRFPDGTNGLHHHPAHR GMGQFPSPHHHQQQQPQHAFNALMGEHIHYGAGNMNAT^
SMQ QK NNQYFNHHPYPHNHYMPD HPAAGHQMNGTNQHFRDCNPKHSGGSSTPGGSGGSSTPGGSGSSSGGGAGSSNSGGGSGSGNMPASVAHVPAAMLPPNVIDTDFID
EEV MSLVIE GLDRIKELPELWLGQNEFDFMTDPVCKQQPSRVSC
36
GATCAAGTTAACATGAGGCCAGTAGGAGAAGCCCTAATCCAAAAGGACTAGAGTCCTTGTCAAAAGGGGAACTTTGGACACAGAGATACACATACAGGGGGGCGGGGGGTGG AAAACGTCACATGAAGATGAAGGTGGGGATCAGTGTGATGCATCTACAAGTCAAGGGACACCAAAGATTGCCGGGAAACCACCAAAAGCCAGGAAAGAGACACGGAATAGAT TCTCTCTCACGGTCTTCAGAACCAACCCTGCCAACAACTTGGCCTTGTACCTCTAGCCTCCAGAACTGTGAGACAATAATGTTTTGTTGΓTTAAAGCTTGATCAGCCTΓAAG TTTGTATTAGACTGGTGCAAAAGTAATTACAGTTTTCGCCATTGCTTTCAATGGCAAAAATCACAATTACTTTTGCACCAACCTAAATAGTACTGTGTTATGGCAGCTCTGG GAAATGAATACAACCATTCAGTGCTGTGAGGGCCACAGACAGATCACTTGCTCGCTCACCCAGGTTCACGGGATAAACCCTGGTTATACGGAACTTCTGGGAGCCCTGGGTT ACTGTAAGTGCCCCCTAACTGGACTCCCTGTTTCCTGTCTTAC TTCTCTAACCATTCTCCACAGCACTGCCCTGATCTTTCTAAAATCCAAATCTTTCCTATCTCATGGCT TCACAAQCTTTTACCTGCCTCCCAATGTCTTTGGGATACAGCAAAATTTCTCAGCTTGAGGCCACAATGCCCTTGGCATCCGGCCCCAGCATATTTCTCCAACCTTATTTCT CTCATCTTTGCATTCACTCCCTAGCCATACATTTTCTACCCCACTCCTAATGGGACCAAACTTCCATTCATCCTGAGGCCTCCACTTAGTCACCATCTCCACCGGAAAGCCΓ TCCCAAAGCACCCAGGAGGGGGGTAGGTGTCCCTCCTATGTGCTCTCCAAAGCCCTTTCCTTCAATGCCTTTGTGGCATTTATCACAGTGTGTTCAAGGCCTGTTTGTCAGT TTTCTCCCTGTGACCATGAGTTCCTATCTTGTTTGTATCTCCAGGCACCAAGAAAGCACTTGGCACTTGGAGGACATTCAGTGGACGGATGAGAATAAATGAACAAAGCATG CCATGTTCCAACCAGCTGGTCCCAGAACTATTTTGTTCTCCTTTAAGGGATGGGGGATGGGCAGGTGACCTTTCCAGGGATTTCCCAATAGTAGGTAGAACCACTGGAGCTG GATGGAGCTCCACCTTTCCTTAGTGGTTGCAAGAGGAATTTAGATTAGACATTCAAAAGCTGTTTCTTGTGTCGAAAGACACTTGCAGTACAAAGAAGGGAAAGTAAACAAΓ CCCGCGATTTTTCAGGTTGGGTTTTACCAATATTTTAGAATCTGTTTTTTTATAGGAAGTGGCCCCTTCAGGTATCCAAGCCTCTGATACGGTAAACTGCATGTCCTGACCT ACAGGTAAAGGTGGTGGGAGGTTAGGAGAATAGGGAATTGTTGCAACTAACAATGCAA'ΓGTGTCATGTGCCCGTATCTCTAAAAAGTAAATATTTTTGAGGTTTAAAAATΓA TTGCCTGCACGGTTTGCCGGAGAGCCTGGAAGAGGAAAGAAGACAAGACACAAAGTAACAACATTTACAAAAATATGCCTGACTAGGAAAAGACAGAGGGGTCATAGACGA AAATAATCAGGATTGGGTCTCTTTTGCAAATTCCTGAACGGGGAAATGTATCAGAATTTCCAGTCCTCAAGAAACAGGGCCTTTAAAAGTCTTGTGTGCAAGAAGGGGGAAA AAGACGAGGGGGGGGCGGGGAGGCGGACTCGCTCTTCGCAGCAGGAAGTCTTCAATGGCTATCGAGTTATGAAGAAACAACTGCCCAGAAGTCCTTATTCGGAGCGCTAAAC TCGATTTTACCACATAAAGAGCAATGTAAAAGCTCAGAACAGCCCCATCATGGTGTTGGGGAAACAACTCGGCTTCCCCATGTGAGAAAGCCAGAGAGCTCCGACTTGGTAG TAGCCCAGACCTGTGTTAGGGGTTTTATTTGCAAGTCAATGAACCAAACGGGCGACCAGGCTCGTTGTGCCGCGTTGTGGAAGCAAGGTTATTATTATCGCCCATTGCCCCA CTGAACAATTTCACTGAAAAGGAAGAGTCCCAGCCGTGTGTGTGCGCGTGGTGCCATACGGGACGTGCAGCTACGTGCCCACCTCCAGAACGACTTTATTTACAAAGCGATT ACCACGTTATCTATTTGTTTTCCTTTTCCAGCAAGAGCAGCCTTACTCAGCCCTCAAATTTCTTAATTACAAACCCGTTTGCTTCTAAATCAACCCCAAACCGTCAGGCAGA GCCCGGAGGGAGGCTCTGCAAGTTTGTACACACCCCCACCTCCCGGATCCAGGGCAACAGCAGAAGCAAGTAACTGTGTATGTGCAAAAAGGTGGATCTGGGGACGAGGATC GCTGAGTTTGTTTACAGAGCAGAGACGCCTCAGCTCGGATGCCAAAGCTACCAAGAGCTGCAAACGCAAACTTAGCAGAAGCACACGTACCCCGGGAGCGGCAGGCGGGCCC GAAAGCGCGGACTGGAATTCCAGGGCGCGGGAGCGGGGGTGGCCGGGCCCTCGAGCGCGCTCCGTCCACCTGCAGCGGCTGCCCCTCCCCGCCCCCAGCTCCTGTCCTTGAA AGGAGTGGAGGAAAAAAATGCATCTACAAGCGGTGATCTAGAGTAGGTCTACCCACTGCCCGTATGAAAACACAAAGGCACAGCCTAGGAAGGCGCGCTCAGGAAAGGGCGC ATTATTTGTCCGGGTCTTTAAAACCCAACTCGAGGAAGCACAGCCATTCTTCGCTGCCTGTGGAAGCTTTTGCAAAACCGGGGAGGCACAAGGGCACTCTGGAGGGCGGGGG GCGCTGGGCGAGTCCCCTTT'RCCCGTAGAGAGCGGGGCAGATCGCTAGGTGAACCGAGTGAGAAAGCTGGGGGTGGGGTAGATCCAGCCTGAGGGGGGCGGTGAGCTCTCCT CGTGGCTATCCCGGCAGGCTCTACCTTCGGGCGGGGCGGCAGGGGAGGATTTTCCCCCTGCCTCGGGGGTGGCTGAGCCAACCTCGCGTTTCTGGGCCGGGAAGAAACCAGA GTCGGGGGGCGACGGGGCGACTGGGCGGCCCCCGGGCCCCGCAGCCTCTGCAGCACGTGCCGCGGGCGGCGGGGACGCGGCTCCGGGACCCGGTCCAGGGTGTTCGCGGTGT TCCGGAATCCGCGTCTTGGCGCCGCCCGCCCTGGAGGCTCTCGCTCCGCCTTTCCGAAATGCCTATATTAACTGTGGCCAAAGCCCTAAGAAACACAGCTCATTGTTGGCAG CTGCCGGGCGGTCCTGCCGAGCTGTGAGGGCAACGGAGGGGAAATAAAAGGGAACGGCTCCGAATCTGCCCCAGCGGCCGCTGCGAGACCTCGGCGCCGACATCGCGACAGC GAAGCGCTTTGCACGCCAGGAAGGTCCCCTCTATGTGCTGCTGAGCCGGTCCTGGACGCGACGAGCCCGCCCTCGGTCTTCGGAGCAGAAATCGCAAAAACGGAAGGTAAGC GCGACGGGCGAAGCTGGCTGGGGCTCTTGCCAGCCCAGTCCTCCGAGGGCAGGGTTTGCCCGGAGGAAGAACGTGAGGCGAAACTGGGGAATAACAACAGGATGTGCTACAA CAGGATGAGGAGGGCTGATTTAATGCCTGAAGTTCGCAGCAGGGCTACGGGGCACTTCCTTTTATAGGCCACTTCGGGGAGCAAAGGGGGTGTGGGCTCGGGTCCCCCCGCC CGATCGCAGGGGAAGGGGCTGTTTGTGCAGCGTCCGGCTGTGTTATGAGTGGTAGCTCTTCCGTGGTGGCTAGCCCGGGTGCACAGGCTGTTAGTGGGATCTTGGGGGTGGT GGTTCGCAGCCGACGTGCGCCCGGGAATCCTGGGGGGCAGAGGCGAGCAAAAGTGGGGTGCGCTGTGGTGGGCGACACGTGTGGCGCGGGTCTCATTATCTGCCCTTTTCAC TTCCAGGACTGGAAATGGCAGACCATATGATGGCCATGAACCACGGGCGCTTCCCCGACGGCACCAATGGGCTGCACCATCACCCTGCCCACCGCATGGGCATGGGGCAGTT CCCGAGCCCCCATCACCACCAGCAGCAGCAGCCCCAGCACGCCTTCAACGCCCTAATGGGCGAGCACATACACTACGGCGCGGGCAACATGAATGCCACGAGCGGCATCAGG CATGCGATGGGGCCGGGGACTGTGAACGGAGGGCACCCCCCGAGCGCGCTGGCCCCCGCGGCCΛGGTTTAACAACTCCCAGTTCATGGGTCCCCCGGTGGCCAGCCAGGGAG GCTCCCTGCCGGCCAGCATGCAGCTGCAGAAGCTCAACAACCAGTATTTCAACCATCACCCCTACCCCCACAACCACTACATGCCGGATTTGCACCCTGCTGCAGGCCACCA GATGAACGGGACAAACCAGCACTTCCGAGATTGCAACCCCAAGCACAGCGGCGGCAGCAGCACCCCCGGCGGCTCGGGCGGCAGCAGCACCCCCGGCGGCTCTGGCAGCAGC TCGGGCGGCGGCGCGGGCAGCAGCAACAGCGGCGGCGGCAGCGGCAGCGGCAACATGCCCGCCTCCGTGGCCCACGTCCCCGCTGCAATGCTGCCGCCCAATGTCATAGACA CTGATTTCATCGACGAGGAAGTTCTTATGTCCTTGGTGATAGAAATGGGTTTGGACCGCATCAAGGAGCTGCCCGAACTCTGGCTGGGGCAAAACGAGTTTGATTTTATGAC GGACTTCGTGTGCAAACAGCAGCCCAGCAGAGTGAGCTGTTGACTCGATCGAAACCCCGGCGAAAGAAATCAAACCCCCAACTTCTTCGGCGTGAATTAAAAGAAACATTCC CTTAGACACAGTATCTCACTTTTCAGATCTTGAAAGGTTTGAGAACTTGGAAACAAAGTAAACTATAAACTTGTACAAATTGGTTTTAAAAAAAATTGCTGCCACTTTTTTT TCCTGTTTTTGTTTCGTTTTTGTAGCCTTGACATTCACCCACCTCCCTTATGTAGTTGAAATATCTAGCTAACTTGGTCTTTTTCGTTGTTTGTTTTTACTCCTTTCCCTCA CTTTCTCCAGTGCTCAACTGTTAGATATTAATCTTGGCAAACTGCTTAATCTTGTGGATTTTGTAGATGGTTTCAAATGACTGAACTGCATTCAGATTTACGAGTGAAAGGA AAAATTGCATTAGTTGGTTGCATGAACTTCGAAGGGCAGATATTACTGCACAAACTGCCATCTCGCTTCATTTTTTTAACTATGCATTTGAGTACAGACTAATTTTTAAAAT ATGCTAAACTGGAAGATTAAACAGATGTGGGCCAAACTGTTCTGGATCAGGAAAGTCATACTGTTCACTTTCAAGTTGGCTGTCCCCCCCGCCGCCCCCCCCCACCCCCATA TGTACAGATGATAATAGGGTGTGGAATGTCGTCAGTGGCAAACATTTCACAGATTTTTATTTTGTTTCTGTCTTCAACATTTTTGACACTGTGCTAATAGTTATATTCAGTA CATGAAAAGATACTACTGTGTTGAAAGCCTTTTAGGAAATTTTGACAGTATTTTTGTACAAAACATTTTTTTGAAAAAATACTTGTTAATTTATTCTATTTTAATTTGCCAA TGTCAATAAAAAGTTAAGAAATAACTTGTTTTCTAGAAGTCATTTGGGGGTGGTTGTTCCCTTTGGTGGCTTTTTTCCCCCCGTCTTTGAGTTGAACACTATTGATGAGAGT AAGCATTCCAAAGGATAAATTACAGGACACTAAAACAGGTCATGATGAGCTTAAGCGGAGAGCAGGATTTAACATAATTGGCATAATGCTTCATTGTTATCATTGTAACATG
ATTATCTTTTTCAATGGGCAGGAGGCAAAAAAAATCAAGTGTTTCTGTTTATACCTGATTCAACTACTTAAATAGAGGTAGATTGGAATAATACACTGATTGATTGATGGGT GGCATTAAATATAAATCTACCTTTATCTCCAGTGATGAGAGTTTTATTTCTCAGCAAAAGTGCCAAGGATAGGTACATATTTTCTAGCGTAATCTCTGAAACATGTCTGACT GGTTTATAGTTCTGAGAAGAAGAGCGAAATCCCCCTTGAAGCCTTTGTCCCA
37
MSRSPDAKEDPVECPLCMEPLEIDDINFFPCTCGYQICRFC HRIRTDENGLCPACRKPYPEDPAVYKPLSQEELQRIKNEKKQKQNERKQKISENRKH ASVRWQKNLVF
WG SQRIΛωPEVLKRPEYFGKFGKIHKTVINNSTSYAGSQ^PSASAYOTYIRSEDALRAIQCVN VVVDGRTLKLASL^
KEEMQAGKHQEYEQK QELYKLNPNFLQLSTGSVDKNKNKVTPLQRYDTPIDKPSDSLSIGNGDNSQQISNSDTPSPPPG SKSNPVIPISSSNHSARSPFEGAVTESQS
FSDNFRHPNPIPSG PPFPSSHRHPV GLQHQNHRASSHQKQSQYHP QTGKQLLALVLLNNQRDD GFDPFDVTRKALAD IEKELSVQDQPSLSPTSLQNSSSHTTTAKG
PGSGFLHPAAATNANS NS1FSV PQRFPQFQQHRAVYNSFSFPGQAARYPWMAFPRNSIMHLNHTA PTSNSNF DI.N PPQHNTG GGIPVAGIPASSGNSLDS QDDNP
PHW KSLQALTEMDGPSAAPSQTHHSAPFSTQIPLHRASWNPYPPPSNPSSFHSPPPGFQTAFRPPSKTPTDLLQSSTLDRH
38
TGGTGGCCCGTCTGGCTGTGGAACCCACCGAAAGCTGAGAGTCTCTCTCTCAGCCGTAAAGGTCGGACTCGCTGAAGCAATCAGGCCCGGTTTTGAAGAGTTTTTTCCCCGA
CGCTCGTTCGGTGGTTTCTTGTGAGGACGCGGCAGCCCGTGGAGTCGGCTGAGGGAAAAGCGAGGCAAGGCAGGCGGGTCGTCAAAGTCCTACATTTTAGCTTTCAGTGCTG
AACTTCCTTCTCCCTTAAATTATTATAAACTTTTGCTGCTGTTTAATAAACGTGAAGATGTCTCGCAGTCCTGATGCGAAGGAAGACCCTGTGGAGTGCCCTCTTTGCATGG
AGCCCTTGGAGATAGATGATATCAACTTTTTCCCTTGCACCTGTGGCTACCAGATTTGCCGATTTTGTTGGCATCGAATTCGCACTGATGAAAATGGGCTTTGTCCTGCATG
TAGAAAGCCATATCCAGAAGACCCAGCAGTTTATAAACCACTCTCCCAGGAAGAGCTGCAAAGGATAAAGAATGAGAAAAAACAGAAACAAAATGAGAGAAAACAGAAAATA
TCAGAAAATCGCAAACATTTGGCTAGTGTACGTGTCGTACAAAAAAACCTCGTCTTTGTTGTAGGTTTATCTCAGCGCCTAGCAGACCCAGAGGTTTTAAAACGACCAGAAT
ATTTTGGGAAGTTTGGTAAAATACATAAAGTTGTCATCAATAATAGCACATCATATGCAGGCTCACAGGGTCCAAGTGCCAGTGCTTATGTAACCTATATCCGGTCAGAAGA CGCTCTCAGAGCCATACAGTGTGTCAACAATGTGGTAGTAGATGGCAGAACACTTAAGGCATCTCTAGGTACAACAAAATACTGCAGTTACTTCTTAAAGAATATGCAGTGT
CCAAAACCTGACTGCATGTATCTTCATGAATTGGGGGATGAGGCGGCCAGCTTCACAAAAGAGGAAATGCAGGCGGGTAAACACCAAGAATATGAACAGAAGCTACTTCAAG
AATTATATAAATTAAATCCCAATTTTCTTCAGCTATCTACGGGTTCAGTTGATAAAAATAAGAACAAAGTGACACCACTGCAGAGGTACGATACCCCCATTGACAAACCTTC
AGATTCTCTCAGTATAGGGAACGGTGATAATTCCCAGCAGATATCTAACAGTGATACGCCTTCACCACCACCTGGTTTGTCAAAATCCAATCCAGTCATCCCCATCAGTTCA
TCCAATCACAGTGCACGGTCCCCTTTTGAAGGGGCAGTAACAGAGTCACAGTCGTTATTCTCAGACAATTTTCGCCATCCCAACCCTATCCCAAGTGGGCTTCCTCCTTTTC
CCAGCTCCCACAGACATCCAGTGACTGGCCTACAGCACCAGAACCACAGAGCCTCTTCACATCAGAAACAATCCCAGTATCATCCTCTACAGACTGGCAAGCAGCTTTTGGC
TTTGGTTCTTCTAAACAACCAGAGGGATGACTTGGGTTTTGATCCCTTCGATGTCACTCGAAAAGCCTTAGCAGACCTGATTGAGAAGGAACTGTCCGTTCAAGACCAACCT
TCCCTTTCGCCCACATCTCTTCAGAACTCCTCTTCACACACTACAACCGCCAAAGGTCCAGGCTCTGGATTCCTGCATCCTGCTGCAGCTACAAATGCCAATTCTCTCAATA
GTACCTTTTCAGTCTTGCCCCAGAGGTTCCCTCAATTTCAGCAGCACCGAGCGGTTTATAATTCATTCAGTTTTCCAGGCCAGGCAGCCCGCTATCCTTGGATGGCCTTTCC
ACGCAATAGCATCATGCACTTGAACCACACAGCAAACCCCACCTCAAATAGTAATTTCTTGGACTTGAATCTCCCGCCACAGCACAACACAGGTCTGGGAGGGATCCCTGTA
GCAGGTATTCCAGCGTCTTCAGGAAACAGTTTAGACTCTCTTCAAGATGACAATCCTCCACACTGGCTAAAATCCCTTCAGGCCCTCACAGAGATGGACGGCCCCAGCGCTG
CTCCATCACAGACCCACCACAGCGCCCCCTTCAGCACACAGATCCCGCTGCACAGAGCCAGTTGGAATCCCTACCCTCCTCCTTCAAACCCTTCCAGCTTCCACTCCCCACC
CCCAGGCTTTCAGACGGCCTTCAGACCCCCCAGCAAAACCCCCACAGATTTACTACAGAGTTCAACACTGGACCGCCAT'IAGGCAAAGAGGAGCAACCATTAGAAAATGCAG
GATTTGTCCCACTCTGTTTTCTCCCTCTCAGCCCACCACCCACAGCTCCCTTCTCATCTCTTATGTTCTGAAGAATCCAGTACCTGATCAATTTTTTTTCTCCCTAACCCCA
GATGCAATGCGATCACAGGGTCATTACCATCTCTTTATTAATTGTAAAAATTTTTGTTGATCCAGCATTTGAGTGACACTGTTGAATGTTTCTAAAAATGCCTTTTTAAGGA
GAGAAAAAAAAATCAAAGGGCAGTCTCAATACTTAGAAAATTATTGTTTGTCTGTTGCGCATAATAATGACATAATCTGCTTAGCAGAAAATGACGATTAATCTATAGGAAA
GCTCAAGTAAATGCATTATCAACTGCAGAAGTTTGAAAACCAGGTTCATTTACGTGAGATTGCTAAATGCATGGGGGAAAGCAGTGGTCCTAGCATCCATCTTGTATTCAGC
TTATCATTATTGCAGGGAAAATGCTTTTAATITAAATTAATTTTTAATTCTTTTGGCAAGTTGATGGCAAGGACTTGATTGTGTCATTAAGCAAAAGAATGTATTGGAAGTT
GATGGAAAGACAAATTCATCTGTAGTAGTAACTGGCCGATTGCTAAAGAGTTCATAAGGAGGTGAGAAGTAATTTTTTTAAAGGAGAAAAATTTTTTGGCTTTAGATTTAAA
GTAAATTGAAATGTTTTAAAGAAAAAAGTATTCACAGATTTAATACCTATTAATAATATAAGAGCTGAAATGTAAGTCATTTCTTCAGTCCTTCTCCTCTGTCGGAATCTTT
TTTGTTTTACCATAAATTCACCTGACGAGGGCACTCTGAGATAGCACTGCTCTGGGGCCATCTGATCACCATCGGGAGCAAATCTCTGACCTCCTTGCCTGCAGCTTTTACT
TAACCCTGTAGTTTCTGGACGTTTGTGCAGTATTGAAAAGACAGGAGAAAAGCAAACAGAAACCTGGTTATAACCTGACGCTAAAACTAAAAACAAGGAAATGTACCTCTTT
CTTCAGAATTAAAACTAAAATCTTAAATAAAACAGAAAACTTGATGATG
39
M ILILGIF F CSTPAWAKEKHYYIGIIETTWDYASDHGEKKLIΞVDTEHSNIYLQNGPDRIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKN
ASRPYTFHSHGITYYKEHEGAIYPDNTTDFQRADDKVYPGEQYTYMLLATEEQSPGEGDGNCVTRIYHSHIDAPKDIASGLIGP IICKKDSLDKEKEKHIDREFWMFSW
DENFS YLEDNIKTYCSEPEKVDKDNEDFQESNRI«SVNGYTFGS PGLSMCAEDRVKWYLFGMGNEVDVHAAFFHGQALTNKNYRIDTINLFPATLFDAYMVAQNPGEWM
SCQN NHLKAG QAFFQVQECNKSSSKDNIRGKHVRHYYIAAEEIIWNYAPSGIDIFTKENTjTAPGSDSAVFFEQGTTRIGGSY KLVYREYTDASFTNRKERGPEEEHIiGI
LGPVIWAEVGDTIRVTFHNKGAYP SIEPIGVRFNKNNEGTYYSPNYNPQSRSVPPSASHVAPTETFTYE TVPKEVGPTNADPVC AKMYYSAVDPTKDIFTGLIGPMKIC
KKGSLHANGRQKDVDKEFYLFPTVFDENESLLLEDNIRMFTTAPDQVDKEDEDFQESNK HSMNGFMYGNQPGLTNCKGDSWWYLFSAGNEADVHGIYFSGNTYLWRGERR
DTANLFPQTSLTLHMWPDTEGTFNVECLTTDHYTGGMKQKYTVNQCRRQSEDSTPYLGERTYYIAAVEVEWDYSPQREWEKE HHLQEQNVSNAFLDKGEPYIGSKYKKWY Q TDSTFRVPVERKAEEEHLσI GPQLHAD GDK KIIFKIMATRPYSIHAHGVQ ESSTVTPTLPGETLTYVWKI ERSGAGTEDSACIP AYYST DQVKDLYSGLIGP
LIVCRRPYLKVFNPRRK EFAL FLVFDENES Y DDNIKTYSDHPEKVNKDDEEFIESNKMHAINGR FGNLQGLTMHVGDEVNWYLMGMGNEID HTVHFHGHSFQYKHR
GVYSSDVFDIFPGTYQTLEMFPRTPGI LLHCHV DHIHAGMETTYTVLQNEDTKSG
40
ATGAAGATTTTGATACTTGGTATTTTTCTGTTTTTATGTAGTACCCCAGCCTGGGCGAAAGAAAAGCATTATTACATTGGAATTATTGAAACGACTTGGGA'ITATGCCTCTG
ACCATGGGGAAAAGAAACTTATTTCTGTTGACACGGAACATTCCAATATCTATCTTCAAAATGGCCCAGATAGAATTGGGAGACTATATAAGAAGGCCCTTTATCTTCAGTA
CACAGATGAAACCTTTAGGACAACTATAGAAAAACCGGTCTGGCTTGGGTTTTTAGGCCCTATTATCAAAGCTGAAACTGGAGATAAAGTTTATGTACACT"IAAAAAACCTT
GCCTCTAGGCCCTACACCTTTCATTCACATGGAATAACTTACTATAAGGAACATGAGGGGGCCATCTACCCTGATAACACCACAGATTTTCAAAGAGCAGATGACAAAGTAT
ATCCAGGAGAGCAGTATACATACATGTTGCTTGCCACTGAAGAACAAAGTCCTGGGGAAGGAGATGGCAATTGTGTGACTAGGATTTACCATTCCCACATTGATGCTCCAAA
AGATATTGCCTCAGGACTCATCGGACCTTTAATAATCTGTAAAAAAGATTCTCTAGATAAAGAAAAAGAAAAACATATTGACCGAGAATTTGTGGTGATGTTTTCTGTGGTG
GATGAAAATTTCAGCTGGTACCTAGAAGACAACATTAAAACCTACTGCTCAGAACCAGAGAAAGTTGACAAAGACAACGAAGACTTCCAGGAGAGTAACAGAATGTATTCTG
TGAATGGATACACTTTTGGAAGTCTCCCAGGACTCTCCATGTGTGCTGAAGACAGAGTAAAATGGTACCTTTTTGGTATGGGTAATGAAGTTGATGTGCACGCAGCTTTCTT
TCACGGGCAAGCACTGACTAACAAGAACTACCGTATTGACACAATCAACCTCTTTCCTGCTACCCTGTTTGATGCTTATATGGTGGCCCAGAACCCTGGAGAATGGATGCTC
AGCTGTCAGAATCTAAACCATCTGAAAGCCGGTTTGCAAGCCTTTTTCCAGGTCCAGGAGTGTAACAAGTCTTCATCAAAGGATAATATCCGTGGGAAGCATGTTAGACACT
ACTACATTGCCGCTGAGGAAATCATCTGGAACTATGCTCCCTCTGGTATAGACATCTTCACTAAAGAAAACTTAACAGCACCTGGAAGTGACTCAGCGGTGTTTTTTGAACA
AGGTACCACAAGAATTGGAGGCTCTTATAAAAAGCTGGTTTATCGTGAGTACACAGATGCCTCCTTCACAAATCGAAAGGAGAGAGGCCCTGAAGAAGAGCATCTTGGCATC
CTGGGTCCTGTCATTTGGGCAGAGGTGGGAGACACCATCAGAGTAACCTTCCATAACAAAGGAGCATATCCCCTCAGTATTGAGCCGATTGGGGTGAGATTCAATAAGAACA
ACGAGGGCACATACTATTCCCCAAATTACAACCCCCAGAGCAGAAGTGTGCCTCCTTCAGCCTCCCATGTGGCACCCACAGAAACATTCACCTATGAATGGACTGTCCCCAA
AGAAGTAGGACCCACTAATGCAGATCCTGTGTGTCTAGCTAAGATGTATTATTCTGCTGTGGATCCCACTAAAGATATATTCACTGGGCTTATTGGGCCAATGAAAATATGC
AAGAAAGGAAGTTTACATGCAAATGGGAGACAGAAAGATGTAGACAAGGAATTCTATTTGTTTCCTACAGTATTTGATGAGAATGAGAGTTTACTCCTGGAAGATAATATTA
GAATGTTTACAACTGCACCTGATCAGGTGGATAAGGAAGATGAAGACTTTCAGGAATCTAATAAAATGCACTCCATGAATGGATTCATGTATGGGAATCAGCCGGGTCTCAC
TATGTGCAAAGGAGATTCGGTCGTGTGGTACTTATTCAGCGCCGGAAATGAGGCCGATGTACATGGAATATACTTTTCAGGAAACACATATCTGTGGAGAGGAGAACGGAGA
GACACAGCAAACCTCTTCCCTCAAACAAGTCTTACGCTCCACATGTGGCCTGACACAGAGGGGACTTTTAATGTTGAATGCCTTACAACTGATCATTACACAGGCGGCATGA
AGCAAAAATATACTGTGAACCAATGCAGGCGGCAGTCTGAGGATTCCACCTTCTACCTGGGAGAGAGGACATACTATATCGCAGCAGTGGAGGTGGAATGGGATTATTCCCC
ACAAAGGGAGTGGGAAAAGGAGCTGCATCATTTACAAGAGCAGAATGTTTCAAATGCATTTTTAGATAAGGGAGAGTTTTACATAGGCTCAAAGTACAAGAAAGTTGTGTAT
CGGCAGTATACTGATAGCACATTCCGTGTTCCAGTGGAGAGAAAAGCTGAAGAAGAACATCTGGGAATTCTAGGTCCACAACTTCATGCAGATGTTGGAGACAAAGTCAAAA
TTATCTTTAAAAACATGGCCACAAGGCCCTACTCAATACATGCCCATGGGGTACAAACAGAGAGTTCTACAGTTACTCCAACATTACCAGGTGAAACTCTCACTTACGTATG
GAAAATCCCAGAAAGATCTGGAGCTGGAACAGAGGATTCTGCTTGTATTCCATGGGCTTATTATTCAACTGTGGATCAAGTTAAGGACCTCTACAGTGGATTAATTGGCCCC
CTGATTGTTTGTCGAAGACCTTACT GAAAGTATTCAATCCCAGAAGGAAGCTGGAATTTGCCCTTCTGTTTCTAGTTTTTGATGAGAATGAATCTTGGTACTTAGATGACA
ACATCΛAAACATACTCTGATCACCCCGAGAAAGTAAACAAAGATGATGAGGAATTCATAGAAAGCAATAAAATGCATGCTATTAATGGAAGAATGTTTGGAAACCTACAAGG
CCTCACAATGCACGTGGGAGATGAAGTCAACTGGTATCTGATGGGAATGGGCAATGAAATAGACTTACACACTGTACATTTTCACGGCCATAGCTTCCAATACAAGCACAGG
GGAGTTTATAGTTCTGATGTCTTTGACATTTTCCCTGGAACATACCAAACCCTAGAAATGTTTCCAAGAACACCTGGAATTTGGTTACTCCACTGCCATGTGACCGACCACA
TTCATGCTGGAATGGAAACCACTTACACCGTTCTACAAAATGAAGACACCAAATCTGGCTGAATGAAATAAATTGGTGATAAGTGGAAAAAAGAGAAAAACCAATGATTCAT
AACAATGTATGTGAAAGTGTAAAATAGAATGTTACTTTGGAATGACTATAAACATTAAAAGAGACTGGAGCAT
41
^WFESVVVDV NRFLGDYVVD DTSQ SLGIWKGAVALKN QIKENALSQ-,DVPFK KVGHIGNLKLIIPWKN YTQPVEAV EEI LLIVPSSRIK DPLKEEKQLMEAKQ
QELKKIEEAKQKVVDQEQH PEKQDTFAEKLVTQIIKNLQVKISSIHIRYEDDITNRDKPLSFGIS QN SMQTTDQY VPCLHDETEKLVRKLIR DNLFAYWNVKSQMFY SDYDNSLDDLKNGIVNEWIVPEGYDFVFRPISANAKLIVMNRRSDFDFSAPKINLEIELHNIAIEFNKPQYFSIME ESVD IMAQN PYRKFKPDVPLHHHARE WAYAIH
GV EVNVCPR M S KHIRKHRQKVKQYKELYKKKLTSKKPPGELIIIVSLEE EKT DVFNITIARQTAEVEVKKAGYKIYKEGVKDPEDNKGWFSWLWSWSEQNTNEQQPD
VQPET EEMLTPEEKA LYEAIGYSETAVDPT KTFEALKFFVHLIKSMSIVLRENHQKPELVDIVIEEFSTLIVQRPGAQAIKFETKIDSFHITGLPDNSEKPR LSSLIDD
AMS FQITFEINPLDETVSQRCIIEAEPLEIIYDARTVNSIVEPFRPPKEVH AQLTAAT TKLEEFRSKTATG LYIIETQKVLDLKINLKASYIIVPQDGIFSPTSNLL D GHLKVTΕKSRSELPD KQGEANL EI^C)RAYDSFDIQLTS QL SRVGDNWREA KLS STQHIL P^MP LELSKA^WFMDVRMP FKIYGKLPLIS RISDKI L,QG
IME IESIPKPEPVTEVSAPVKSFQIQTSTSLGTSQISQKIIP LELPSVSEDDSEEEFFDAPCSP EEPLQFPTGVKSIRTRKLQKQDCSVNMTTFKIRFEVPKVLIEFYH VGDCE SVVEILVLGI^AEIEIRTYDLKANAFLKEFCLKCPEYLDENKKPVYLVTTLDOT
YLHNI PQSEEKSAPVSTTETEDKGDVIKKLA K STNEDIITLQILAE SC QIFIQDQKCNISEIKIEGLDSENIMRPSETEINAKLRNIIVLDSDITAIYKKAVYITGK
EVFSFK1WSYMDATAGSAYTD IVVDIQVN IVGCIE VF TKFLYSI^AFID FQAAKQAIΛEATVQAAG^1AATGVKEIAQRSSRMALDINIKAP VVIPQSPVSENVFVA
DFGLITMTNTFHMITESQSSPPPVIDLITIKLSE RLYRSRFINDAYQEVLDL LPIJQ EVVVEP-KILC EWYQEVPCFNVNAQLKPMEFI SQEDIT'RIFKTLHGNI YEKD
GSASPAVTKDQYSATSGVTTNASHHSGGATVVTAAVVEVHSRAL VKTTLNISFKTDDLT^
I DDKRPHVKKATP IIGLTVGFDKKD^-ΦIK KVFJX3CVTDAVFQEM ICAS EF QTVANVFLEAYTTGTAVETS QTWTAKEEVPTQESVKWEIN IIK PEIVFVAD
MΓKNDAPALVITTQCEICYKGN ENSTMTAAIKDLQVRACPFLPVKRKGKITTV QPCDLFYQTTQKGTDPQVIDNSVKS TLKVSPVIINTNITITΞALYTTKETIPEETA SSTAHLWEKKDTKT KMWFLEESNETEKIAPTTELVPKGEMIKMNIDSIFIVLEAGIGHRTVPMLLAKSRFSGEGKNWSSLINLHCQLELEVHYYNEMPGV EPLLEPLEID QΓEDFRP NLGIKMKKKAKMAIVESDPEEENYKVPEYKTVISFHSKDQLNITLSKCG VMLNN VKAFTEAATGSSADFVKDLAPFMI NSLGLTISVSPSDSFSV NIPMA KSYVLKNGES SMDYIRTKDNDHFNAMTSLSSKLFFILLTPVNHSTADKIPLTKVGRRLYTVRHRESGVERSIVCQIDTVEGSKKVTIRSPVQIRNHFSVP SVYEGDTLLG TASPENEFNIPLGSYRSFIFLKPEDENYQMCEGIDFEEIIKNDGA KKKCRSKNPSKESFLINIVPEKDNLTS SVYSEDGWDLPYIMHL PPILLRNLLPYKIAYYIEGI
ENSVFT SEGHSAQICTAQ GKAPJHLKLLDYLNHDWKSEYHIKPNQCDISFVSFTCVTEMEKTDLDIAVHMTYNTGQTVVAFHSPYW VNKTGRMLQYKADGIHRKHPPNY K PV FSFQPNHFFNNN VQ MVTDSELSNQFSIDTVGSHGAVKCKGLiα4DYQVGVTIDLSSFNITRIVTFTPFYMIKNKSKYHISVAEEGNDK LS DLEQCIPFWPEYAS S LIQVERSEDPPKRIYFNKQENCILLR DNELGGIIAEVN AEHSTVITFLDYHDGAATFLLINHTKHE VQYNQSS SEIEDSLPPGKAVFYTWADPVGSRRLK RCRK SHGEVTQKDDM^Φ1PIDLGE TI LVSFFEG QRIILFTEDPRVFKVT ESEKAELAEQEIAVALQDVGISLVNNYTKQEVAYIGITSSDVV ETKPKKKARWKPMSVKH EK _,EREFKEYTESSPSEDKVIQ DTNVPVR TPTGHNMKILQPHVIA RRNYLPALKVEYNTSAHQSSFRIQIYRIQIQNQIHGAVFPFVFYPVKPPKSVTMDSAPKPFTDVSI \^RSAGHSQISRIKYFKVLIQEMDLIRLDLGFIYALTDLMTEAEVTENTEVE FHKDIEAFKEEYKTASLVDQSQVSLYEYFHISPIK H SVSLSSGREEAKDSKQNGGLIP VHSLNLL KSIGAT TDVQDVVFKLAFFELNYQFHTTSDLQSEVIRHYSKQAIKQMYVLILGLDVLGNPFGLIREFSEGVEAFFYEPYQGAIQGPEEFVEGMALGLKA VGG AVGGLAGAASKITGAMAKGVAA TMDEDYQQKRREAMNKQPAGFREGITRGGKGLVSGFVSGITGIVTKPIKGAQKGGAAGFFKGVGKGLVGAVARETGGIIDMASSTFQGI
KRAΓETSEVESLRPPRFFNEDGVIRPYRLRDGTGNQMLQKIQFYRE I THSSSSDDDDDDDDDDESD NH
42
CAGATCCACAAGTGATCGATATGTCAGTAAAATCCCTGACACTAAAGGTTTCACCAGTTATTATAAATACTATGATTACCATAACTTCAGCACTGTATACAACTAAGGAAAC CATCCCAGAAGAAACGGCTTCTTCTACTGCACATTTATGGGAAAAGAAGGATACAAAGACTTTAAAAATGTGGTTTCTTGAAGAATCAAATGAAACTGAAAAAATAGCTCCC CAACTGAATTGGTACCCAAAGGCGAGATGATAAAAATGAACATTGATTCTATTTTTATAGTTCTTGAGGCTGGAATTGGTCATAGAACAGTACCTATGCTTCTGGCAAAGT CACGTTTTTCAGGGGAAGGCAAAAACTGGAGTTCCCTAATAAATCTGCACTGTCAGCTTGAGCTAGAAGTGCATTATTATAATGAAATGTTTGGTGTATGGGAGCCTTTGCT TGAACCCTTAGAAATTGATCAGACTGAGGATTTTAGFTCCATGGAATCTTGGTATCAAGATGAAAAAGAAAGCAAAAATGGCCATTGTTGAGTCAGATCC'IGAAGAAGAAAAC TACAAAGTGCCAGAATARAAAACTGTCATCAGTTTCCATTCAAAAGACCAATTAAACATTACATTATCCAAATGTGGTCTTGTAATGTTAAACAATTTAGTCAAGGCATTTA CAGAAGCTGCCACTGGATCTTCAGCTGACTTCGTAAAGGATCTAGCACCATTTATGATTTTAAATTCCCTTGGACTTACTATTTCTGTTTCGCCAAGTGATTCTTTTAGTGT ACTCAACATTCCTATGGCAAAATCATA GTATTGAAAAATGGAGAAAGTTTAAGTATGGATTATATCCGAACCAAGGACAATGATCATTTCAATGCAATGACCAGCCTAAGC AGCAAACTCTTCTTCATΓCTTCTTACACCTGTTAACCATTCTACTGCTGATAAGATTCCTTTAACAAAAGTGGGACGACGTCTGTACACTGTAAGACACAGAGAGTCTGGCG RRGAAAGATCTATTGTTRGTCAAATTGATACAGTAGAAGGAAGTAAGAAGGTCACAATTCGCTCCCCAGTGCAGATAAGAAATCATTTTTCAGTCCCACTGTCTGTTTACGA AGGGGATACCTTATTGGGAACTGCCTCACCTGAAAATGAATTCAACATACCATTAGGATCTTACCGATCATTCATTTTTCTGAAGCCAGAAGATGAGAACTATCAAATGTGT GAAGGAATTGACTTTGAAGAGATTATAAAAAATGATGGTGCTCTTCTAAAGAAGAAATGTAGATCTAAAAACCCTTCTAAGGAATCATTTCTCATTAATATTGTTCCAGAAA AAGATAATTTAACATCTCTATCAGTGTATTCAGAAGATGGTTGGGATTTACCATACATAATGCATTTGTGGCCACCTATCCTGCTCCGAAATCTTCTTCCTTACAAAATTGC ΓTATTATATAGAGGGAAΓΓGAAAATTCGGTTTTTACTCTAAGTGAAGGACATTCAGCCCAGATTTGTACTGCACAGTTGGGTAAAGCCAGGCTACATTTAAAATTACTTGAC ΓATCTCAATCACGATTGGAAAAGTGAATATCACATAAAGCCTAATCAGCAAGACATTAGTTTTGTCAGTTTTACTTGTGTTACAGAAATGGAAAAGACTGATTTAGATATTG CTGTCCATATGACTTACAATACTGGTCAGACAGTTGTGGCATTTCATAGTCCTTATTGGATGGTCAATAAAACTGGCCGCATGTTACAGTACAAAGCAGACGGAATTCATCG AAGCATCCACCTAATTATAAAAAGCCAGTTCTCTTTTCTTTTCAGCCAAATCACTTTTTTAATAACAATAAGGTTCAACTTATGGTAACTGATAGTGAGTTGTCCAATCAG RRTTCAATTGATACTGTRGGRAGTCATGGAGCTGTTAAATGTAAAGGCCTGAAAATGGACTATCAAGTTGGTGTCACTATAGACCTGAGCAGTTTTAACATTACTAGAATTG RΒACATTTACCCCTTTTRATATGATTAAAAACAAAAGCAAATACCATATATCAGTGGCTGAAGAAGGAAATGATAAATGGCTCTCTCTTGATTTGGAGCAGTGTATCCCCTT ΓTGGCCTGAGTATGCTTCTAGTAAACTTCTTATTCAAGTCGAAAGGAGTGAAGATCCTCCCAAAAGGATATATTTTAACAAGCAGGAAAATTGTATTCTATTGCGTCTAGAT AACGAGCTTGGAGGTATΓATAGCAGAAGTGAATT GGCCGAGCATTCTACΛGTTATTACATTTTTAGATTATCATGATGGAGCAGCTACATTCCTCTTAATAAATCACACAA AGAATGAACTTGTTCAATACAATCAAAGTTCTCTCAGTGAAATAGAAGATTCCCTCCCTCCTGGTAAAGCCGTGTTTTATACATGGGCTGATCCGGTGGGCTCTAGAAGGCT GAAGTGGAGATGTAGAAAAAGCCATGGTGAAGTAACACAGAAGGATGATATGATGATGCCTATAGATTTGGGGGAAAAGACAATATATTTAGTTTCATTCTTTGAAGGTTTA CAACGCATTATTTTATTCACTGAAGATCCAAGGGTATTTAAAGTAACATATGAAAGTGAGAAAGCAGAGTTAGCAGAGCAAGAAATTGCAG'IGGCATTACAAGATGTTGGAA TTTCTCTTGTCAACAATTACACGAAGCAAGAAGTAGCCTATATAGGCATTACAAGTTCTGATGTGGTTTGGGAAACAAAGCCCAAGAAGAAGGCAAGATGGAAGCCAATGAG ΓGTAAAGCACACTGA3AAGTTAGAGAGAGAATTTAAGGAATATACTGAATCTTCTCCTTCAGAAGATAAGGTTATTCAGTTGGACACTAATGTTCCGGTTCGCCTAACCCCT ACTGGTCATAACATGAAAAΓΓCTGCAGCCGCATGTAATAGCTCTACGAAGAAATTATCTTCCAGCATTAAAAGTGGAATATAACACATCTGCACATCAATCATCATTTAGAA TTCAGATTTACAGAATACAGAΓCCAAAATCAGATACATGGTGCTGTATTTCCCTTTGTGTTTTATCCTGTTAAACCTCCAΔAGTCGGTCACCATGGATTCAGCACCAAAGCC CTTTACAGATGTCAGTATTGTCATGAGATCTGCAGGACATTCCCAGATATCACGTATTAAGTATTTCAAAGTATTGATTCAAGAAATGGATCTCAGGTTAGATCTTGGGTTT ATCTATGCTTTAACAGACCRTATGACAGAAGCTGAGGTGACTGAAAATACAGAGGTTGAGCTTTTTCATAAAGATATAGAAGCTTTCAAAGAAGAATATAAAACAGCCTCAT TAGTAGATCAATCACAAGΓCAGCCTCTATGAATATTTTCATATATCTCCTATCAAGTTACATTTAAGTGTTTCACTGAGTTCCGGCAGAGAAGAAGCTAAAGATTCAAAACA AAATGGAGGACTGATTCCAGTΓCATTCTTTAAATCTTTTGCTGAAGAGTATTGGTGCCACACTGACAGATGTACAAGATGTAGTTTTTAAGCTTGCATTTTTTGAACTCAAC TATCAGTTCCATACAACAΓCCGATCTACAGTCTGAAGTCATAAGACACTATTCAAAACAGGCCATTAAGCAGATGTATGTACTCATTCTTGGACTTGATGTTTTGGGAAATC CATΓTGGCTTAATTAGAGAATΓTTCTGAAGGTGTAGAAGCATTTTTTTATGAACCTTACCAGGGAGCCATCCAGGGTCCTGAAGAGTTTGTGGAAGGAATGGCACTAGGACT TAAGGCACTAGTTGGTGGAGCRGTTGGTGGATTGGCTGGTGCTGCCTCCAAAATCACCGGTGCTATGGCTAAGGGGGTAGCAGCTATGACCATGGATGAAGACTACCAACAG AAΒAGAAGAGAAGCCARGAATAAGCAACCAGCTGGTTTTAGAGAAGGCATCACTCGTGGAΣGAAAAGGCTTAGTTTCTGGATTTGTTAGTGGCATAACAGGAATTGTTACAA AACCAATCAAAGGAGCRCAAAAAGGAGGAGCAGCTGGTTTCTTTAAAGGTGTTGGGAAAGGTTTAGTAGGAGCGGTAGCAAGGCCAACTGGAGGCATCATAGACATGGCTAG CAGTACATTTCAGX3GGATAAAAAGAGCTACAGAGACTTCTGAAGTGGAGAGTCTGCGACCTCCTCGGTTCTTCAATGAAGATGGAGTTATCAGACCGTACAGGTTGAGGGAT GGGACTGGAAATCAAATGΓΓACAGAAAATTCAATTCTACAGGGAGTGGATTATGACTCACAGTAGCAGTAGTGATGATGATGATGATGATGATGATGATGATGAGTCAGATC TAAACCATTAAAATTCAΓAΓGΓTCTTTATTTTACTTGGAATGTTTCATTAACATGTTTTGTATGACTTATACCATAATGCCCATATGTCCATTTATAGGGAGGTAAAACACA TTTTCTTTTAAAATGRTRTCCTACACATTTTCATAAAGCAAAATAATTGTATTATTTAAGCACAGAAAAAAATGTATCTTACATCCAAAGTAGGGAGGGCATCCAACATATT ATAGATTTGCTTTTAΓAΓATTTTATAGCTTTGTATTGCATAGTTTGTCTTTAAGAGTTCAAGTTAGACTTAAATATAATTTTGATGTTCACTGGTTTTATTTTAAATTGCCT TCTTATTTGTTAGCAAAATGCCTTTTTTTAATGGTCTCTGTAAATTTTCTGGGCTTTAATGTAATGCCACTGTGT
43
MSHHGGAPKAST VVASRRSSTVSRAPERRPAEELNRTGPEGYSVGRGGRWRGTSRPPEAVAAGHEELPLCFALKSHFVGAVIGRGGSKIKNIQSTTNTTIQIIQEQPESLV KIFGSKAMQTKAKAVIDNFVKL JEE^ FNSECGIDTAFQPSVGKDGSTDN VVAGDRP IDWDQIREEΣ KWQKTKHAD PPIKKNFYKESTA SA ISKVEADSWRKENF IT TODLKMEKRPIPNPRCRFDDAFQCYPEVMENLKKAGFQKPTPIQSQA PIV ^IDLIGVAQTGTGKT CYLIMPGFIHLVLQPSLKGQR RPGMLVIJTPTREIIALQVEGEC CKYSYKG RSVCVYGGGNRDEQIEELKKGVDIIIATPGRLNDLQMSNFVN KNITYLV DEAD M DMGFEPQIMKILLDVRPDRQTVMTSATWPHSVHR AQSYLKEPMIV YVGTLDLVAVSSVKQNII\ΓΓTEEEKWSH QTFLQS SSTDKVIVFVSRKAVADH SSDLILGNISVESLHGDREQRDREKALENFKTGKVRI IA DLASRGLDVHDV HVY NFDFPRNIEEYVHRIGRΓGRAGRTGVSITTLTRNDWRVASE INILERANQSIPEELVSMAERFEAHQRKREMERKMERPQGRPKKFH
44
AGAGTGGGCGGGATAGAGAGCGTGGGCGGGGGGGCTAGCCTCGTGCGGGCTCCTTAAGTAGCGGCTGCGTGGCTTCCCTGGCACGCTAGTCTTACGACGTCACGGTCAGGTG GTGCAGAGCTGGACGGCAACGACGTCGGACGCGCCCCTTCTTGGAACAATGTCCCACCACGGAGGAGCTCCCAAGGCCTCTACGTGGGTCGTTGCTAGTCGGCGAAGCTCGA CAGTGTCCCGAGCGCCAGAGAGGAGGCCGGCGGAGGAGTTGAATCGAACAGGTCCTGAGGGATATAGTGTCGGCAGAGGTGGTCGCTGGAGAGGCACCTCTAGGCCCCCGGA GGCCGTGGCCGCTGGΓCACGAGGAACTGCCGCTGTGTTTTGCTTTGAAGAGCCACTTTGTTGGCGCGGTAATCGGTCGTGGTGGGTCAAAAATAAAGAATATACAAAGTACA ACAAACACCACAATCCAAAΓAAΓACAAGAACAACCAGAATCAΓTAGTCAAAATTTTTGGCAGCAAGGCAATGCAAACGAAAGCAAAAGCAGTGATAGACAATTTTGTTAAAA AGCTAGAAGAAAATTACAARTCAGAATGCGGAATTGATACTGCATTCCAACCTTCTGTTGGAAAAGATGGAAGCACAGATAACAATGTTGTTGCAGGAGATCGGCCATTGAT AGARTGGGATCAAATRAGAGAGGAAGGTTTGAAATGGCAAAAAACAAAGTGGGCAGATTRACCACCAATTAAGAAAAACTTTTATAAAGAGTCCACTGCCACAAGTGCCATG TCAAAAGTAGAAGCAGATAGTTGGAGGAAAGAAAATTTTAATATAACGTGGGATGACTTGAAGGATGGGGAGAAACGACCTATCCCCAATCCTACCTGCACATTTGATGACG CCTRTCAATGTTATCCRGAGGTTATGGAAAACATTAAAAAGGCAGGTTTTCAAAAGCCAACACCTATTCAGTCACAGGCATGGCCCATTGTGTTGCAAGGAATAGATCTTAT AGGAGTAGCCCAGACTGGAACAGGAAAGACATTGTGTTATTΓAAΓGCCTGGATTTATTCAΓCTGGTCCTTCAACCCAGCCTTAAAGGTCAAAGGAATAGACCCGGCATGTTA ETTCTAACTCCCACTCGGGAATTAGCACTTCAAGTAGAAGGAGAATGTTGCAAATATTCARATAAAGGGCTTCGGAGTGTTTGTGTATATGGTGGTGGAAATAGAGATGAAC AAATAGAAGAGCTTAAAAAAGGTGTAGATATCATAATTGCAACTCCCGGAAGATTGAATGAΓCTGCAAA GAGTAACTTCGTCAATCTGAAGAATATAACCTACTTGGTTTT AGATGAAGCAGACAAGATGΓTGGACATGGGATTTGAACCCCAGATAATGAAGATTTTGΓΓAGATGTGCGCCCAGATAGGCAGACAGTTATGACCAGTGCTACATGGCCTCAT TCAGTTCATCGCCTCGCACAATCTTATTTGAAAGAACCAATGATΓGTCTATGTTGGTACAΓΓGGATCTAGTTGCTGTAAGTTCAGTGAAGCAAAATATAATTGTAACCACCG AGGAAGAGAAATGGAGΓCACATGCAAACTTTTCTACAGAGTATGTCATCCACAGACAAAGΓCATTGTCTTCGTTTCTCGAAAAGCTGTTGCGGATCACTTATCAAGTGACCT AATACTTGGAAATATATCAGTAGAGTCTCTGCATGGAGATAGAGAACAGAGAGATCGGGAGAAAGCATTAGAGAACTTTAAAACAGGCAAAGTGAGAATACTAATTGCAACT GATCTAGCCTCTAGAGGACTTGATGTCCATGACGTTACACATGTCTATAATTTTGACTTTCCACGGAATATTGAAGAATACGTACACCGAATAGGGCGCACGGGAAGAGCAG GGAGGACTGGTGTTTCCATTACAACTTTGACTAGAAATGATTGGAGGGTTGCCTCTGAATTGATTAATATTCTGGAAAGAGCAAATCAGAGTATTCCAGAGGAGCTTGTATC ATGGCTGAGAGGTTTGAGGCACATCAACGGAAAAGGGAAATGGAAAGAAAAATGGAAAGACCTCAAGGAAGGCCCAAGAAGTTTCATTAATGTCTTCTGTACTAGTGGGGT GAGAATTCAAGATTTTTTAGAAATATAGTAAGACAGAAGTATTGGACATGTTGGCAGTATGAAGAGACCGGACTGATTTGACTGATTCTTAAAATAATAGTGTTTGAAAAT ATAGAATCCAGTGTTTIATACTTTCTTTAATAAAAATAGAAGTATTTAAACTTAAAAAAAAAAAAAAAAAAAAAAAAA
45
RVTSRSGPAPARRNSVTTGYGGVRALCGWTPSSGATPRNRL LQ GSPGRRYYSLPPHQKVP PSLSPTMQAGTIAR KKKEGDKINEGDLIAEVETDKATVGFESLEECY MAKILVAEGTRDVPIGAIICITVGKPEDIEAFKNYTLDSSAAPTPQAAPAPTPAATASPPTPSAQAPGSSYPPHMQVLLPALSPTMTMGTVQR EKKVGEKLSEGD LAEIE TDKATIGFEVQEEGYLAKILVPEGTRDVP GTPLCIIVEKEADISAFADYRPTEVTDLKPQVPPPTPPPVAAVPPTPQPLAPTPSAPCPATPAGPKGRVFVSPIIAKKIIAVEK GIDLTQVKGTGPDGRITKKDIDSFVPSKVAPAPAAWPPTGPGMAPVPTGVFTDIPISNIRRVIAQRLMQSKQTIPHYYLSIDVNMGEVL VRKELNKILEGRSKISVNDFI IKASALACLKVPEANSSWMDTVIRQNHVVDVSVAVSTPAG ITPIVFNAHIKGVETIANDVVS ATKAREGKLQPHEFQGGTFTISNLGMFGIKNFSAIINPPQACILAIGA
SEDKLVPADNEKGFDVASMMSVTLSCDHRWDGAVGAQWI-AEFRKYLEKPITMLL
46
CGAGTGACCTCGCGATCTGGCCCGGCTCCCGCTCGTCGCAACAGCGTGACTACAGGGTATGGCGGGGTCCGGGCACTGTGCGGCTGGACCCCCAG'ΓTCTGGGGCCACGCCGC
GGAACCGCTTACTGCTGCAGCTTTTGGGGTCGCCCGGCCGCCGCTATTACAGTCTTCCCCCGCATCAGAAGGTTCCATTGCCTTCTCTTTCCCCCACAATGCAGGCAGGCAC
CATAGCCCGTTGGAAAAAAAAAGAGGGGGACAAAATCAATGAAGGTGACCTAATTGCAGAGGTTGAAACTGATAAAGCCACTGTTGGATTTGAGAGCCTGGAGGAGTGTTAT
ATGGCAAAGATACTTGTTGCTGAAGGTACCAGGGATGTTCCCATCGGAGCGATCATCTGTATCACAGTTGGCAAGCCTGAGGATATTGAGGCCTTTAAAAATTATACACTGG
ATTCCTCAGCAGCACCTΔCCCCACAAGCGGCCCCAGCACCAACCCCTGCTGCCACTGCTTCGCCACCTACACCTTCTGCTCAGGCTCCTGGTAGCTCATATCCCCCTCACAT GCAGGTACTTCTTCCTGCCCTCTCTCCCACCATGACCATGGGCACAGTTCAGAGATGGGAAAAAAAAGTGGGTGAGAAGCTAAGTGAAGGAGACTTACTGGCAGAGATAGAA ACTGACAAAGCCACTATAGGTTTTGAAGTACAGGAAGAAGGTTATCTGGCAAAAATCCTGGTCCCTGAAGGCACAAGAGATGTCCCTCTAGGAACCCCACTCTGTATCATTG TAGAAAAAGAGGCAGATATATCAGCATTTGCTGACTATAGGCCAACCGAAGTAACAGATTTAAAACCACAAGTGCCACCACCTACCCCACCCCCGGTGGCCGCTGTTCCTCC AACTCCCCAGCCTTTAGCTCCTACACCTTCAGCACCCTGCCCAGCTACTCCTGCTGGACCAAAGGGAAGGGTGTTTGTTAGCCCTCTTGCAAAGAAGTTGGCAGTAGAGAAA GGGATTGATCTTACACAAGTAAAAGGGACAGGACCAGATGGTAGAATCACCAAGAAGGATATCGACTCTTTTGTGCCTAGTAAAGTTGCTCCTGCTCCGGCAGCTGTTGTGC CTCCCACAGGTCCTGGAATGGCACCAGTTCCTACAGGTGTCTTCACAGATATCCCAATCAGCAACATTCGTCGGGTTATTGCACAGCGATTAATGCAATCAAAGCAAACCAT ACCTCATTATTACCTTTCTATCGATGTAAATATGGGAGAAGTTTTGTTGGTACGGAAAGAACTTAATAAGATATTAGAAGGGAGAAGCAAAATTTCTGTCAATGACTTCATC ATAAAAGCTTCAGCTTTGGCATGTTTAAAAGTTCCCGAAGCAAATTCTTCTTGGATGGACACAGTTATAAGACAAAATCATGTTGTTGATGTCAGTGTTGCGGTCAGTACTC
CTGCAGGACTCATCACACCTATTGTGTTTAATGCACATATAAAAGGAGTGGAAACCATTGCTAATGATGTTGTTTCTTTAGCAACCAAAGCAAGAGAGGG'IAAACTACAGCC ACATGAATTCCAGGGTGGCACTTTTACGATCTCCAATTTAGGAATGTTTGGAATTAAGAATTTCTCTGCTATTATTAACCCACCTCAAGCATGTATTTTGGCAATTGGTGCT TCAGAGGATAAACTGGTCCCTGCAGATAATGAAAAAGGGTTTGATGTGGCTAGCATGATGTCTGTTACACTCAGTTGTGATCACCGGGTGGTGGATGGAGCAGTTGGAGCCC AGIGGCTTGCTGAGTTTAGAAAGTACCTTGAAAAACCTATCACTATGTTGTTGTAACTAACTCAAGAATTTCTAAACTCTCCCAGGTCACACTGATTCATTCTTAACAAGAT ATTTATATGTTATTAAACAGGTGGTTGCTTTTTATTTTAACCAGTTATTTTTATTATTGAGTCTGCTCAGATAAGTTATTTATAATGGGCATTACTGAATTTTTAAAATGCC GATTACACCCAAATATTGTGCACATTTAATAATCAGACACCAGATTTTTAGCTCTGTACTCCTAATTAAGGGACATGTATGTGGCCTTGCCTAGCCCTTTGGTGATAAGTAC TTCCTCTAGGAAATGTACGATAGGTAGAATTGTGGTTCCCTAAAGACAAGTACATAAAGGTGACCCTGATGAAACCTTGAAGTTCTGAAATTTAACTGCCTAAAATGTTCTC CTTAGATGTGAGAGAAAGAGAAATCAGAAAAATTAATTCTCTTGGGGGAAGGGCTTGAATTGAAGCTTTACTTTAGAATTTAGCCCTGGTTTGAAATTTTCCATTACATGAT CTTGGTTTATCATCGATGGGAAGGGTAGAAAACTTCAAGGAAAATAAGTGAAATTTTAAAAGTCAGCATTTTCTTAGACCTCTTCAGCTGATTGTTTATTTTTCTATGAATT CTGTACTCAAAATTACACATTTGTTTAAATAAATATCCACACAAATTCTCAGTTACATCAAGTAGCTGGTTTATATTTAGATTATCTCAAGTAGGGGGGAATAACCATGTGT
AGGAATT
47
MAASSLEQKlSRLEAKLKQFJ^REARRRIDLNLDI SPQRPRPT QLPIJiNDGGSRSPSSESSPQHPTPPARPRHMLGLPST FTPRS ESIEIDQK QEIMKQTGYIiTIGGQR YQAEIND EN GEMGSGTCGQV KMRFRKTGHVIAVKQMRRSGNKEENKRI MDLDVVLKSHDCPYIVQCFGTFITN DVFIAME MGTCAEKLKKRMQGPIPERILGKMTV QEEPPL PGHMGFSGDFQSFVKDC TKDHRKRPKYNK EHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR
48
GAATTCCTGCCGGACTGACGGGCGGCCGGGCGGTGCGCGGCGGCGGTGGCGGCGGGGAAGATGGCGGCGTCCTCCCTGGAACAGAAGCTGTCCCGCCTGGAAGCAAAGCTGA
AGCAGGAGAACCGGGAGGCCCGGCGGAGGATCGACCTCAACCTGGATATCAGCCCCCAGCGGCCCAGGCCCACCCTGCAGCTCCCGCTGGCCAACGATGGGGGCAGCCGCTC
GCCATCCTCAGAGAGCTCCCCGCAGCACCCCACGCCCCCCGCCCGGCCCCGCCACATGCTGGGGCTCCCGTCAACCCTGTTCACACCCCGCAGCATGGAGAGCATTGAGATT GACCAGAAGCTGCAGGAGATCATGAAGCAGACGGGCTACCTGACCATCGGGGGCCAGCGCTACCAGGCAGAAATCAACGACCTGGAGAACTTGGGCGAGATGGGCAGCGGCA CCTGCGGCCAGGTGTGGAAGATGCGCTTCCGGAAGACCGGCCACGTCATTGCCGTTAAGCAAATGCGGCGCTCCGGGAACAAGGAGGAGAACAAGCGCATCCTCATGGACCT GGATGTGGTGCTGAAGAGCCACGACTGCCCCTACATCGTGCAGTGCTTTGGGACGTTCATCACCAACACGGACGTCTTCATCGCCATGGAGCTCATGGGCACCTGCGCTGAG AAGCTCAAGAAGCGGATGCAGGGCCCCATCCCCGAGCGCATTCTGGGCAAGATGACAGTGGCGATTGTGAAGGCGCTGTACTACCTGAAGGAGAAGCACGGTGTCATCCACC GCGACGTCAAGCCCTCCAACATCCTGCTGGACGAGCGGGGCCAGATCAAGCTCTGCGACTTCGGCATCAGCGGCCGCCTGGTGGACTCCAAAGCCAAGACGCGGAGCGCCGG CTGTGCCGCCTACATGGCACCCGAGCGCATTGACCCCCCAGACCCCACCAAGCCGGACTATGACATCCGGGCCGACGTATGGAGCCTGGGCATCTCGTTGGTGGAGCTGGCA ACAGGACAGTTTCCCTACAAGAACTGCAAGACGGACTTTGAGGTCCTCACCAAAGTCCTACAGGAAGAGCCCCCGCTTCTGCCCGGACACATGGGCTTCTCGGGGGACTTCC AGTCCTTCGTCAAAGACTGCCTTACTAAAGATCACAGGAAGAGACCAAAGTATAATAAGCTACTTGAACACAGCTTCATCAAGCGCTACGAGACGCTGGAGGTGGACGTGGC GTCCTGGTTCAAGGATGTCATGGCGAAGACTGAGTCACCGCGGACTAGCGGCGTCCTGAGCCAGCCCCACCTGCCCTTCTTCAGGTAGCTGCTTGGCGGCGGCCAGCCCCAC AGGGGGCCAGGGGCATGGCCACAGGCCCCCCTCCCCACTTGGCCACCCAGCTGCCTGCCAGGGGAGACCTGGGACCTGGAC
49
^Π•TSHQPQDRYKAV IFFM G GTL P WFFMTAT YFT RLD SQ^RVS VTAELSKDAQASAAPAAP PE NS SAIFN^^V^ITLCAMLPLL F Y NSFLHQ IPQS RI GS VAI LVFLITAILVKVQLDA PFFVITMIKIVLINSFGAILQGS FGLAGLLPASYTAPIMSGQGLAGFFASVAMICAIASGSE SESAFGYFITACAVII TIICY G PRLEFYRYYQQLKLEGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHSIKAILKNISVLAFSVCFIFTITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLT FNIFDW GRSLTAVFMWPGKDSRWLPSLVLARLVFVPLLLLCNIKPRRYLTΛTVFEHDAWFIFF AAFAFSNGYLASLCMCFGPKKVKPAEAETAGAIMAFFLCIIGLALGAVF SFLFRAIV
50
GGGCTGCGCTGTCCAGCTGTGGCTATGGCCCCAGCCCCGAGATGAGGAGGGAGAGAACTAGGGGCCCGCAGGCCTGGGAATTTCCGTCCCCCACCAAGTCCGGATGCTCACT
CCAAAGTCTCAGCAGGCCCCTGAGGGAGGGAGCTGTCAGCCAGGGAAAACCGAGAACACCATCACCATGACAACCAGTCACCAGCCTCAGGACAGATACAAAGCTGTCTGGC
TTATCTTCTTCATGCTGGGTCTGGGAACGCTGCTCCCGTGGAATTTTTTCATGACGGCCACICAGTATTTCACAAACCGCCTGGACATGTCCCAGAATGTGTCCTTGGTCAC
TGCTGAACTGAGCAAGGACGCCCAGGCGTCAGCCGCCCCTGCAGCACCCTTGCCTGAGCGGAACTCTCTCAGTGCCATCTTCAACAATGTCATGACCCTATGTGCCATGCTG
CCCCTGCTGTTATTCACCTACCTCAACTCCTTCCTGCATCAGAGGATCCCCCAGTCCGTACGGATCCTGGGCAGCCTGGTGGCCATCCTGCTGGTGTTTCTGATCACTGCCA
TCCTGGTGAAGGTGCAGCTGGATGCTCTGCCCTTCTTTGTCATCACCATGATCAAGATCGT'GCTCATTAATTCATTTGGTGCCATCCTGCAGGGCAGCCTGTTTGGTCTGGC
TGGCCTTCTGCCTGCCAGCTACACGGCCCCCATCATGAGTGGCCAGGGCCTAGCAGGCTTCTTTGCCTCCGTGGCCATGATCTGCGCTAT GCCAG GGCTCGGAACTATCA
GAAAGTGCCTTCGGCTACTTTATCACAGCCTGTGCTGTTATCATTTTGACCATCATCTGTTACCTGGGCCTGCCCCGCCTGGAATTCTACCGCTACTACCAGCAGCTCAAGC
TTGAAGGACCCGGGGAGCAGGAGACCAAGTTGGACCTCATTAGCAAAGGAGAGGAGCCAAGAGCAGGCAAAGAGGAATCTGGAGTTTCAGTCTCCAACTCTCAGCCCACCAA
TGAAAGCCACTCTATCAAAGCCATCCTGAAAAATATCTCAGTCCTGGCTTTCTCTGTCTGCTTCATCTTCACTATCACCATTGGGATGTTTCCAGCCGTGACTGTTGAGGTC
AAGTCCAGCATCGCAGGCAGCAGCACCTGGGAACGTTACTTCATTCCTGTGTCCTGTTTCTTGACTTTCAATATCTTTGACTGGTTGGGCCGGAGCCTCACAGCTGTATTCA
TGTGGCCTGGGAAGGACAGCCGCTGGCTGCCAAGCCTGGTGCTGGCCCGGCTGGTGTTTGTGCCACTGCTGCTGCTGTGCAACATTAAGCCCCGCCGCTACCTGACTGTGGT
CTTCGAGCACGATGCCTGGTTCATCTTCTTCATGGCTGCCTTTGCCTTCTCCAACGGCTACCTCGCCAGCCTCTGCATGTGCTTCGGGCCCAAGAAAGTGAAGCCAGCTGAG
GCAGAGACCGCAGGAGCCATCATGGCCTTCTTCCTGTGTCTGGGTCTGGCACTGGGGGCTGTTTTCTCCTTCCTGTTCCGGGCAATTGTGTGACAAAGGATGGACAGAAGGA
CTGCCTGCCTCCCTCCCTGTCTGCCTCCTGCCCCTTCCTTCTGCCAGGGGTGATCCTGAGTGGTCTGGCGGTTTTTTCTTCTAACTGACTTCTGCTTTCCACGGCGTGTGCT
GGGCCCGGATCTCCAGGCCCTGGGGAGGGAGCCTCTGGACGGACAGTGGGGACATTGTGGGTTTGGGGCTCAGAGTCGAGGGACGGGG GTAGCCTCGGCATTTGCTTGAGT TTCTCCACTCTTGGCTCTGACTGATCCCTGCTTGTGCAGGCCAGTGGAGGCTCTTGGGCTTGGAGAACACGTGTGTCTCTGTGTATGTGTCTGTGTGTCTGCGTCCGTGTCT GTCAGACTGTCTGCCTGTCCTGGGGTGGCTAGGAGCTGGGTCTGACCGTTGTATGGTT"IGACCTGATATACTCCATTCTCCCCTGCGCCTCCTCCTCTGTGTTTTTTCCATG TCCCCCTCCCAACTCCCCATGCCCAGTTTTTACCCATCATGCACCCTGTACAGTTGCCACGTTACTGCCTTTTTTAAAAATATATTTGACAGAAACCAGGTGCCTTCAGAGG CTCTCTGATTTAAATAAACCTTTCTTGTTTTTTT
51 KTPADTGFAFPDWAYKPESSPGSRQIQLWHFILE LRKEEYQGVIA QGDYGEFVIKDPDEVARLWGVRKCKPQMNYDKLSRALRYYYNKRILHKTKGKRFTYKFNFNKLV
LVNYPFIDVGLAGGAVPQSAPPVPSGGSHFRFPPSTPSEVLSPTEDPRSPPACSSSSSSLFSAWARRLGRGSVSDCSDGTSELEEPLGEDPRARPPGPPDLGAFRGPPLAR
LPHDPGVFRVYPRPRGGFEPLSPFPVSPLAGPGS PPQLSPALPMTPTHLAYTPSPT SPMYPSGGGGPSGSGGGSHFSFSPEDMKRYLQAHTQSVYNYHLSPRAF HYPG
LWPQPQRPDKCP PPMAPETPPVPSSASSSSSSSSSPFKFK QRPPLGRRQRAAGEKAVAAADKSGGSAGG1AEGAGALAPPPPPPQIKVEPISEGESEEVEVTDISDEDE
EDOEVFKTPRAPPAPEKPEPGEAPGASQCMP KLRFKRRWSEDCR EGGGGPAGGFEDEGEDKKVRGEGPGEAGGP TPRRVSSDIjQHATAQLS EHRDS
52
TCTGAGAGGCGAGGCCGGGTGAGGCGGCGAGGGCGGCCCGACGGGCGCGGGACGGGACGGGGCAGCGAGGGCGCCGGGAGCCGCGGCCCGGAATCGGGGCGCTTCGCCCCGG GCCCCCCAGCATGAAGACCCCGGCGGACACAGGGTTTGCCTTCCCGGATTGGGCCTACAAGCCAGAGTCGTCCCCTGGCTCAAGGCAGATCCAGCTGTGGCACTTTATCCTG GAGCTGCTGCGGAAGGAGGAGTACCAGGGCGTCATTGCCTGGCAGGGGGACTACGGGGAATTCGTCATCAAAGACCCTGATGAGGTGGCCCGGCTGTGGGGCGTTCGCAAGT GCAAGCCCCAGATGAATTACGACAAGCTGAGCCGGGCCCTGCGCTATTACTATAACAAGCGCATTCTGCACAAGACCAAGGGGAAACGGTTCACCTACAAGTTCAATTTCAA CAAACTGGTGCTGGTCAATTACCCATTCATTGATGTGGGGTTGGCTGGGGGTGCAGTGCCCCAGAGTGCCCCGCCAGTGCCGTCGGGTGGTAGCCACTTCCGCTTCCCTCCC TCAACGCCCTCCGAGGTGCTGTCCCCCACCGAGGACCCCCGCTCACCACCAGCCTGCTCTTCATCTTCATCTTCCCTCTTCTCGGCTGTGGTGGCCCGCCGCCTGGGCCGAG GCTCAGTCAGTGACTGTAGTGATGGCACGTCAGAGCTGGAGGAACCGCTGGGAGAGGATCCCCGCGCCCGACCACCCGGCCCTCCGGATCTGGGTGCCTTCCGAGGGCCCCC GCTGGCCCGCCTGCCCCATGACCCTGGTGTCTTCCGAGTCTATCCCCGGCCTCGGGGTGGCCCTGAACCCCTCAGCCCCTTCCCTGTGTCGCCTCTGGCCGGTCCTGGATCC CTGCTGCCCCCTCAGCTCTCCCCGGCTCTGCCCATGACGCCCACCCACCTGGCCTACACTCCCTCGCCCACGCTGAGCCCGATGTACCCCAGTGGTGGCGGGGGGCCCAGCG GCTCAGGGGGAGGCTCCCACTTCTCCTTCAGCCCTGAGGACATGAAACGGTACCTGCAGGCCCACACCCAAAGCGTCTACAACTACCACCTCAGCCCCCGCGCCTTCCTGCA CTACCCTGGGCTGGTGGTGCCCCAGCCCCAGCGCCCTGACAAGTGCCCGCTGCCGCCCATGGCACCCGAGACCCCACCGGTCCCCTCCTCGGCCTCGTCATCCTCTTCTTCT TCTTCCTCCCCATTCAAGTTTAAGCTCCAGCGGCCCCCACTCGGACGCCGGCAGCGGGCAGCTGGGGAGAAGGCCGTAGCCGCTGCTGACAAGAGCGGTGGCAGTGCAGGCG GGCTGGCTGAGGGGGCAGGGGCGCTAGCCCCACCGCCCCCGCCACCACAGATCAAGGTGGAGCCCATCTCGGAAGGCGAGTCGGAGGAGGTAGAGGTGACTGACATCAGTGA TGAGGATGAGGAAGACGGGGAGGTGTTCAAGACGCCCCGTGCCCCACCTGCACCCCCTAAGCCTGAGCCCGGCGAGGCACCCGGGGCATCCCAGTGCATGCCCCTCAAGCTA CGCTTTAAGCGGCGCTGGAGTGAAGACTGTCGCCTCGAAGGGGGTGGGGGCCCCGCTGGGGGCTTTGAGGATGAGGGTGAGGACAAGAAGGTGCGTGGGGAGGGGCCTGGGG AGGCTGGGGGGCCCCTCACCCCAAGGCGGGTGAGCTCTGACCTCCAGCATGCCACGGCCCAGCTCTCCCTGGAGCACCGAGACTCCTGAGGGCTGTGGGCAGGGGACCTGTG TGCCCCGCACCCCCCATGCTTCTTTTGCTGCCTTAAGCCCCCTATGCCCTGGAGGTGAGGGCAGCTCTCTTGTCTCTTCCCTGCCTCCTCCCTTTTCCC1CCCCACATTTTG TATAAAACTTTAATTTCTTTTTTTTAAAAATGGTGGGGGTGGGTGGGTGCCCAGGGCTAGGGGCTATTCCCTGTCTCTGTGGGTTTCTAAGCTCTGGGCAAATTGGTGGTAG GGGGAGGGAGGGGGAAGTTAAGGGGGTCACCTCCATTCTGGGGAATTTATATTTGAATTGAGGCTTTGGCCTTAACACCCAGGAACTTTTCTATTACAATCGCTTAGGAAGT AAAGCCTTGTCTCCCTCCCTGTTCTCTGCCTCTTGTACCCCTCTGACCCACCCGCTCTGCCCCACTCCCAGCCCTCCTCAGCCCCAGCCCTGCCTGCCCTGCCCCTCCAGGG GGCCATGAGTGCCTAGGTTTCTCATACCCCACAAGGTCACAGCAGGGGAGGGAGGGACAATTTTATAATGAACCAAAAATTCCATGTGTTGGGGGGTGGGGGGCGGAGGAGG GTGAGGGGTGCCGCCCATGGGCCACAAATCTCTACAAGTGCCTGCTATCCCTCTCCCACTCCCCACCCCAGCACCGGTCCAACCCCTTCATCCCCAGCTGCTCCTAGGACTG GCCCATGGGCAGGCGGGTGGGGGGATGGGAAGGGGGTGCCCTGAAACCAAACTGGAAGCCCCCTCTGCCTCCCAGCTGGGGCCTCTGGGGTGGGGTGGGGGGCTGTGGTCAA GCCTTATTCTGTATTGGGGACTGAGGGTGGGGGGAGTAGAGGGGCCGCTGGAGAATGTATTCAAAACAATAAACTTTGGACCTTTGGAAAA
53
MΞGGSSCSQTPSRAIPATRRWLGDGVQLPPGDYSTTPGGTLFSTTPGGTRIIYDRKFLMECRNSPVTKTPPRDLPTIPGVTSPSSDEPPMEASQSHLRNSPEDKRAGGEES QFEMDI
54
GCGGGAGGGCAGCGAGAGGTTCGCGGGTGCAGCGCACAGGAGACCATGTCCGGGGGCAGCAGCTGCAGCCAGACCCCAAGCCGGGCCATCCCCGCCACTCGCCGGGTGGTGC TCGGCGACGGCGTGCAGCTCCCGCCCGGGGACTACAGCACGACCCCCGGCGGCACGCTCTTCAGCACCACCCCGGGAGGTACCAGGATCATCTATGACCGGAAATTCCTGAT GGAGTGTCGGAACTCACCTGTGACCAAAACACCCCCAAGGGATCTGCCCACCATTCCGGGGGTCACCAGCCCTTCCAGTGATGAGCCCCCCATGGAAGCCAGCCAGAGCCAC CTGCGCAATAGCCCAGAAGATAAGCGGGCGGGCGGTGAAGAGTCACAGTTTGAGATGGACATTTAAAGCACCAGCCATCGTGTGGAGCACTACCAAGGGGCCCCTCAGGGCC TTCCTGGGAGGAGTCCCACCAGCCAGGCCTTATGAAAGTGATCATACTGGGCAGGCGTTGGCGTGGGGTCGGACACCCCAGCCCTTTCTCCCTCACTCAGGGCACCTGCCCC CTCCTCTTCGTGAACACCAGCAGATACCTCCTTGTGCCTCCACTGATGCAGGAGCTGCCACCCCAAGGGGAGTGACCCCTGCCAGCACACCCTGCAGCCAAGGGCCAGGAAG TGGACAAGAACGAACCCTTCCTTCCGAATGATCAGCAGTTCCAGCCCCTCGCTGCTGGGGGCGCAACCACCCCTTCCTTAGGTTGATGTGCTTGGGAAAGCTCCCTCCCCCT CCTTCCCCAAGAGAGGAAATAAAAGCCACCTTCGCCCTAGGGCCAAGAAAAAAAAAAAAAAAAAAA
55
MEHTGHYLH AFLMTTVFSLSPGTKANYTRLWANSTSSWDSVIQNKTGRNQNENINTNPITPEVDYKGNSTNMPETSHIVALTSKSEQELYIPSWSNSPSTVQSIENTS S
HGEIFKKDVCAEN ^I MA LICLIIIAV F ICTFLFLSTVVTJtfIKVSSLR SKQ GKRQP S GDF ASGLWPAESD WKRTKQLTGPNLV^1QSTG LTATRERKDEEGTE
K TNKQIG
56
AGTTGCAGTGGAAAGAAATGTGTCATCTGTGGTTTGGTTTTTAAAAGTGGAAAACTAGCTGCACATATCCTTTTTTACTGCAGATTTACTTTAAGGCTCATATTCTCCAAGT
CTATTCTGCTTTAAAAAGAAGACAAGAAAAGAAGTGGTTTATCAAAATCACGTTATAATCAGATTTTGACCAAGCATTTTGTAAGATTGCCAAGTATGCCCACGGACATGGA
ACACACAGGACATTACCTACATCTTGCCTTTCTGATGACAACAGTTTTTTCTTTGTCTCCTGGAACAAAAGCAAACTATACCCGTCTGTGGGCTAACAGTACTTCTTCCTGG
GATTCAGTTATTCAAAACAAGACAGGCAGAAACCAAAATGAAAACATTAACACAAACCCTATAACTCCTGAAGTAGATTATAAAGGTAATTCTACAAACATGCCTGAAACAT
CTCACATCGTAGCTTTAACTTCTAAATCTGAACAGGAGCTTTATATACCTTCTGTCGTCAGCAACAGTCCTTCAACAGTACAGAGCATTGAAAACACAAGCAAAAGTCATGG
TGAAATTTTCAAAAAGGATGTCTGTGCGGAAAACAACAACAACATGGCTATGCTAATTTGCTTAATTATAATTGCAGTGCTTTTTCTTATCTGTACCTTTCTATTTCTATCA
ACTGTGGTTTTGGCAAACAAAGTCTCTTCTCTCAGACGATCAAAACAAGTAGGCAAGCGTCAGCCTAGAAGCAATGGCGATTTTCTGGCAAGCGGTCTATGGCCCGCTGAAT
CAGACACTTGGAAAAGAACAAAACAGCTCACAGGACCCAACCTAGTGATGCAATCTACTGGAGTGCTCACAGCTACAAGGGAAAGAAAAGATGAAGAAGGAACTGAAAAACT
TACTAACAAACAGATAGGTTAGTGAAGAAAAATGCAAAGTAGCAATGAGAAGGCTTATGGAGTAAAAATGAAGTCAGTTGG'IATTTAATCCCAAAGTGT'IGTTCTGATTATC
TAAAATTTGACATGGTAGACCTTGCAATTTAGAATCAAGCAGGTGAGACAGGGAGAAGTATGCCTGCTTAATTATTTAAACTGTGTACTTTTGTTTTGACACTGAATATTTT
AAAAAGCAAATAATAAAATAACTAAGCATTTGAGGAAAATTTTAAGGATAAATTGAGGAAACTGATTAATAGAGATAGCAAGGGATAATTAAATAAATATTCCCTATGTAGC
AACAGTGGTTAGATGATCTTTGTCTGAATGTAATAAAACTTTGAATAGTTTTAGTGTGTCCTTAAAGCCAAGTATATGCTTTAACATCAAATGGAAGTCAAATTCCTAATGC
ATAGATAGAGAGAGCTAAACTGTGTAATTTAATGGTATCTTCCTTGCTGGATGTGGCAGAATCCACACCAGCTTATCAACCAACACAGCTAATTTTAGAATAGGTCCTTTAT
CTTTCCATATGGCACACGTAAGAAAGTGTTTTTCTACTATTAATATTAAATTAAAACCTTTACTTTTGTATAATAAATTAAAACTCAGAATAAACCTGTGACCACGT
57 EHTGHYLHIΛF MTTVFS SPGTKANYTRL ANSTSSWDSVIQNKTGRNQNENINTNPITPEVDYKGNSTNMPETSHIVALTSKSEQELYIPSVVSNSPSTVQSIENTSKS
HGEIFKKDVCAENNKNMAMLICLIIIAVLF ICTFLFLSTVVLANKVSSLRRSKQVGKRQPRSNGDFLASG WPAESDTWKRTKQLTGPNLVMQSTGVLTATRERKDEEGTE
KLTNKQIG
58
AGTTGCAGTGGAAAGAAATGTGTCATCTGTGGTTTGGTTTTTAAAAGTGGAAAACTAGC'RGCACATATCCTTTTTTACTGCAGATTTACTTTAAGGCTCATATTCTCCAAGT CTATTCTGCTTTAAAAAGAAGACAAGAAAAGAAGTGGTTTATCAAAATCACGTTATAATCAGATTTTGACCAAGCATT'RTGTAAGATTGCCAAGTATGCCCACGGACATGGA ACACACAGGACATTACCTACATCTTGCCTTTCTGATGACAACAGTTTTTTCTTTGTCTCCTGGAACAAAAGCAAACTATACCCGTCTGTGGGCTAACAGTACTTCTTCCTGG GATTCAGTTATTCAAAACAAGACAGGCAGAAACCAAAATGAAAACATTAACACAAACCCTATAACTCCTGAAGTAGATTATAAAGGTAATTCTACAAACATGCCTGAAACAT CTCACATCGTAGCTTTAACT CTAAATCTGAACAGGAGCTTTATATACCTTCTGTCGTCAGCAACAGTCCTTCAACAGTACAGAGCATTGAAAACACAAGCAAAAGTCATGG
TGAAATTTTCAAAAAGGATGTCTGTGCGGAAAACAACAACAACATGGCTATGCTAATTTGCTTAATTATAATTGCAGTGCTTTTTCTTATCTGTACCTTTCTATTTCTATCA
ACTGTGGTTTTGGCAAACAAAGTCTCTTCTCTCAGACGATCAAAACAAGTAGGCAAGCGTCAGCCTAGAAGCAATGGCGATTTTCTGGCAAGCGGTCTATGGCCCGCTGAAT CAGACACTTGGAAAAGAACAAAACAGCTCACAGGACCCAACCTAGTGATGCAATCTACTGGAGTGCTCACAGCTACAAGGGAAAGAAAAGATGAAGAAGGAACTGAAAAACT TACTAACAAACAGATAGGTTAGTGAAGAAAAATGCAAAGTAGCAATGAGAAGGCTTATGGAGTAAAAATGAAGTCAGTTGGTATTTAATCCCAAAGTGTTGTTCTGATTATC TAAAATTTGACATGGTAGACCTTGCAATTTAGAATCAAGCAGGTGAGACAGGGAGAAGTATGCCTGCTTAATTATTTAAACTGTGTACTTTTGTTTTGACACTGAATATTTT AAAAAGCAAATAATAAAATAACTAAGCATTTGAGGAAAATTTTAAGGATAAATTGAGGAAACTGATTAATAGAGATAGCAAGGGATAATTAAATAAATATTCCCTATGTAGC AACAGTGGTTAGATGATCTTTGTCTGAATGTAATAAAACTTTGAATAGTTTTAGTGTGTCCTTAAAGCCAAGTATATGCTTTAACATCAAATGGAAGTCAAATTCCTAATGC ATAGATAGAGAGAGCTAAACTGTGTAATTTAATGGTATCTTCCTTGCTGGATGTGGCAGAATCCACACCAGCTTATCAACCAACACAGCTAATTTTAGAATAGGTCCTTTAT CTTTCCATATGGCACACGTAAGAAAGTGTTTTTCTACTATTAATATTAAATTAAAACCTTTACTTTTGTATAATAAATTAAAACTCAGAATAAACCTGTGACCACGT
59
MGIbSF PVIiATESDWADCKSPQP GHMLL TAVLFLAPVAGTPAAPPKAV KLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLI PTHTQPSYRFKANNNDSGEYT CQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHS KDKPLVKVTFFQNGKSKKFSRSDPNFSI PQANHSHSGDYHCTGNIGYT-.YSSKPVTITVQAPSSSPMGI IVAWTGIAVAAIVAAWALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI
60
ATGGGAATCCTGTCATTCTTACCTGTCCTTGCCACTGAGAGTGACTGGGCTGACTGCAAGTCCCCCCAGCCTTGGGGTCATATGCTTCTGTGGACAGCTGTGCTATTCCTGG
CTCCTGTTGCTGGGACACCTGCAGCTCCCCCAAAGGCTGTGCTGAAACTCGAGCCCCAGTGGATCAACGTGCTCCAGGAGGACTCTGTGACTCTGACATGCCGGGGGACTCA
CAGCCCTGAGAGCGACTCCATTCAGTGGTTCCACAATGGGAATCTCATTCCCACCCACACGCAGCCCAGCTACAGGTTCAAGGCCAACAACAATGACAGCGGGGAGTACACG
TGCCAGACTGGCCAGACCAGCCTCAGCGACCCTGTGCATCTGACTGTGCTTTCTGAGTGGCTGGTGCTCCAGACCCCTCACCTGGAGTTCCAGGAGGGAGAAACCATCGTGC
TGAGGTGCCACAGCTGGAAGGACAAGCCTCTGGTCAAGGTCACATTCTTCCAGAATGGAAAATCCAAGAAATTTTCCCGTTCGGATCCCAACTTCTCCATCCCACAAGCAAA
CCACAGTCACAGTGGTGATTACCACTGCACAGGAAACATAGGCTACACGCTGTACTCATCCAAGCCTGTGACCATCACTGTCCAAGCTCCCAGCTCTTCACCGATGGGGATC
ATTGTGGCTGTGGTCACTGGGATTGCTGTAGCGGCCATTGTTGCTGCTGTAGTGGCCT'IGATCTACTGCAGGAAAAAGCGGATTTCAGCCAATCCCACTAATCCTGATGAGG
CTGACAAAGTTGGGGCTGAGAACACAATCACCTATTCACTTCTCATGCACCCGGATGCTCTGGAAGAGCCTGATGACCAGAACCGTATTTAG
61
MYQDYPGNFDTSSRGSSGSPAHAEΞYSSGGGGQQKFRVDMPGSGSAFI PTINAITTSQDLQWMVQPTVITSMSNPYPRSHPYSPLPGIiASVPGHMA PRPGVIKTIGTTVGR RRRDEQ SPEEEEKRRIRRERNKLAAAKCRNRRRELIEKLQAETEELEEEKSGLQKEIAELQKEKEKLEFMLVAHGPVCKISPEERRSPPAPGLQPMRSGGGSVGAVWKQE PLEEDSPSSSSAG DKAQRSVIKPI SIAGGFYGEEPLHTPIWTSTPAVTPGTSN VFTYPSVLEQESPASPSESCSKAHRRSSSSGDQSSDSLNSPTLLAL
62
ATCATGTACCAGGATTATCCCGGGAACTTTGACACCTCGTCCCGGGGCAGCAGCGGCTCTCCTGCGCACGCCGAGTCCTACTCCAGCGGCGGCGGCGGCCAGCAGAAATTCC GGGTAGATATGCCTGGCTCAGGCAGTGCATTCATCCCCACCATCAACGCCATCACGACCAGCCAGGACCTGCAGTGGATGGTGCAGCCCACAGTGATCACCTCCATGTCCAA CCCATACCCTCGCTCGCACCCCTACAGCCCCCIGCCGGGCCTGGCCTCTGTCCCTGGACACATGGCCCTCCCAAGACCTGGCGTGATCAAGACCATTGGCACCACCGTGGGC CGCAGGAGGAGAGATGAGCAGCTGTCTCCTGAAGAGGAGGAGAAGCGTCGCATCCGGCGGGAGAGGAACAAGCTGGCTGCAGCCAAGTGCCGGAACCGACGCCGGGAGCTGA CAGAGAAGCTGCAGGCGGAGACAGAGGAGCTGGAGGAGGAGAAGTCAGGCCTGCAGAAGGAGATTGCTGAGCTGCAGAAGGAGAAGGAGAAGCTGGAGTTCATGTTGGTGGC TCACGGCCCAGTGTGCAAGATTAGCCCCGAGGAGCGCCGATCGCCCCCAGCCCCTGGGCTGCAGCCCATGCGCAGTGGGGGTGGCTCGGTGGGCGCTGTAGTGGTGAAACAG GAGCCCCTGGAAGAGGACAGCCCCTCGTCCTCGTCGGCGGGGCTGGACAAGGCCCAGCGCTCTGTCATCAAGCCCATCAGCATTGCTGGGGGCTTCTACGGTGAGGAGCCCC TGCACACCCCCATCGTGGTGACCTCCACACCTGCTGTCACTCCGGGCACCTCGAACCTCGTCTTCACCTATCCTAGCGTCCTGGAGCAGGAGTCACCCGCATCTCCCTCCGA ATCCTGCTCCAAGGCTCACCGCAGAAGCAGTAGCAGCGGGGACCAATCATCAGACTCCTTGAACTCCCCCACTCTGCTGGCTCTGTAACCCAGTGCACCTCCCTCCGGAGC
63
MYQDYPGNFDTSSRGSSGSPAHAESYSSGGGGQQKFRVDMPGSGSAFI PTINAITTSQDLQ MVQPTVITSMSNPYPRSHPYSPLPGLASVPGHMA PRPGVIKTIGTTVGR RRRDEQLSPEEEEKRRIRRERNKLAAAKCRNRRRELTEK QAETEE-.EEEKSGLQKEIAE QKEKEKLEFMLVAHGPVCKISPEERRSPPAPGLQPMRSGGGSVGAVVVKQE PLEEDSPSSSSAGLDKAQRSVIKPISIAGGFYGEEPLHTPIWTSTPAVTPGTSNLVFTYPSVtiEQESPASPSESCSKAHRRSSSSGDQSSDS NSPTL AL
64
ATCATGTACCAGGATTATCCCGGGAACTTTGACACCTCGTCCCGGGGCAGCAGCGGCTCTCCTGCGCACGCCGAGTCCTACTCCAGCGGCGGCGGCGGCCAGCAGAAATTCC GGGTAGATATGCCTGGCTCAGGCAGTGCATTCATCCCCACCATCAACGCCATCACGACCAGCCAGGACCTGCAGTGGATGGTGCAGCCCACAGTGATCACCTCCATGTCCAA CCCATACCCTCGCTCGCACCCCTACAGCCCCC1GCCGGGCCTGGCCTCTGTCCCTGGACACATGGCCCTCCCAAGACCTGGCGTGATCAAGACCATTGGCACCACCGTGGGC CGCAGGAGGAGAGATGAGCAGCTGTCTCCTGAAGAGGAGGAGAAGCGTCGCATCCGGCGGGAGAGGAACAAGCTGGCTGCAGCCAAGTGCCGGAACCGACGCCGGGAGCTGA CAGAGAAGCTGCAGGCGGAGACAGAGGAGCTGGAGGAGGAGAAGTCAGGCCTGCAGAAGGAGATTGCTGAGCTGCAGAAGGAGAAGGAGAAGCTGGAGTTCATGTTGGTGGC TCACGGCCCAGTGTGCAAGATTAGCCCCGAGGAGCGCCGATCGCCCCCAGCCCCTGGGCTGCAGCCCATGCGCAGTGGGGGTGGCTCGGTGGGCGCTGTAGTGGTGAAACAG GAGCCCCTGGAAGAGGACAGCCCCTCGTCCTCGTCGGCGGGGCTGGACAAGGCCCAGCGCTCTGTCATCAAGCCCATCAGCATTGCTGGGGGCTTCTACGGTGAGGAGCCCC TGCACACCCCCATCGTGGTGACCTCCACACCTGCTGTCACTCCGGGCACCTCGAACCTCGTCTTCACCTATCCTAGCGTCCTGGAGCAGGAGTCACCCGCATCTCCCTCCGA ATCCTGCTCCAAGGCTCACCGCAGAAGCAGTAGCAGCGGGGACCAATCATCAGACTCCTTGAACTCCCCCACTCTGCTGGCTCTGTAACCCAGTGCACCTCCCTCCGGAGC
65
MEAENAGSYSLQQAQAFYTFPFQQLMAEAPNMAWNEQQMPEEVPAPAPAQEPVQEAPKGRKRKPRTTΞPKQPVEPKKPVESKKSGKSAKPKEKQEKITDIFKVKRKVDRFN
GVSEAELLTKTLPDI TFNLDIVI IGINPGLMAAYKGHHYPGPGNHFWKCLFMSGLSEVQLNHMDDHTLPGKYGIGFTNMVERTTPGSKDLSSKEFREGGRILVQKLQKYQP
RIAVFNGKCIYEI FSKEVFGVKVKNLEFGLQPHKI PDTETLCYVMPSSSARCAQFPRAQDKVHYYIKLKDLRDQ KGIERNMDVCEVQYTFDLQ AQEDAKKMAVKEEKYDP
GYEAAYGGAYGENPCSSEPCGFSSNGLIESVELRGESAFSGIPNGQWMTQSFTDQI PSFSNHCGTQEQEEESHA
66
GCACCAGGCGCCCAGTGGAGCCGTTTGGGAGAATTGCCTGCGCCACGCAGCGGGGCCGGACAGGCGGTAAGGATCTGATTAGGCTTTCGAACTTGAGTTTGACTGATGTCTT
CTGTGTGGTGTCCGCTAAATCCCACAGCATATAGGATCAGTCGCATTGGTTATAAGGTTTGCTTCTGGCTGGGTGCGGTGGCTCATGCCTGTAATCCAACATTGGGAGGCCA
AGGCAGGCGGACCACCTGAAGTCGGGAGCTTGAGTCCAGCCACTGTCTGGGTACTGCCAGCCATCGGGCCCAGGTCTCTGGGGTTGTCTTACCGCAGTGAGTACCACGCGGT
ACTACAGAGACCGGCTGCCCGTGTGCCCGGCAGGTGGAGCCGCCGCATCAGCGGCCTCGGGGAATGGAAGCGGAGAACGCGGGCAGCTATTCCCTTCAGCAAGCTCAAGCTT
TTTATACGTTTCCATTTCAACAACTGATGGCTGAAGCTCCTAATATGGCAGTTGTGAATGAACAGCAAATGCCAGAAGAAGTTCCAGCCCCAGCTCCTGCTCAGGAACCAGT
GCAAGAGGCTCCAAAAGGAAGAAAAAGAAAACCCAGAACAACAGAACCAAAACAACCAGTGGAACCCAAAAAACCTGTTGAGTCAAAAAAATCTGGCAAGTCTGCAAAACCA
AAAGAAAAACAAGAAAAAATTACAGACACATTTAAAGTAAAAAGAAAAGTAGACCGTTTTAATGGTGTTTCAGAAGCTGAACTTCTGACCAAGACTCTCCCCGATATTTTGA
CCTTCAATCTGGACATTGTCATTATTGGCATAAACCCGGGACTAATGGCTGCTTACAAAGGGCATCATTACCCTGGACCTGGAAACCATTTTTGGAAGTGTTTGTTTATGTC
AGGGCTCAGTGAGGTCCAGCTGAACCATATGGATGATCACACTCTACCAGGGAAGTATGGTATTGGATTTACCAACATGGTGGAAAGGACCACGCCCGGCAGCAAAGATCTC
TCCAGTAAAGAATTTCGTGAAGGAGGACGTATTCTAGTACAGAAATTACAGAAATATCAGCCACGAATAGCAGTGTTTAATGGAAAATGTATTTATGAAATTTTTAGTAAAG
AAGTTTTTGGAGTAAAGGTTAAGAACTTGGAATTTGGGCTTCAGCCCCATAAGATTCCAGACACAGAAACTCTCTGCTA'IGTTATGCCATCATCCAGTGCAAGATGTGCTCA
GTTTCCTCGAGCCCAAGACAAAGTTCATTACTACATAAAACTGAAGGACTTAAGAGATCAGTTGAAAGGCATTGAACGAAATATGGACGTTCAAGAGGTGCAATATACATTT
GACCTACAGCTTGCCCAAGAGGATGCAAAGAAGATGGCTGTTAAGGAAGAAAAATATGATCCAGGTTATGAGGCAGCATATGGTGGTGCTTACGGAGAAAATCCATGCAGCA
GTGAACCTTGTGGCTTCTCTTCAAATGGGCTAATTGAGAGCGTGGAGTTAAGAGGAGAATCAGCTTTCAGTGGCATTCCTAATGGGCAGTGGATGACCCAGTCATTTACAGA
CCAAATTCCTTCCTTTAGTAATCACTGTGGAACACAAGAACAGGAAGAAGAAAGCCATGCTTAAGAATGGTGCTTCTCAGCTCTGCTTAAATGCTGCAGTTTTAATGCAGTT
GTCAACAAGTAGAACCTCAGTTTGCTAACTGAAGTGTTTTATTAGTATTTTACTCTAGTGGTGTAATTGTAATGTAGAACAGTTGTGTGGTAGTGTGAACCGTATGAACCTA
AGTAGTTTGGAAGAAAAAGTAGGGTTTTTGTATACTAGCTTTTGTATTTGAATTAATTATCATTCCAGCTTTTTATATACTATATTTCATTTATGAAGAAATTGATTTTCTT
TTGGGAGTCACTTTTAATCTGTAATTTTAAAATACAAGTCTGAATATTTATAGTTGATTCTTAACTGTGCATAAACCTAGATATACCATTATCCCTTTTATACCTAAGAAGG
GCATGCTAATAATTACCACTGTCAAAGAGGCAAAGGTGTTGATTTTTGTATATAAGTTAAGCCTCAGTGGAGTCTCATTTGTTAGTTTTTAGTGGTAACTAAGGGTAAACTC
AGGGTTCCCTGAGCTATATGCACACTCAGACCTCTTTGCTTTACCAGTGGTGTTTGTGAGTTGCTCAGTAGTAAAAACTGGCCCTTACCTGACAGAGCCCTGGCTTTGACCT
GCTCAGCCCTGTGTGTTAATCCTCTAGTAGCCAATTAACTACTCTGGGGTGGCAGGTTCCAGAGAATCGAGTAGACCTTTTGCCACTCATC GTGTTTTACTTGAGACATGT
AAATATGATAGCKSAAGGAACTGAATTTCTCCATTCATATTTATAACCATTCTAGTTTTATCTTCCTTGGCTTTAAGAGTGTGCCATGGAAAGTGATAAGAAATGAACTTCTA
GGCTAAGCAAAAAGATGCTGGAGATATTTGATACTCTCATTTAAACTGGTGCTTTATGTACATGAGATGTACTAAAATAAGTAATATAGAATTTTTCTTGCTAGGTAAATCC
AGTAAGCCAATAATTTTAAAGATTCTTTATCTGCATCATTGCTGTTTGTTACTATAAATTAAATGAACCTCATGGAAAGGTTGAGGTGTATACCTT GTGATTTTCTAATGA GTΓTTCCATGGTGCTACAAATAATCCAGACTACCAGGTCTGGTAGATATTAAAGCTGGGTACTAAGAAATGTTATTTGCATCCTCTCAGTTACTCCTGAATATTCTGATTTC ATACGTACCCAGGGAGCATΣCTGTTTTGTCAATCAATATAAAATATTTATGAGGTCTCCCCCACCCCCAGGAGGTTATATGATTGCTCTTCTCTTTATAATAAGAGAAACAA ATΓCTTATTGTGAATCTTAACATGCTTTTTAGCTGTGGCTATGATGGATTTTATTTTTTCCTAGGTCAAGCTGTGTAAAAGTCATTTATGTTATTTAAATGATGTACTGTAC TGCTGTTTACATGGACGTTTTGTGCGGGTGCTTTGAAGTGCCTTGCATCAGGGATTAGGAGCAATTAAATTATTTTTTCACGGGACTGTGTAAAGCATGTAACTAGGTATTG CTRTGGTATATAACTATTGTAGCTTTACAAGAGATTGTTTTATTTGAATGGGGAAAATACCCTTTAAATTATGACGGACATCCACTAGAGATGGGTTTGAGGATTTTCCAAG CGΓGTAATAATGATGTTTTTCCTAACATGACAGATGAGTAGTAAATGTTGATATATCCTATACATGACAGTGTGAGACTTTTTCATTAAATAATATTGAAAGATTTTAAAAT TCATTTGAAAGTCTGATGGCTTTTACAATAAAAGATATTAAGAATTGTTA
67
MG LSQGSPLS EETKFmADHVRP IGILQF HIYHAVKDPJIKDVLK GDEVEYMLVSFDHENKKVRLVLSGEKV ETLQEKGERTNPNHPT WRPEYGSYMIEGTPGQPYGG
TMSEFNTVEA IMRK RKEATSILEENQALCTITSFPR GCPGFTLPEVKPNPVEGGASKSLFFPDEAI KHPRFST TR IRH RGEKVVINVPIFKDKNTPSPFI ETFTED
DEASRASKPDHIYrΦAMGFGMGNCCliQVTFQACSISEARYLYDQLAτiCFIV ALSAASPFYRGYVSDIDCRWGVIΞASVDDRTREERGLEPLK NNYRISKSRYDS IDSYL
SKCGEKYNDIDLTIDKEIYEQLLQEGIDHLLAQHVAHLFIRDPLTLFEEKIHLDDA ESDHFENIQSTNWQTMRFKPPPPNSDIGWRVEFRPMEVQLTDFENSAYWFWLL
TRVILSYKLDFLIPLSKVDENMKVAQKF 3AV CGMFYFRKDICKGGNAVVDGCGK^^
LIKKRASGELMTVARWMREFIANHPDYKQDSVITDEMNYSLILKCNQIANELCECPELLGSAFRKVKYSGSKTDSSN
68
GGCACGAGGCTGAGTATCCATCTCGCGCCCGGAAGCGGGCGACCGCCGTCAGCCCGGAGGAGGAGGAGGAGGAGGAGGAGGAGGGGGCGGCCATGGGGCTGCTGTCCCAGGG CTCGCCGCTGAGCTGGGAGGAAACCAAGCGCCATGCCGACCACGTGCGGCGGCACGGGATCCTCCAGTTCCTGCACATCTACCACGCCGTCAAGGACCGGCACAAGGACGTT CTCAAGTGGGGCGATGAGGTGGAATACATGTTGGTATCTTTTGATCATGAAAATAAAAAAGTCCGGTTGGTCCTGTCTGGGGAGAAAGTTCTTGAAACTCTGCAAGAGAAGG GΒGAAAGGACAAACCCAAACCATCCTACCCTTTGGAGACCAGAGTATGGGAGTTACATGATTGAAGGGACACCAGGACAGCCCTACGGAGGAACAATGICCGAGTTCAATAC AGΓTGAGGCCAACATGCGAAAACGCCGGAAGGAGGCTACTTCTATATTAGAAGAAAATCAGGCTCTTTGCACAATAACTTCATTTCCCAGATTAGGCTGTCCTGGGTTCACA CTGCCCGAGGTCAAACCCAACCCAGTGGAAGGAGGAGCTTCCAAGTCCCTCTTCTTTCCAGATGAAGCAATAAACAAGCACCCTCGCTTCAGTACCTΪAACAAGAAATATCC GACATAGAAGAAGAGAAAAGGTTGTCATCAATGTACCAATATTTAAGGACAAGAATACACCATCTCCATTTATAGAAACATTTACTGAGGATGATGAAGCTTCAAGGGCTTC TAAGCCGGATCATATTTACATGGATGCCATGGGATTTGGAATGGGCAATTGCTGTCTCCAGGTGACATTCCAAGCCTGCAGTATATCTGAGGCCAGATACCTTTATGATCAG TTGGCTACTATCTGTCCAATTGTTATGGCTTTGAGTGCTGCATCTCCCTTTTACCGAGGCTATGTGTCAGACATTGATTGTCGCTGGGGAGTGATTTCIGCATCTGTAGATG ATAGAACTCGGGAGGAGCGAGGACTGGAGCCATTGAAGAACAATAACTATAGGATCAGTAAATCCCGATATGACTCAATAGACAGCTATTTATCTAAGTGTGGTGAGAAATA TAAΓGACATCGACTTGACGATAGATAAAGAGATCTACGAACAGCTGTTGCAGGAAGGCATTGATCATCTCCTGGCCCAGCATGTTGCTCATCTCTTTA'ITAGAGACCCACTG ACACTGTTTGAAGAGAAAATACACCTGGATGATGCTAATGAGTCTGACCATTTTGAGAATATTCAGTCCACAAATTGGCAGACAATGAGATTTAAGCCCCCTCCTCCAAACT CAGACATTGGATGGAGAGTAGAATTTCGACCCATGGAGGTGCAATTAACAGACTTTGAGAACTCTGCCTATGTGGTGTTTGTGGTACTGCTCACCAGAGTGATCCTTTCCTA CAAATTGGATTTTCTCATTCCACTGTCAAAGGTTGATGAGAACATGAAGGTAGCACAGAAAAGAGATGCTGTCTTGCAGGGAATGTTTTATTTCAGGAAAGATATTTGCAAA
GGTGGCAATGCAGTGGTGGATGGTTGTGGCAAGGCCCAGAACAGCACGGAGCTCGCTGCAGAGGAGTACACCCTCATGAGCATAGACACCATCATCAA'IGGGAAGGAAGGTG
TGRTTCCTGGACTGATCCCAATTCTGAACTCTTACCTTGAAAACATGGAAGTGGATGTGGACACCAGATGTAGTATTCTGAACTACCTAAAGCTAATTAAGAAGAGAGCATC TGGAGAACTAATGACAGTTGCCAGATGGATGAGGGAGTTTATCGCAAACCATCCTGACTACAAGCAAGACAGTGTCATAACTGATGAAATGAATTATAGCCTTATTTTGAAG TGTAACCAAATTGCAAATGAATTATGTGAATGCCCAGAGTTACTTGGATCAGCATTTAGGAAAGTAAAATATAGTGGAAGTAAAACTGACTCATCCAACTAGACATTCTACA GAAAGAAAAATGCATTATTGACGAACTGGCTACAGTACCATGCCTCTCAGCCCGTGTGTATAATATGAAGACCAAATGATAGAACTGTACTGTTTTCTGGGCCAGTGAGCCA GAAATTGATTAAGGCTTTCTTTGGTAGGTAAATCTAGAGTTTATACAGTGTACATGTACATAGTAAAGTATTTTTGATTAACAATGTATTTTAATAACATATCTAAAGTCAT CATGAACTGGCTTGTACATTTTTAAATTCTTACTCTGGAGCAACCTACTGTCTAAGCAGTTTTGTAAATGTACTGGTAATTGTACAATACTTGCATTCCAGAGTTAAAATGT TTACTGTAAATTTTTGTTCTTTTAAAGACTACCTGGGACCTGATTTATTGAAATTTTTCTCTTTAAAAACATTTTCTCTCGTTAATTTTCCTTTGTCATTTCCTTTGTTGTC TACATTAAATCACTTGAATCCATTGAAAGTGCTTCAAGGGTAATCTTGGGTTTCTAGCACCTTATCTATGATGTTTCTTTTGCAATTGGAATAATCACTTGGTCACCTTGCC CCAAGCTTTCCCCTCTGAATAAATACCCATTGAACTCTGAAAAAAAAAAAAAAAAAAA
69 TτSASSHL KGIKQVYMS PQGEKVQA^1YIWIDGTGEGLRCKTRT DSEPKCVEE PEWNFDGSST QSEGSNSD^rY VPA MFRDPFRKDP K VLCEVFKYNRRPAETN HTCKRI^Cl WSNQHPWFσMEQEYTIJMGTDGHPFGWPSNGFPGPQGPYYCGVGA RAYGRDIVEAHYRACLYAGVKIAGT AEVMPAQ EFQIGPCEGISMGDH WVARFI HRVCEDFGVIATFDPKPIPGN NGAGCHTNFSTKAMREENGLKYIEEAIEKLSKRHQYHIRAYDPKGGLDNARRLTGFHETSNINDFSAGVANRSASIRIPRTVGQEKKGY
FEDRRPSANCDPFSVTEALIRTCLLNETGDEPFQYKN
70
GTTTAGTGTTAACCTCAGCTACACTGAAGGAATAGACCTTAGTCCTCACAAGTATAAGTTCTAGCTTGGAAGCCTGGGTTCTGCAGTAGCTGTGGAACTTAAGCCTCTGAGC TCAGGGATGCAGAGGCATTGAGTTACTACCAAGGGCCTGATCTTTTCTTTAGCAGGCATCTGTGTTAATTGTTTCAAAAGGTGGTGATCAG'ITTTACAGCCTATTATAAAGG AGATTTTTGCCTACTATAAAACTAATCCCCCTGAAAGAGTGAGTAAACATAACTTTTTGTGTGTTGACTTCCACAAGGGAAGGAGTTGGCACTTACACTCTGACTTTTGATT
TCCCACTTAAATAAAGGCATCAAGCAGGTGTACATGTCCCTGCCTCAGGGTGAGAAAGTCCAGGCCATGTATATCTGGATCGATGGTACTGGAGAAGGACTGCGCTGCAAGA CCCGGACCCTGGACAGTGAGCCCAAGTGTGTGGAAGAGTTGCCTGAGTGGAATTTCGATGGCTCTAGTACTTTACAGTCTGAGGGTTCCAACAG'IGACATGTATCTCGTGCC TGCTGCCATGTTTCGGGACCCCTTCCGTAAGGACCCTAACAAGCTGGTGTTATGTGAAGTTTTCAAGTACAATCGAAGGCCTGCAGGTGTGTTATAGCACAGCTATGGATAC CCCTCCTCAATCTGTGAATGCTGTGAAGGGGAGGGAGAAGACATTCTGAAATCAGCATTGGGAAGACTAGGCAATTTCAGCACTATTTTAAGAATCTGAGTGATTCTTTTCC CTGAACTTCTGCTTTGAGGAAGAGATAATATGGCCCATCTTTCTATGGTCTTCTCTGTTGGTTGCATAAAATAGCATTGGATTTGTCCAGATCTG'TTTGCCGGTCTTGGAGT CCCCAGTAACAGCCTTCCTGCCTGGAATGTAGGCCAGGACAAATGTAAACCAATGGACAAATGTTTCTCAAAAATTATAGAATGGCTCCAAGTGCCTGAGAAATGAAGAATA AATCTGACAACCAGAAGCAGCTGTCTTGTGAATAGAGGGTTAAGTGCCTGGCATTTGGTGCTTGGGAGGTGGCCAGAATGCAGATAAGGTGAAAGT'rGCCCTGTTCTAAATC CACTCCCATGTGACTTGGTTGTAACTGAGTTTAGTTAAAACTGAAGTCTTTCAGAGTCTTCCTACAGATGTACAATTAACAGCTTCTCTCATTTTTCTGACTCGGTGATCCC AAGAAGGCCTATACTGGGTCAGTTCATACCATAGTGCACACCTCAGTTGTATAGAATCCAAGGACTATTCTCCCATCAGCATCGGTATTCAGCATCTATGTCTTTAGATCCC TGATGGCGTATTATTGACTCTTTTTTCTAGAGACCAATTTGAGGCACACCTGTAAACGGATAATGGACATGGTGAGCAACCAGCACCCCTGGTTTGGCATGGAGCAGGAGTA TACCCTCATGGGGACAGATGGGCACCCCTTTGGTTGGCCTTCCAACGGCTTCCCAGGGCCCCAGGGTAAGTCTCCTTGGGTTAGAGGTGAAATTCCCAGAAGTGTCTAACTG TGCAGGAATGCCCCTTCCCAGGGATGGGAATGACTTTCAGAATCAAGAAGCAAAATAATACAGTAAAGGCGAAACAGCCCTCACATCACCAAAGTCCAAAAATGGATATGAA TATATAAAGTAAGGTTTTAGGGGGAACGTTTGGCCCCACTGAAGCTGTGGTGAAGAGGAACTCCCCTATTGCCCCTCCCCTGCCCCGCACCTGCAGATGAAGGCAAGGATAG TGATTCAAGAGGGCAAGGCTTAAGGGCCTTCTGATCTCTGACTTTGGGATTCTCTGGATTTCTTGACTCTTAG'rGTTTTGTCCTGATGCTTCTGTAGGTCCATATTACTGTG GTGTGGGAGCAGACAGAGCCTATGGCAGGGACATCGTGGAGGCCCATTACCGGGCCTGCTTGTATGCTGGAGTCAAGATTGCGGGGACTAATGCCGAGGTCATGCCTGCCCA GGTAAGTATAGCTCCAATCCATCAATGAAGAAGGGTAGGTAGGTGTACATAGGACTTTTGCTAGTAAGGGCTGCTGATACACCACTCACTAACCCAAAACCTAAGAACGGGT TGGAGTACAGGTGAGAAGAGAACAGGTTTAGGAGATTCTGAGTTGGAGTGAGCAGTTAGCTTTGTTTTAATGGCCAAGCTTCTCGTTTCTAGTGGGAATTTCAGATTGGACC TTGTGAAGGAATCAGCATGGGAGATCATCTCTGGGTGGCCCGTTTCATCTTGCATCGTGTGTGTGAAGACTTTGGAGTGATAGCAACCTTTGATCCTAAGCCCATTCCTGGG AACTGGAATGGTGCAGGCTGCCATACCAACTTCAGCACCAAGGCCATGCGGGAGGAGAATGGTCTGAAGTGAGTACCTTCTGCTGGGGCCATCTTTAATCTCCTGTGGCAGA AAACTTGGGAGGAGACTTAGCAATCTCTCAGCAAAGTCTCCTTTGCAGGATGACTTGCAAATATTTGCCAAAGATGAGTAAACTTGACTTCTCAGTCTGGACGTACTTTAGG TGTTGACACTTGCCTTCACATTCTCTCATTTTGTTCCTATTTGAAAAATACCAAATAATACTTCTGATTCACAGTGATAAATATTTGTTATAATTTATATAATATATATTAG TCATATATCATTATATAAATATATATCGATATATATATTTGTGACATATGTCATGGTGACAGGGAAAAGTTGACAAATTCATGCATTTGAAAATCTTTTAGAACTAAATTAG TAACAATACAGGCATGTGGATAAGCTTAATGCTTATGAGGGGGAGAAAGTTTCAAATGATTAGTCTTTTCAACAAACAGTAACTTTGTACTGCTTGTCGGGCACTGTTCTCA CCACTGAGACACACAGGTAAGAAGATGCAGCCACTGCCCTCATGAAGTATTTGTTCTACTGGTATCATATTTTGGTGCACTTCATTCTTGGCTCCATACCTGGAGACAAGGT TGGAC GCCATCTTTTCTGTTTACTCTAGGTACATCGAGGAGGCCATTGAGAAACTAAGCAAGCGGCACCAGTACCACATCCGTGCCTATGATCCCAAGGGAGGCCTGGACA ATGCCCGACGTCTAACTGGATTCCATGAAACCTCCAACATCAACGACTTTTCTGCTGGTGTAGCCAATCGTAGCGCCAGCATACGCATTCCCCGGACTGTTGGCCAGGAGAA GAAGGGTTACTTTGAAGATCGTCGCCCCTCTGCCAACTGCGACCCCTTTTCGGTGACAGAAGCCCTCATCCGCACGTGTCTTCTCAATGAAACCGGCGATGAGCCCTTCCAG TACAAAAATTAAGTGGACTAGACCTCCAGCTGTTGAGCCCCTCCTAGTTCTTCATCCCACTCCAACTCTTCCCCCTCTCCCAGTTGTCCCGATTGTAACTCAAAGGGTGGAA TATCAAGGTCGTTTTTTTCATTCCATGTGCCCAGTTAATCTTGCTTTCTTTGTTTGGCTGGGATAGAGGGGTCAAGΪTATTAATTTCTTCACACCTACCCTCCTTTTTTTCC CTATCAC GAAGCTTTTTAGTGCATTAGTGGGGAGGAGGGTGGGGAGACATAACCACTGCTTCCATTTAATGGGGTGCACCTGTCCAATAGGCGTAGCTATCCGGACAGAGC ACGTTTGCAGAAGGGGGTCTCTTCTTCCAGGTAGCTGAAAGGGGAAGACCTGACGTACTCTGGTTAGGTTAGGACTTGCCCTCGTGGTGGAAACTTTTCTTAAAAAGTTATA ACCAACTTTTCTATTAAAAGTGGGAATTAGGAGAGAAGGTAGGGGTTGGGAATCAGAGAGAATGGCTTTGGTCTCTTGCTTGTGGGACTAGCCTGGCTTGGGACTAAATGCC CTGCTCTGAACACGAAGCTTAGTATAAACTGATGGATATCCCTACCTTGAAAGAAGAAAAGGTTCTTACTGCTTGGTCCTTGATTTATCACACAAAGCAGAATAGTATTTrT ATATTTAAATGTAAAGACAAAAAACTATATGTATGGTTTTGTGGATTATGTGTGTT'ITGCTAAAGGAAAAAACCATCCAGGTCACGGGGCACCAAATTTGAGACAAATAGTC GGATTAGAAATAAAGCATCTCATTTTGAGTAGAGAGCAAGGGAAGTGGTTCTTAGATGGTGATCTGGGATTAGGCCCTCAAGACCCTTTTGGGTTTCTGCCCTGCCCACCCT CTGGAGAAGGTGGGCACTGGATTAGTTAACAGACAACACGTTACTAGCAGTCACTTGATCTCCGTGGCTTTGGTTTAAAAGACACACTTGTCCACATAGGTTTAGAGATAAG AGTTGGCTGGTCAACTTGAGCATGTTACTGACAGAGGGGGTATTGGGGTTATTTTCTGGTAGGAATAGCATGTCACTAAAGCAGGCCTTTTGATATTAAATTTTTTAAAAAG CAAAATTATAGAAGTTTAGATTTTAATCAAATTTGTAGGGTTTCTAGGTAATTTTTACAGAATTGCTTGTTTGCTTCAACTGTCTCCTACCTCTGCTCTTGGAGGAGATGGG GACAGGGCTGGAGTCAAAACACTTGTAATTTTGTATCTTGATGTCTTTGTTAAGACTGCTGAAGAATTATTTTTTTTCTTTTATAATAAGGAATAAACCCCACCTTTATTCC TTCATTTCATCTACCATTTTCTGGTTCTTGTGTTGGCTGTGGCAGGCCAGCTGTGGTTTTCTTTTGCCATGACAACTTCTAATTGCCATGTACAGTATGTTCAAAGTCAAAT AACTCCTCATTGTAAACAAACTGTGTAACTGCCCAAAGCAGCACTTATAAATCAGCCTAACATAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
71
MTN QEOT.TALSADLAIFERKIQHIAKEMTIDLSHYEIDHLA RVNSEQSAKNWLILLLKCGRILSDNIVNGRKIYLIELEKPVKFANQFVDIIELPLPKNKKYPIEGWEHI
EIVMPFLPKESINEMINRVNMYF XLTQ TIKVSEPKVDGER PNPSIAVSFTDKTVNHTCIKVHPYSIKKYLRFSKNE
72
AGGGATTCTTCTGCCTCCACTTCAGGTTTTAGCAGCTTGGTGCTAAATTGCTGTCTCAAAATGCAGAGGATCTAATTTGCAGAGGAAAACAGCCAAAGAAGGAAGAGGAGGA
AAAGGAAAAAAAAAGGGGTATATTGTGGATGCTCTACTTTTCTTGGAAATGCAAAAGATTATGCATATTTCTGTCCTCCTTTCTCCTGTTTTATGGGGAC'IGATTTTTGGTe
TCTCTTCTAACAGCATACAGATAGGGGGGCTATTTCCTAGGGGCGCCGATCAAGAATACAGTGCATTTCGAGTAGGGATGGTTCAGTTTTCCACTTCGGAGTTCAGACTGAC
ACCCCACATCGACAATTTGGAGGTGGCAAACAGCTTCGCAGTCACTAATGCTTTCTGCTCCCAGTTTTCGAGAGGAGTCTATGCTATTTTTGGATTTTATGACAAGAAGTCT
GTAAATACCATCACATCATTTTGCGGAACACTCCACGTCTCCTTCATCACTCCCAGCTTCCCAACAGATGGCACACA'ICCATTTGTCATTCAGATGAGACCCGACCTCAAAG
GAGCTCTCCTTAGCTTGATTGAATACTATCAATGGGACAAGTTTGCATACCTCTATGACAGTGACAGAGGCTTATCAACACTGCAAGCTGTGCTGGATTCTGCTGCTGAAAA
GAAATGGCAAGTGACTGCTATCAATGTGGGAAACATTAACAATGACAAGAAAGATGAGATGTACCGATCACTTTTTCAAGATCTGGAGTTAAAAAAGGAACGGCGTGTAATT
CTGGACTGTGAAAGGGATAAAGTAAACGACATTGTAGACCAGGTTATTACCATTGGAAAACACGTTAAAGGGTACCACTACATCATTGCAAATCTGGAATTTACTGATGGAG
ACCTATTAAAAATCCAGTTTGGAGGTGCAAATGTCTCTGGATTTCAGATAGTGGACTATGATGATTCGTTGGTATCTAAATTTATAGAAAGATGGTCAACACTGGAAGAAAA
AGAATACCCTGGAGCTCACACAACAACAATTAAGTATACTTCTGCTCTGACCTATGATGCCGTTCAAGTGATGACTGAAGCCTTCCGCAACCTAAGGAAGCAAAGAATTGAA
ATCTCCCGAAGGGGGAATGCAGGAGACTGTCTGGCAAACCCAGCAGTGCCCTGGGGACAAGGTGTAGAAATAGAAAGGGCCCTCAAACAGGTTCAGGTTGAAGGTCTCTCAG
GAAATATAAAGTTTGACCAGAATGGAAAAAGAATAAACTATACAATTAACATCATGGAGCTCAAAACTAATGGGCCCCGGAAGATTGGCTACTGGAGTGAAGTGGACAAAAT
GGTTGTTACCCTTACTGAGCTCCCTTCTGGAAATGACACCTCTGGGCTTGAGAATAAGACTGTTGTTGTCACCACAATTTTGGAATCTCCGTATGTTATGATGAAGAAAAAT
CATGAAATGCTTGAAGGCAATGAGCGCTATGAGGGCTACTGTGTTGACCTGGCTGCAGAAATCGCCAAACATTGTGGGTTCAAGTACAAGTTGACAATTGTTGGTGATGGCA
AGTATGGGGCCAGGGATGCAGACACGAAAATTTGGAATGGGATGGTTGGAGAACTTGTATATGGGAAAGCTGATATTGCAATTGCTCCATTAACTATTACCCTTGTGAGAGA
AGAGGTGATTGACTTCTCAAAGCCCTTCATGAGCCTCGGGATATCTATCATGATCAAGAAGCCTCAGAAGTCCAAACCAGGAGTGTTTTCCTTTCTTGATCCTTTAGCCTAT
GAGATCTGGATGTGCATTGTTTTTGCCTACATTGGGGTCAGTGTAGTTTTATTCCTGGTCAGCAGATTTAGCCCCTACGAGTGGCACACTGAGGAGTTTGAAGATGGAAGAG
AAACACAAAGTAGTGAATCAACTAATGAATTTGGGATTTTTAATAGTCTCTGGTTTTCCTTGGGTGCCTTTATGCGGCAAGGATGCGATATTTCGCCAAGATCCCTCTCTGG
GCGCATTGTTGGAGGTGTGTGGTGGTTCTTTACCCTGATCATAATCTCCTCCTACACGGCTAACTTAGCTGCCTTCCTGACTGTAGAGAGGATGGTGTCTCCCATCGAAAGT
GCTGAGGATCTTTCTAAGCAAACAGAAATTGCTTATGGAACATTAGACTCTGGCTCCACTAAAGAGTTTTTCAGGAGATCTAAAATTGCAGTGTTTGATAAAATGTGGACCT
ACATGCGGAGTGCGGAGCCCTCTGTGTTTGTGAGGACTACσσCCGAAGGGGTGGCTAGAGTGCGGAAGTCCAAAGGGAAATATGCCTACTTGTTGGAGTCCACGATGAACGA
GTACATTGAGCAAAGGAAGCCTTGCGACACCATGAAAGTTGGTGGAAACCTGGATTCCAAAGGCTATGGCATCGCAACACCTAAAGGATCCTCATTAGGAACCCCAGTAAAT
CTTGCAGTATTGAAACTCAGTGAGCAAGGCGTCTTAGACAAGCTGAAAAACAAATGGTGGTACGATAAAGGTGAATGTGGAGCCAAGGACTCTGGAAGTAAGGAAAAGACCA
GTGCCCTCAGTCTGAGCAACGTTGCTGGAGTATTCTACATCCTTGTCGGGGGCCTTGGTTTGGCAATGCTGGTGGCTTTGATTGAGTTCTGTTACAAGTCAAGGGCCGAGGC
GAAACGAATGAAGGTGGCAAAGAATGCACAGAATATTAACCCATCTTCCTCGCAGAATTCACAGAATTTTGCAACTTATAAGGAAGGTTACAACGTATA'IGGCATCGAAAGT
GTTAAAATTTAGGGGATGACCTTGAATGATGCCATGAGGAACAAGGCAAGGCTGTCAATTACAGGAAGTACTGGAGAAAATGGACGTGTTATGACTCCAGAATTTCCCAAAG
CAGTGCATGCTGTCCCTTACGTGAGTCCTGGCATGGGAATGAATGTCAGTGTGACTGATCTCTCGTGATTGATAAGAACCTTTTGAGTGCCTTACACAATGGTTTTCTTGTG
TGTTTATTGTCAAAGTGGTGAGAGGCATCCAGTATCTTGAAGACTTTTCTTTCAGCCAAGAATTCTTAAATATGTGGAGTTCATCTTGAATTGTAAGGAATGATTAATTAAA
ACACAACATCTTTTTCTACTCGAGTTACAGACAAAGCGTGGTGGACATGCACAGCTAACATGGAAGTACTATAATTTACCTGAAGTCTTTGTACAGACAACAAACCTGTTTC
TGCAGCCACTATTGTTAGTCTCTTGATTCATAATGACTTAAGCACACTTGACATCAACTGCATCAAGATGTGACATGTTTTAT
73
MLRVRCLRGGSRGAEAVHYIGSRLGRT TGWVQRTFQSTQAATASSRNSCAADDKATEPLPKDCPVSSYNE DPLEEVIVGRAENACVPPFTIEVKANTYEKYWPFYQKQGG HYFPKDHLKKAVAEIEEMCNILKTEGVTVRRPDPIDWSLKYKTPDFESTGLYSAMPPJ3ILIVVGNEIIEAPMAWRSRFFEYRAYRSIIKDYFHRGAKWTTAPKPTMADELYN QDYPIHSVEDRHKLAAQGKPVTTEFEPCFDAADFIRAGRDIFAQRSQVTNYLGIEWNRRHLAPDYRVHIISFKDPNP HIDATFNIIGPGIVLSNPDRPCHQIDLFKKAGWT IITPPTPIIPDDHPLVmSSKWLSh©TV MLDEKRVMVDANEVPIQKMFEKLGITTIKV IRNANSLGGGFHCWTCDVRRRGTLQSYLD
74
GAATTCGGCACGAGCGACGCGGCCCAGAGGCCAGGAACATTCCGCGCGTGGACCAGCCGGGCCAGGGCGATGCTGCGGGTGCGGTGTCTGCGCGGCGGGAGCCGCGGCGCCG AGGCGGTGCACTACATCGGATCTCGGCTTGGACGAACCTTGACAGGATGGGTGCAGCGAACTTTCCAGAGCACCCAGGCAGCTACGGCTTCCTCCCGGAACTCCTGTGCAGC TGACGACAAAGCCACTGAGCCTCTGCCCAAGGACTGCCCTGTCTCTTCTTACAACGAATGGGACCCCTTAGAGGAAGTGATAGTGGGCAGAGCAGAAAACGCCTGTGTTCCA CCGTTCACCATCGAGGTGAAGGCCAACACATATGAAAAGTACTGGCCATTTTACCAGAAGCAAGGAGGGCATTATTTTCCCAAAGATCATTTGAAAAAGGCTGTTGCTGAAA TTGAAGAAATGTGCAATATTTTAAAAACGGAAGGAGTGACAGTAAGGAGGCCTGACCCCATTGACTGGTCATTGAAGTATAAAACTCCTGATTTTGAGT'CTACGGGTTTATA CAGTGCAATGCCTCGAGACATCCTGATAGTTGTGGGCAATGAGATTATCGAGGCTCCCATGGCATGGCGTTCACGCTTCTTTGAGTACCGAGCGTACAGGTCAATTATCAAA GACTACTTCCACCGTGGCGCCAAGTGGACAACAGCTCCTAAGCCCACAATGGCTGATGAGCTTTATAACCAGGATTATCCCATCCACTCTGTAGAAGACAGACACAAATTGG CTGCTCAGGGAAAATTTGTGACAACTGAGTTTGAGCCATGCTTTGATGCTGCTGACTTCATTCGAGCTGGAAGAGATATTTTTGCACAGAGAAGCCAGGTTACAAACTACCT AGGCATTGAATGGATGCGTAGGCATCTTGCTCCAGACTACAGAGTGCATATCATCTCCTTTAAAGATCCCAATCCCATGCATATTGATGCTACCTTCAACATCATTGGACCT GGTATTGTGCTTTCCAACCCTGACCGACCATGTCACCAGATTGATCTTTTCAAGAAAGCAGGATGGACTATCATTACTCCTCCAACACCAATCATCCCAGACGATCATCCAC TCTGGATGTCATCCAAATGGCTTTCCATGAATGTCTTAATGCTAGATGAAAAACGTGTTATGGTGGATGCCAATGAAGTTCCAATTCAAAAGATGTTTGAAAAGCTGGGTAT CACTACCATTAAAGTTAACATTCGTAATGCCAATTCCCTGGGAGGAGGCTTCCATTGCTGGACCTGCGATGTCCGGCGCCGAGGCACCCTACAGTCCTACTTGGACTGAACA GGCCTGATGGAGCTTGTGGCTGGCCTCAGATACACCTAAGAAGCTTAGGGGCAAGGTTCATTCTCCTGCTTTAAAAAGTGCATGAACTGTAGTGCTTTAAACAATCATCTCC TTAACAGGGGTCGTAAGCCTGGTTTGCTTCTATTACTTTTCTTTGACATAAAGAAAATAACTTCTGCTAGGTATTACTCTCTACTCCTAAAGTTATTTACTATTTGGCTTCA AGTATAAAATTITGGTGAATGTGTACCAAGAAAAAAT AGTCACCTGAGTAACTTGGCCACTAATAATTAACCATCTACCTCTGTTTTTAATTTTCTTTCCAAAAGGCAGCT TGAAATGTTGGTCCTAATCTTAATTTTTTTTCCTCTTCTATAGACTTGAGAATGTTTTTCTCTAAATGAGAGAAAGACTTAGAATGTACACAGATCCAAAATAGAATCAGAT TATCTCTTTTTITCTAAAGGAGAGAAAGACTTAGAACATACACAGATCCTAAGTAGAACCAGGTAATTGTCTCTTTTTCTAATAAGGAATTTGGGTAATT'ITTAATTTTTTG TTTTTTAAAAAATAACCTAGACTATGCAAAACATCAAAGTGAATTTTCCATGAATGTTTTTAATATTCTCATCTCAACATTGTGATATATGCTACTAAAAACCTTTTCATAT ACATCTTACCTCATTTCAAGTGAATTATTTTAATCTTTTTCTCTCTTTCCAAAAATTTACAGGAATGTTTAGTGTAATTGGATTTCGCTATCAGTTCCCATCCTTAAGTTTT GATATTCAATATCTGATAGATACACTGCATCTTTGGTCATCTAAGATTTGTTTACAAATGTGCAAATTATTTAGAGCATAGACTTTATAAGCATTAAAAAAAACTAATGGAG GTAAAACCTAAATGCGATGTGAAATAATTTTAGTGTTGATACTGTATGTGTATTTTTATTCTAATAAACTTTTGTG'ITCCAGATTGAAAA
75 EAIAKYDFKATADDELSFKRGDI KVLNEECDQNV«KAELNGKrX3FIPKNYIEMKPHPWFFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLR
DGAGKYF WVVKF SLNE VDYHRSTSVS NQQIFLRDIEQVPQQPTYVQALFDFDPQEr3ELGFRRGDFIHVMDNSDPm KGACHGQTGMFPR-«VTPVNR V
76
GCCAGTGAATTCGGGGGCTCAGCCCTCCTCCCTCCCTTCCCCCTGCTTCAGGCTGCTGAGCACTGAGCAGCGCTCAGAATGGAAGCCATCGCCAAATATGACTTCAAAGCTA
CTGCAGACGACGAGCTGAGCTTCAAAAGGGGGGACATCCTCAAGGTTTTGAACGAAGAATGTGATCAGAACTGGTACAAGGCAGAGCTTAATGGAAAAGACGGCTTCATTCC
CAAGAACTACATAGAAATGAAACCACATCCGTGGΪTTTTTGGCAAAATCCCCAGAGCCAAGGCAGAAGAAATGCTTAGCAAACAGCGGCACGATGGGGCCTTTCTTATCCGA
GAGAGTGAGAGCGCTCCTGGGGACTTCTCCCTCTCTGTCAAGTTTGGAAACGATGTGCAGCACTTCAAGGTGCTCCGAGATGGAGCCGGGAAGTACTTCCTCTGGGTGGTGA AGTTCAATTCTTTGAATGAGCTGGTGGATTATCACAGATCTACATCTGTCTCCAGAAACCAGCAGATATTCCTGCGGGACATAGAACAGGTGCCACAGCAGCCGACATACGT CCAGGCCCTCTTTGACTTTGATCCCCAGGAGGATGGAGAGCTGGGCTTCCGCCGGGGAGATTTTATCCATGTCATGGATAACTCAGACCCCAACTGGTGGAAAGGAGCTTGC CACGGGCAGACCGGCATGTTTCCCCGCAATTATGTCACCCCCGTGAACCGGAACGTCTAAGAGTCAAGAAGCAA'ITATTTAAAGAAAGTGAAAAATGTAAAACACATACAAA AGAATTAAACCCACAAGCTGCCTCTGACAGCAGCCTGTGAGGGAGTGCAGAACACCTGGCCGGGTCACCCTGTGACCCTCTCACTTTGGTTGGAACTTTAGGGGGTGGGAGG GGGCGTTGGATTTAAAAATGCCAAAACTTACCTATAAATTAAGAAGAGTTTTTATTACAAATTTTCACTGCTGCTCCICTTTCCCCTCCTTTGTCTTTTTTTTCATCCTTTT ΓTCTCTTCTGTCCATCAGTGCATGACGTTTAAGGCCACGTATAGTCCTAGCTGACGCCAATAATAAAAAACAAGAAACCAAAAAAAAAAAACCCGAAT'ICA
77 ALLIGKRCDVPTNGCGPDRWNSAFTRKDEIITSLVSALDSMCSALSKLNAEVACVAVHDESAFWGTEKGRMFLNARKELQSDFLRFCRGPPWKDPEAEHPKKVQRGEGGGR SLPRSSLEHGSDVYLLRKMVEEVFDVLYSEALGRASVVPLPYERLLREPGLLAVQGLPEGLAFRRPAEYDPKALMAILEHSHRIRFKLKRPLEDGGRDΞKALVELNGVSLIP KGSRDCGLHGQAPKVPPQDLPPTATSSSMASFLYSTALPNHAIRELKQEAPSCPLAFSDLGLSRPMPEPKATGAQDFSDCCGQKPTGPGGPLIQNVHASKRILFSIVHDKSE KHDAFIKETEDINTLRECVQILFNSRYAEALGLDH VPVPYRKIACDPEAVEIVGIPDKIPFKRPCTYGVPKLKRILEERHSIHFIIKRMFDERIFTGNKFTKDTTKLEPAS PPEDTSAEVSRATVLDLAGNARSDKGSMSEDCGPGTSGELGGLRPIKIEPEDLDIIQVTVPDPSPTSEENTDSMPGHLPSEDSGYGMEMLTDKGLSEDARPEERPVEDSHGD VIRPLRKQVELLFLJRRRYAKAIGISEPVKVPYSKFLMHPEELFVVGLPEGISLRRPNCFGIAKLRKILEASNSIQFVIKRPELLTEGVKEPIMDSQGTASSLGFSPPALPPER DSGDPLVDESLKRQGFQENYDARLSRIDIANTLREQVQDLFNKKYGEALGIKYPVQVPYKRIKSNPGSVIIEGLPPGIPFRKPCTFGSQN ERIIIAVADKIKFTVTRPFQGL IPKPDEDDANRLGEKVI REQVKELFNEKYGEALGIJΛRPVLVPYKLIRDSPDAVEVTGLPDDIPFRNPNTYDIHRLEKILKAREHVPJWI INQ QPFAEICNDAKVPAKDSS IPKR RKRVSEGNSVSSSSSSSSSSSSNPDSVASANQISLVQWPMYMVDYAGLNVQLPGPLNY
78
RAAATGGCAGCCAATGGAGGGTGGTGTTGCGCGGGGCTGGGATTAGGGCCGGGGCGAATGGCTGGCAATCTTACTGGGATTACAGAACAAAGAGCCICCCCGCGCTCCCGCT CTCCGCTCCTCTCCCCXSCGCCGCCCCGCCCTCCGCCGCAGCCCGCGCCGGGGGTGGGGGCCGCCGAGCGCCAGCCCCCCGGCCGGCCGATTCCCCCCCCGCGCCCCCTCCCC GCGCCTCCCTCCCCGCCCTCGCCGCGCCGCCGTCCTCGCCTCCCTCTGCCTCTCCTTCCCCCATTCTCCCGGATTAATTAAGGAGGCAGCGGCAGGAGGCTGAGTCCTGGCC GCGGGCCGGGGCCGGGGCGCCGCTGGCAGGAGCGCTTGGGGATCCTCCAAGGCGACCATGGCCTTGCTGGGTAAGCGCTGTGACGTCCCCACCAACGGCTGCGGACCCGACC GCTGGAACTCCGCGTTCACCCGCAAAGACGAGATCATCACCAGCCTCGTGTCTGCCTTAGACTCCATGTGCTCAGCGCTGTCCAAACTGAACGCCGAGGTGGCCTGTGTCGC CGTGCACGATGAGAGCGCCTTTGTGGTGGGCACAGAGAAGGGGAGAATGTTCCTGAATGCCCGGAAGGAGCTACAGTCAGACTTCCTCAGGTTCTGCCGAGGGCCCCCGTGG AAGGATCCGGAGGCAGAGCACCCCAAGAAGGTGCAGCGGGGCGAGGGTGGAGGCCGTAGCCTCCCTCGGTCCTCCCTGGAACATGGCTCAGATGTGTACCTTCTGCGGAAGA RGGTAGAGGAGGTGTTTGATGTTCTTTATAGCGAGGCCCTGGGAAGGGCCAGTGTGGTGCCACTGCCCTATGAGAGGCTGCTCAGGGAGCCAGGGCTGCTGGCCGTGCAGGG GCTGCCCGAAGGCCTGGCCTTCCGAAGGCCAGCCGAGTATGACCCCAAGGCCCTCATGGCCATCCTGGAACACAGCCACCGCATCCGCTTCAAGCTCAAGAGGCCACTTGAG GATGGCGGGCGGGACTCGAAGGCCCTGGTGGAGCTGAACGGTGTCTCCCTGATTCCCAAGGGGTCACGGGACTGTGGCCTGCATGGCCAGGCCCCCAAGGTGCCACCCCAGG ACCTGCCCCCAACCGCCACCTCCTCCTCCATGGCCAGCTTCCTGTACAGCACGGCGCTCCCCAACCACGCCATCCGAGAGCTCAAGCAGGAAGCACCTTCCTGCCCCCTTGC CCCCAGCGACCTGGGCCTGAGTCGGCCCATGCCAGAGCCCAAGGCCACCGGTGCCCAAGACTTCTCCGACTGTTGTGGACAGAAGCCCACTGGGCCTGGTGGGCCTCTCATC CAGAACGTCCATGCCTCCAAGCGCATTCTCTTCTCCATCGTCCATGACAAGTCAGAGAAGTGGGACGCCTTCATAAAGGAAACCGAGGACATCAACACGCTCCGGGAGTGTG ΓGCAGATCCTGTTTAACAGCAGATATGCGGAAGCCCTGGGCCTGGACCACATGGTCCCCGTGCCCTACCGGAAGATTGCCTGTGACCCGGAGGCTGTGGAGATCGTGGGCAT CCCGGACAAGATCCCCTTCAAGCGCCCCTGCACTTATGGAGTCCCCAAGCTGAAGCGGATCCTGGAGGAGCGCCATAGTATCCACTTCATCATTAAGAGGATGTTTGATGAG CGAATTTTCACAGGGAACAAGTTTACCAAAGACACCACGAAGCTGGAGCCAGCCAGCCCGCCAGAGGACACCTCTGCAGAGGTCTCTAGGGCCACCGTCCTTGACCTTGCTG GGAATGCTCGGTCAGACAAGGGCAGCATGTCTGAAGACTGTGGGCCAGGAACCTCCGGGGAGCTGGGCGGGCTGAGGCCGATCAAAATTGAGCCAGAGGATCTGGACATCAT ΓCAGGTCACCGTCCCAGACCCCTCGCCAACCTCTGAGGAAATGACAGACTCGATGCCTGGGCACCTGCCATCGGAGGATTCTGGTTATGGGATGGAGATGCTGACAGACAAA GGTCTGAGTGAGGACGCGCGGCCGGAGGAGAGGCCCGTGGAGGACAGCCACGGTGACGTGATCCGGCCCCTGCGGAAGCAGGTGGAGCTGCTCT'ICAACACACGATACGCCA AGGCCATTGGCATCTCGGAGCCCGTCAAGGTGCCGTACTCCAAGTTTCTGATGCACCCGGAGGAGCTGTTTGTGGTGGGACTGCCTGAAGGCATCTCCCTCCGCAGGCCCAA CΓGCTΓCGGGATCGCCAAGCTCCGGAAGATTCTGGAGGCCAGCAACAGCATCCAGTTTGTCATCAAGAGGCCCGAGCTGCTCACTGAGGGAGTCAAAGAGCCCATCATGGAT AGTCAAGGAACTGCCTCCTCACTTGGCTTCTCTCCCCCTGCCCTGCCCCCAGAGAGGGATTCCGGGGACCCTCTGGTGGACGAGAGCCTGAAGAGACAGGGCTTTCAAGAAA ATTATGACGCGAGGCTCTCACGGATCGACATCGCCAACACACTAAGGGAGCAGGTCCAGGACCTTTTCAATAAGAAATACGGGGAAGCCTTGGGCATCAAGTACCCGGTCCA GGTCCCCTACAAGCGGATCAAGAGTAACCCCGGCTCCGTGATCATCGAGGGGCTGCCCCCAGGAATCCCGTTCCGAAAGCCCTGTACCTTCGGCTCCCAGAACCTGGAGAGG ATTCTTGCTGTGGCTGACAAGATCAAGTTCACAGTCACCAGGCCTTTCCAAGGACTCATCCCAAAGCCTGATGAAGATGACGCCAACAGACTCGGGGAGAAGGTGATCCTGC GGGAGCAGGTGAAGGAACTCTTCAACGAGAAATACGGTGAGGCCCTGGGCCTGAACCGGCCGGTGCTGGTCCCTTATAAACTAATCCGGGACAGCCCAGACGCCGTGGAGGT CACGGGTCTGCCTGATGACATCCCCTTCCGGAACCCCAACACGTACGACATCCACCGGCTGGAGAAGATCCTGAAGGCCCGAGAGCATGTCCGCATGGTCATCATTAACCAG CΓCCAACCCTTTGCAGAAATCTGCAATGATGCCAAGGTGCCAGCCAAAGACAGCAGCATTCCCAAGCGCAAGAGAAAGCGGGTCTCGGAAGGAAATTCCGTCTCCTCTTCCT CCTCGTCTTCCTCTTCCTCGTCCTCTAACCCGGATTCAGTGGCATCGGCCAACCAGATCTCACTCGTGCAA'IGGCCAATGTACATGGTGGACTATGCCGGCCTGAACGTGCA GCTCCCGGGACCTCTTAATTACTAGACCTCAGTACTGAATCAGGACCTCACTCAGAAAGACTAAAGGAAATGTAATTTATGTACAAAATGTATATTCGGATATGTATCGATG CCTTTTAGTTTTTCCAATGATTTTTACACTATATTCCTGCCACCAAGGCCTTTTTAAATAAGTAAAAAAAAAAAAAAAAAAAAAAA
79 tWSRLSSRLQAI^SAPCRSLSCAQDVLHRTPLYDFHLAHGGKMVAFAGWSLPVQYRDSHVNSHLHTRQHCSLFDVSHMLQTKIFGCDRVK MESLVVGDIAELKPNQGTLSL FTNEAGGILDDLIVTSASEGHLYVVSNAGCREKDLTLMQDKVRELQNKGSDVALEVNDNALLALQGPTAAQVLQAGVADDLRKLPFMTSAVMEVFGVSGCRVTRCGYTGEDG VEISVPAAEAVH AAA LKNPEVKI- GI-AARDεL LEAG CLYGNDIDEHTTP EGSLSWTLGK RRAA IDF GASVIVPQ KSKAQR R GLMCDGA RAQSPI SPEGT VIGAVTSGCPSPCLKK VAMGYVPYEYSRPGTPLLVEVRRKQQPAWSKMPFVSTNYYILK
80 GGACGGCGACAGCGGGTCGGCGGGCCGCAGGAGGGGGTCATGGGTAAAGACTACTACCAGACGTTGGGCCTGGCCCGCGGCGCGTCGGACGAGGAGATCAAGCGGGCCTAC CGCCGCCAGGCGCTGCGCTACCACCCGGACAAGAACAAGGAGCCCGGCGCCGAGGAGAAGTTCAAGGAGATCGCTGAGGCCTACGACGTGCTCAGCGACCCGCGCAAGCGCG AGATCΓTCGACCGCTACGGGGAGGAAGGCCTAAAGGGGAGTGGCCCCAGTGGCGGTAGCGGCGGTGGTGCCAATGGTACCTCTTTCAGCTACACATTCCATGGAGACCCTCA ΓGCCAΓGTTTGCTGAGTTCTTCGGTGGCAGAAATCCCΓΓTGACACCTTTTTTGGGCAGCGGAACGGGGAGGAAGGCATGGACATTGATGACCCATTCTCTGGCTTCCCTATG GGCATGGGTGGCTTCACCAACGTGAACTTTGGCCGCTCCCGCTCTGCCCAAGAGCCCGCCCGAAAGAAGCAAGATCCCCCAGTCACCCACGACCTTCGAGTCTCCCTTGAAG AGATCTACAGCGGCTGTACCAAGAAGATGAAAATCTCCCACAAGCGGCTAAACCCCGACGGAAAGAGCATTCGAAACGAAGACAAAATATTGACCATCGAAGTGAAGAAGGG GTGGAAAGAAGGAACCAAAATCACTTTCCCCAAGGAAGGAGACCAGACCTCCAACAACATTCCAGCTGATATCGTCTTTGTTTTAAAGGACAAGCCCCACAATATCTTTAAG AGAGATGGCTCTGATGTCATTTATCCTGCCAGGATCAGCCTCCGGGAGGCTCTGTGTGGCTGCACAGTGAACGTCCCCACTCTGGACGGCAGGACGATACCCGTCGTATTCA AAGATGTTATCAGGCCTGGCATGCGGCGAAAAGTTCCRGGAGAAGGCCTCCCCCICCCCAAAACACCCGAGAAACGTGGGGACCTCATTATTGAGTTTGAAGTGATCTTCCC CGAAAGGATTCCCCAGACATCAAGAACCGTACTTGAGCAGGTTCTTCCAATATAGCTATCTGAGCTCCCCAAGGACTGACCAGGGACCTTTCCAGAGCTCAAGGATTTCTGG ACCTTTCTACCAGTTGTGGACCATGAGAGGGTGGGAGGGCCCAGGGAGGGCTTTCGTACTGCTGAATGTTTTCCAGAGCATATATTACAATCTTTCAAAGTCGCACACTAGA CTTCAGTGGTTTTTCGAGCTATAGGGCATCAGGTGGTGGGAACAGCAGGAAAAGGCATTCCAGTCTGCCCCACTGGGTCTGGCAGCCCTCCCGGGATGGGCCCACATCCACC TCCAGTCCCTGGCCAGGGGTGAGAGGCAGACCAGCAGARGGACTTGATCCCTCTGTGTCTTTGGGCTTCTGGCTGGTAGATAATGTCAACCTGCAGTCTTGATTCCCAGACC CTGTACACTCCTCCTTTTCTGTTGTGTGATCAGTTTGΓGCTTTATTCTGTATTTGTCTCCCATGTCTTGCTCTTCTCCTGGAGAATTCTGTCTTCTCTTTGGCCATCTCAAA ΓTGAGAACCTAAACTATTCCTGCAGAACTGCCTGGTTGGCGTCCACAAGCAATACCTCTCGTTCCAGCAGGACCAAGGGAGCCAGCCTCCAGTGAGTGACTCCAGCAAGTGC AGCCACCTCTCCCTTGATGGTCTGGGAGCCTGGCCTCAGCAAGGGGCCTTCCTGACCTCTGGCTCCAGTGAAGCTGAATGTCCICACTTTGTGGGTCACACTCTTTACATTT CTGTAAGGCAATCTTGGCACACGTGGGGCTTACCAGTGGCCCAGGTAATTTTTTGTTTCATGGACTATGGACTCTTTCAAAGGGATCTGATCCTTTTGAATRTTGCACAGCC CTAGATACAATCCCTTTTGATAAAAGGGTCTTTGCTTCRGATTACAGGAGCACTGTGGAACGTCTGTAAATATGTTTTTATAATTCCATGTATAGTTGGTGTACACTCAAAA CCTGTCCCCGGCAGCCAGTGCTCTCTGTATAGGGCCARAATGGAATTCTGAAGAAATCTTGGGGAGGGAAGGGGAGTTGGAACAAATGTCTGTTCCCTGGAGGCCAGTCCAG TGCTCAGACCTTTAGACTCATTGTAAGTTGCCACTGCCAACATGAGACCAAAGTGTGTGACTAGTCAATGAAGTGCGACAGCATTAAAGACTGATGCTAAACCTC
81
MQAPRELAVGIDLGTTYSCVGVFQQGRVEILAMXX^RΓTPSYVAFTDTERLVGDAAKSQAALNPHNTVFDAKRLIGRKFADTTVQSDMKHWPFRVVSEGGKPKVPVSYRGE DKTFYPEEIΕSM LSKMKETAEAYIXX^PVKHAVITVPA FNDSQRQATKDAGAIAGL^RΛ
AGDTHLGGEDFDNRLVTMFMEEFRRKHGKDIISGNKRALGRLRTACERAKRTLSSETQATLEIDSLFEGVDFYTSITRARFEELCSDLFRSTLEPVEKALRDAKLDKAQIHDV VLVGGSTRIPKVQKL 3DFFNGKELNKSINPDEAVAYGAAVQAAVL GDKCEKVQDLLLLDVAPLSLGLETAGGVMTTLIQRNATIPTKQTQTPTTYSDNQPGVFIQVYEGE RAMTKDNNLLGRFELSGIPPAPRGVPQIEVTPDIDANGILSVTATDRSTGKANKITITNDKGRLSKEEVERMVHEAEQYKAEDEAQRDRVAAKNSLEAHVFHVKGSLQEES RDKIPEEDRRKMQDKCREVLAWLEHNQLAEKEEYEHQKRELEQICRPIFSRLYGGPGVPGGSSCGTQARQGDPSTGPIIEEVD
82
ATGCAGGCCCCACGGGAGCTCGCGGTGGGCATCGACCTGGGCACCACCTACTCGTGCGTGGGCGTGTTTCAGCAGGGCCGCGTGGAGATCCTGGCCAACGACCAGGGCAACC GCACCACGCCCAGCTACGTGGCCTTCACCGACACCGAGCGGCTGGTCGGGGACGCGGCCAAGAGCCAGGCGGCCCTGAACCCCCACAACACCGTGTTCGATGCCAAGCGGCT GATCGGGCGCAAGTTCGCGGACACCACGGTGCAGTCGGACATGAAGCACTGGCCCTTCCGGGTGGTGAGCGAGGGCGGCAAGCCCAAGGTGCCGGTATCGTACCGCGGGGAG GACAAGACGTTCTACCCCGAGGAGATCTCGTCCATGGTGCTGAGCAAGATGAAGGAGACGGCCGAGGCGTACCTGGGCCAGCCCGTGAAGCACGCAGTGATCACCGTGCCCG CCTATTTCAATGACTCGCAGCGCCAGGCCACCAAGGACGCGGGGGCCATCGCGGGGCTCAACGTGTTGCGGATCATCAATGAGCCCACGGCAGCTGCCATCGCCTATGGGCT GGACCGGCGGGGCGCGGGAGAGCGCAACGTGCTCATTTTTGACCTGGGTGGGGGCACCTTCGATGTGTCGGTTCTCTCCATTGACGCTGGTGTCTTTGAGGTGAAAGCCACT GCTGGAGATACCCACCTGGGAGGAGAGGACTTCGACAACCGGCTCGTGAACCACTTCATGGAAGAATTCCGGCGGAAGCATGGGAAGGACCTGAGCGGGAACAAGCGTGCCC TCGGCAGGCTGCGCACAGCCTGTGAGCGCGCCAAGCGCACCCTGTCCTCCAGCACCCAGGCCACCCTGGAGATAGACTCCCTGTTCGAGGGCGTGGACTTCTACACGTCCAT CACTCGTGCCCGCTTTGAGGAACTGTGCTCAGACCTCTTCCGCAGCACCCTGGAGCCGGTGGAGAAGGCCCTGCGGGATGCCAAGCTGGACAAGGCCCAGATTCATGACGTC GTCCTGGTGGGGGGCTCCACTCGCATCCCCAAGGTGCAGAAGTTGCTGCAGGACTTCTTCAACGGCAAGGAGCTGAACAAGAGCATCAACCCTGATGAGGCTGTGGCCTATG GGGCTGCTGTGCAGGCGGCCGTGTTGATGGGGGACAAATGTGAGAAAGTGCAGGATCTCCTGCTGCTGGATGTGGCTCCCCTGTCTCTGGGGCTGGAGACAGCAGGTGGGGT GATGACCACGCTGATCCAGAGGAACGCCACTATCCCCACCAAGCAGACCCAGACTTTCACCACCTACTCGGACAACCAGCCTGGGGTCTTCATCCAGGTGTATGAGGGTGAG AGGGCCATGACCAAGGACAACAACCTGCTGGGGCGITTTGAACTCAGTGGCATCCCTCCTGCCCCACGTGGAGTCCCCCAGATAGAGGTGACCTTTGACATTGATGCTAATG GCATCCTGAGCGTGACAGCCACTGACAGGAGCACAGGTAAGGCTAACAAGATCACCATCACCAATGACAAGGGCCGGCTGAGCAAGGAGGAGGTGGAGAGGATGGTTCATGA AGCCGAGCAGTACAAGGCTGAGGATGAGGCCCAGAGGGACAGAGTGGCTGCCAAAAACTCGCTGGAGGCCCATGTCTTCCATGTGAAAGGTTCTTTGCAAGAGGAAAGCCTT AGGGACAAGATTCCCGAAGAGGACAGGCGCAAAATGCAAGACAAGTGTCGGGAAGTCCTTGCCTGGCTGGAGCACAACCAGCTGGCAGAGAAGGAGGAGTATGAGCATCAGA AGAGGGAGCTGGAGCAAATCTGTCGCCCCATCTTCTCCAGGCTCTATGGGGGGCCTGGTGTCCCTGGGGGCAGCAGTTGTGGCACTCAAGCCCGCCAGGGGGACCCCAGCAC CGGCCCCATCATTGAGGAGGTTGATTGA
83
MATAKGIAIGIDLGTTYSCVGVFQHGKVEIIA DQGNRTTPSYVAFTDTERLIGDAAKNQVAMNPQNTVFDA RLIGRKFNDPWQADMKL PFQVINEGGKPKVLVSYKGE NKAFYPEEISSWLTKLKETAEAF GHPVT AVIT PAYFNDSQ QATKDAGVIAGLNVLRIINEPTAAAIA GLDKGGQGERHVLIFDLGGG FDVSILTIDDGIFEVKAT AGDTHLGGEDFDNRLVSHFVEEFKRKHKKDISQNKRAVRRLRTACERAKRTLSSSTQANLEIDS YEGIDFYTSITRARFEELCAD FRGTLEPVEKALRDAKMDKAKIHDI VLVGGSTRIPKVQRLLQDYFNGRDLNKSINPDEAVAYGAAVQAAILMGDKSEKVQDLL LDVAPLSLGLETVGGVMTALIKRNSTIPPKQTQIFTTYSDNQPGVLIQVYEGE P^TKDNNLLGRFDLTGIPPAPRGVPQIEVTFDIDA GILNVTATDKSTGKVNKITLTNDKGRLSKEEIEP»T DAEKYKAEDEVQREKIAAKNALESYAFNMKSVVSDEGL GKISESDKNKILDKCNELLS LEVNQLAEKDEFDHKRKELEQMCNPIITKLYQGGCTGPACGTGYVPGRPATGPTIEEVD
84
ATGGCTACTGCCAAGGGAATCGCCATAGGAATCGACCTGGGCACCACCTACTCCTGTGTGGGGGTGTTCCAGCACGGCAAGGTGGAGATCATCGCCAACGACCAGGGCAACC GCACCACCCCCAGCTACGTGGCCTTCACAGACACCGAGCGGCTCATTGGGGATGCGGCCAAGAACCAGGTAGCAATGAATCCCCAGAACACTGTTTTTGATGCTAAACGTCT GATCGGCAGGAAATTTAATGATCCTGTTGTACAAGCAGATATGAAACTTTGGCCTTTTCAAGTGATTAATGAAGGAGGCAAGCCCAAAGTCCTTGTGTCCTACAAAGGGGAG AATAAAGCTTTCTACCCTGAGGAAATCTCTTCGATGGTATTGACTAAGTTGAAGGAGACTGCTGAGGCCTTTTTGGGCCACCCTGTCACCAATGCAGTGATTACCGTGCCAG CCTATTTCAATGACTCTCAACGTCAGGCTACTAAGGATGCAGGTGTGATTGCTGGACTTAATGTGCTAAGAATCATCAATGAGCCCACGGCTGCTGCCATTGCCTATGGTTT AGATAAAGGAGGTCAAGGAGAACGACATGTCCTGATTTTTGATCTGGGTGGAGGCACATTTGATGTGTCAATTCTGACCATAGATGATGGGATTTTTGAGGTAAAGGCCACT GCTGGGGACACTCACCTGGGTGGGGAGGACTTTGACAACAGGCTTGTGAGCCACTTCGTGGAGGAGTTCAAGAGGAAACACAAAAAGGACATCAGCCAGAACAAGCGAGCCG TGAGGCGGCTGCGCACCGCCTGCGAGAGGGCCAAGAGGACCCTGTCGTCCAGCACCCAGGCCAACCTAGAAATTGATTCACTTTATGAAGGCATTGACTTCTATACATCCAT CACCAGAGCTCGATTTGAAGAGTTGTGTGCAGACCTGTTTAGGGGTACCCTGGAGCCTGTAGAAAAAGCGCTTCGGGATGCCAAGATGGATAAGGCTAAAATCCATGACATT GTTTTAGTAGGGGGCTCCACCCGCATCCCCAAGGTGCAGCGGCTGCTTCAGGACTACTTCAATGGACGTGATCTCAACAAGAGCATCAACCCTGATGAGGCCGTAGCATATG GGGCTGCGGTACAAGCAGCCATCCTGATGGGGGACAAGTCTGAGAAGGTACAGGACCTGCTGCTGCTGGACGTGGCTCCCCTGTCCCTGGGTCTGGAGACGGTTGGGGGCGT GATGACTGCCCTGATAAAGCGCAACTCCACCATCCCACCCAAGCAGACACAGATTTTCACCACCTACTCTGACAACCAACCCGGGGTGCTGATCCAGGTGTATGAGGGCGAG AGGGCCATGACAAAGGACAACAACCTGCTGGGGCGGTTTGATCTGACTGGAATCCCTCCAGCACCCAGGGGAGTTCCTCAGATCGAGGTGACGTTTGACATTGATGCCAATG GTATTCTCAATGTCACAGCCACGGACAAGAGCACCGGCAAGGTGAACAAGATCACCATCACCAATGACAAGGGCCGCCTGAGCAAGGAGGAGATTGAGCGGATGGTTCTGGA TGCTGAGAAATATAAAGCTGAAGATGAGGTCCAGAGGGAGAAAATTGCTGCAAAGAATGCCTTAGAATCCTATGCTTTTAACATGAAGAGTGTTGTGAGTGATGAAGGTTTG AAGGGCAAGATTAGTGAGTCTGATAAAAATAAAATATTGGATAAATGCAACGAGCTCCTTTCGTGGCTGGAGGTCAATCAACTGGCAGAGAAAGATGAGTTTGATCATAAGA GAAAGGAATTGGAGCAGATGTGTAACCCTATCATCACAAAACTCTACCAAGGAGGATGCACTGGGCCTGCCTGCGGAACAGGGTATGTGCCTGGAAGGCCTGCCACAGGCCC CACAATTGAAGAAGTAGATTAA
85 ESETEPEPVTLLVKSPNQRHRDLELSGDRGWSVGHLKAHLSRVYPERPRPEDQRLIYSGKLLLDHQC RDLLPKQEKRHVLHLVCNVKSPSKMPEINAKVAESTEEPAGSN RGQYPEDSSSDGLRQREVLRN SSPGWENISRPEAAQQAFQGLGPGFSGYTPYG LQLS FQQIYARQYYMQYLAATAASGAFVPPPSAQEIPWSAPAPAPIHNQFPAENQ PANQNAAPQVVV PGANQNLP»LNAQGGPIVEEDDEINRD LDWTYSAATFSVFLSILYFYSSLSRFL WMGATVVMYLHHVGWFPFRPRPVQNFPNDGPPPDΛRVNQDPNNNL QEGTDPETEDPNHLPPDRDVLDGEQTSPSFMSTAWLVFKTFFASLLPEGPPAIAN
86
GACGTGAACGGTCGTTGCAGAGATTGCGGGCGGCTGAGACGCCGCCTGCCTGGCACCTAGGAGCGCAGCGGAGCCCCGACACCGCCGCCGCCGCCATGGAGTCCGAGACCGA ACCCGAGCCCGTCACGCTCCTGGTGAAGAGCCCCAACCAGCGCCACCGCGACTTGGAGCTGAGTGGCGACCGCGGCTGGAGTGTGGGCCACCTCAAGGCCCACCTGAGCCGC GTCTACCCCGAGCGTCCGCGTCCAGAGGACCAGAGGTTAATTTATTCTGGGAAGCTGTTGTTGGATCACCAATGTCTCAGGGACTTGCTTCCAAAGCAGGAAAAACGGCATG TTTTGCATCTGGTGTGCAATGTGAAGAGTCCTTCAAAAATGCCAGAAATCAACGCCAAGGTGGCTGAATCCACAGAGGAGCCTGCTGGTTCTAATCGGGGACAGTATCCTGA GGATTCCTCAAGTGATGGTTTAAGGCAAAGGGAAGTTCTTCGGAACCTTTCTTCCCCTGGATGGGAAAACATCTCAAGGCCTGAAGCTGCCCAGCAGGCATTCCAAGGCCTG GGTCCTGGTTTCTCCGGTTACACACCCTATGGGTGGCTTCAGCTTTCCTGGTTCCAGCAGATATATGCACGACAGTACTACATGCAATATTTAGCAGCCACTGCTGCATCAG GGGCTTTTGTTCCACCACCAAGTGCACAAGAGATACCTGTGGTCTCTGCACCTGCTCCAGCCCCTATTCACAACCAGTTTCCAGCTGAAAACCAGCCTGCCAATCAGAATGC TGCTCCTCAAGTGGTTGTTAATCCTGGAGCCAATCAAAATTTGCGGATGAATGCACAAGGTGGCCCTATTGTGGAAGAAGATGATGAAATAAATCGAGATTGGTTGGATTGG ACCTATTCAGCAGCTACATTTTCTGTTTTTCTCAGTATCCTCTACTTCTACTCCTCCCTGAGCAGATTCCTCA1GGTCATGGGGGCCACCGTTGTTATGTACCTGCATCACG TTGGGTGGTTTCCATTTAGACCGAGGCCGGTTCAGAACTTCCCAAATGATGGTCCICCTCCTGACGTTGTAAATCAGGACCCCAACAATAACTTACAGGAAGGCACTGATCC TGAAACTGAAGACCCCAACCACCTCCCTCCAGACAGGGATGTACTAGATGGCGAGCAGACCAGCCCCTCCTTTATGAGCACAGCATGGCTTGTCTTCAAGACTTTCTTTGCC TCTCTTCTTCCAGAAGGCCCCCCAGCCATCGCAAACTGATGGTGTTTGTGCTGTAGCTGTTGGAGGCTTTGACAGGAATGGACTGGATCACCTGACTCCAGCTAGATTGCCT CTCCTGGACATGGCAATGATGAGTTTTTAAAAAACAGTGTGGATGATGATATGCTTTTGTGAGCAAGCAAAAGCAGAAACGTGAAGCCGTGATACAAATTGGTGAACAAAAA ATGCCCAAGGCTTCTCATGTCTTTATTCTGAAGAGCTTTAATATATACTCTATGTAGTTTAATAAGCACTGTACGTAGAAGGCCTTAGGTGTTGCATGTCTATGCTTGAGGA ACTTTTCCAAATGTGTGTGTCTGCATGTGTGTTTGTACATAGAAGTCATAGATGCAGAAGTGGTTCTGCTGGTACGATTTGATTCCTGTTGGAATGTTTAAATTACACTAAG GTACTACTTTATATAATCAATGAAATTGCTAGACATGTTTTAGCAGGACTTTTCTAGGAAAGACTTATGTATAATTGCTTTTTAAAATGCAGTGCTTTACTTTAAACTAAG GGGAACTTTGCGGAGGTGAAAACCTTTGCTGGGTTTTCTGTTCAATAAΔGTTTTACTATGAATGACCCTGAAAAAAAAAAAAAAAAAAAAAA
87
MTDRF DQWYLVWLRLLPILDRGSFRNDGLKASDVLPILKEKVAFVSGGRDKRGGPILTFPARSNHDRIRQEDLRKLVIYLASVPSEDVCKRGFTVIIDMRGSK DLIKPLL
KTLQEAFPAEIHVALIIKPDNFWQKQKTNFGSSKFIFETSMVSVEGLTKLVDPSQLTEEFDGSLDYNHEEWIELRLSLEEFFNSAVHLLSRLEDLQEMLARKEFPVDVEGSR
RLIDEHTQLKKKVLKAPVEELDREGQR LQCIRCSDGFSGRNCIPGSADFQSLVPKITSLLDKLHSTRQHLHQMWHVRKLKLDQCFQLRLFEQDAEKMFDWISHNKELF QS
HTEIGVSYQYAI ILQTQHNHFAMNSMNAYVNINRIMSVASRLSEAGHYASQO^KQISTQLDQEWK^^
DLELAIHHHQT EQ QAYTEVSQDGKA LD\^QRPLSPGNSES TATA RΪSKA I^QVLD VHEV HHQRR ESIWQHRKVRLHQRLQLCVFQQD QQ LDWIENHGEAF
SKHTGVGKSLHP UUΛQKPΛDDFEEVAQNTYTNADKLLE-VIEQIΛQTGECDPEEIYKAARHLEVRIQDFVRRVEQRFΑ LDMSVSFHTHTKE WTWMEDLQKEMLEDVCADS
VDAVQE IKQFQMQTATLDATLNVIKEGEDLIQQLRSAPPSLGEPSEARDSAVSNNKTPHSSSISHIESVLQQLDDAQVQMEELFHERKIK DIFLQLRIFEQYTIEVTAE
LDAVMED RQM IDF TEDLTLAE 3R Q HTERKIAMN MTFEVIQQGQDLHQYI E QASGIE ICEKDID AAQVQEL EFLHEKQHELELNAEQ H AEVKQVLGWIRNGESMLNASLVNASSLSEAEQLQREHEQFQLAIESLFHATSLQKTKQSALQVQQKAEVLLQAGHYDADAIRECAEKVALH QQLMLKNEDRLKLVNASVAF YKT8EQVCSVLESLEQEYRRDED CGGRDKLGPAAEIDHVIP ISKH EQKEAFLKACTLARRNAEVFLKYIHRNNVSMPSVASHTRGPEQQVKAILSELLQRENRVLHF T LKKRRLDQCQQYWFERSAKQALDWIQETGEFYLSTHTSTGETTEETQELLKEYGEFRVPAKQTKEKVKL IQLADSFVEKGHIHATEIRK VTTVDKHYRDFSLRMGKYRY SLEKALGVNTEDNKDLELDIIPASLSDREVKLRDANHEVNEEKRKSARKKEFIMAELLQTEKAYVRD HECLETYLWEMTSGVEEIPPGILNKEHIIFGNIQEIYDFHNNIF LKELEKYEQLPEDVGHCFVTWADKFQMYVTYCKNKPDSNQLILEHAGTFFDEIQQRHGLANSISSYLIKPVQRITKYQL LKELLTCCEEGKGELKDGLEVMLSVPKKANDA HVSMLEGFDENLCVQGELILQDAFQVWDPKSLIRKGRERHLFLFEIS VFSKEIKDSSGHTKYVYKNK LTSELGVTEHVEGDPCKFAL SGRTPSSDNKTVLKASNIETK QEWIKNIREVIQERIIHLKGA KEPLQ PKTPAKQRNNSKRDGVEDIDSQGDGSSQPDT1SIASRTSQNTVDSDKDGNLVPRWHLGPGDPFSTYV
88
TGCGAGCCCAGCGTCAAGTGATTCCGGCCTCCTCGAGACAGCGGTGGTGGGATGAGGCTCTGCCGAGGGGACTGGCTGTGAAGGATGAGTTCAGGGTGGGATGACGGACCGC TTCTGGGACCAGTGGTATCTCTGGTATCTCCGCTTGCTCCGGCTGCTGGATCGAGGGTCTTTTCGGAATGATGGTTTGAAAGCTTCTGATGTCCTTCCTATCCTAAAGGAAA AGGTGGCCTTCGTGTCTGGGGGTCGTGATAAGCGAGGCGGACCCATCCTGACCTTCCCTGCTCGCAGCAATCATGACAGAATAAGACAGGAAGACCTGCGGAAACTCGTGAC GTATTTGGCCAGCGTGCCAAGTGAGGACGTGTGCAAACGTGGCTTCACTGTCATCATCGACATGCGGGGCTCCAAGTGGGACCTCATCAAGCCCCTCCTCAAAACGCTGCAG GAAGCCTTTCCAGCTGAGATCCATGTGGCCCTCATCATTAAACCCGACAACTTCTGGCAGAAACAGAAGACCAACTTTGGCAGCTCCAAATTCATCTTTGAGACGAGCAΓGG TATCTGTGGAGGGCCTCACAAAGCTGGTGGACCCCTCCCAGCTGACGGAGGAGTTTGATGGCTCCCTGGACTACAACCATGAGGAGTGGATCGAACTGCGGCTCTCCCTGGA GGAGTTCTTCAACAGCGCCGTGCACCTGCTCTCGCGCCTCGAGGACCTCCAGGAGATGCTAGCCCGGAAGGAGTTTCCTGTGGATGTGGAGGGCTCTCGGCGGCTCATTGAC GAACACACACAGCTCAAGAAAAAGGTGCTGAAGGCCCCTGTGGAGGAGCTGGACCGGGAGGGGCAGCGGCTGCTGCAGTGCATCCGCTGCAGCGACGGCTTCTCAGGACGCA ACTGCATCCCGGGCAGTGCTGACTTCCAGAGCCTGGTGCCCAAGATCACCAGTCTCCTGGACAAGCTGCACTCCACCCGGCAGCACCTGCACCAGATGTGGCACGTGCGCAA GCTCAAGCTGGACCAGTGCTTTCAGCTGCGGCTCTTCGAGCAGGATGCTGAGAAGATGTTTGACTGGATAAGCCACAACAAGGAGTTATTCCTCCAGAGCCACACGGAGAΓC GGAGTCAGCTACCAGTACGCCCTTGACCTCCAGACGCAGCACAATCACTTTGCCATGAACTCCATGAATGCCTATGTCAACATCAACCGCATCATGTCCGTGGCTTCCCGCC TCTCTGAGGCCGGTCATTATGCCTCACAACAAA'ICAAGCAGATCTCCACCCAGCTGGACCAGGAGTGGAAGAGCTTTGCTGCTGCCCTGGATGAACGCAGCACCATCCTCGC CATGTCTGCTGTGTTCCACCAGAAGGCTGAGCAGTTCCTGTCGGGAGTGGATGCCTGGTGCAAGATGTGCAGTGAAGGTGGTCTGCCATCCGAGATGCAAGACCTAGAGCTG GCAATCCACCACCACCAGACCTTGTATGAGCAGGTGACCCAAGCCTACACAGAGGTCAGCCAGGATGGCAAAGCACTACTTGATGTGCTGCAGCGGCCCCTGAGCCCTGGGA ACTCCGAATCCCTCACGGCCACAGCCAACTACTCCAAGGCAGTGCACCAGGTGCTGGACGTGGTGCATGAGGTGTTACATCACCAGCGACGGCTGGAGAGCATCTGGCAGCA CCGCAAGGTGCGGCTCCACCAGCGGCTGCAGCTCTGCGTCTTCCAGCAGGATGTACAGCAGGTGTTGGACTGGATTGAAAACCATGGTGAGGCCTTTCTCAGCAAACACACT GGAGTTGGGAAGTCCCTACATCGAGCCCGGGCCCTGCAGAAGAGGCATGATGACTT'IGAAGAGGTGGCTCAGAATACGTACACCAATGCGGACAAGCTCCTAGAAGCAGCAG AGCAGTTGGCTCAGACGGGGGAATGTGACCCCGAGGAGATCTACAAGGCAGCTCGACACCTGGAGGTGCGCATCCAAGACTTCGTGCGCAGGGTGGAGCAGCGGAAGCTTCT CCTGGACATGTCTGTTTCCTTCCACACACACACCAAAGAGTTGTGGACATGGATGGAAGACCTTCAGAAGGAGATGTTGGAGGATGTCTGTGCAGATTCTGTGGATGCAGTC CAGGAACTGATCAAACAGTTCCAGCAGCAGCAGACCGCCACTCTAGATGCCACACTCAATGTCATCAAGGAAGGCGAAGACCTTATCCAGCAGCTCAGGTCAGCGCCTCCCT CCCTCGGGGAGCCCAGCGAGGCCAGGGACTCGGCTGTGTCCAACAACAAAACACCCCACAGCAGCTCCATCAGCCACATCGAGTCGGTCCTGCAGCAGCTTGATGATGCCCA GGTGCAGATGGAGGAGCTGTTCCACGAGCGGAAGATCAAGCTGGACATCTTCCTGCAACTGCGCATCTTTGAGCAGTACACCATCGAGGTGACAGCAGAGCTAGACGCCTGG AATGAAGACTTGCTTCGGCAGATGAATGACTTCAACACAGAGGACCTAACCCTGGCAGAACAGCGGCTGCAGCGCCACACAGAACGGAAGCTAGCCATGAACAACATGACCT TTGAGGTTATCCAGCAGGGACAGGATCTGCACCAGTACATCACGGAGGTCCAGGCATCAGGAATTGAGTTGATCTGTGAAAAAGACATTGATCTGGCAGCCCAGGTGCAAGA GTTATTGGAATTTCTCCATGAGAAGCAGCATGAATTGGAGCTCAATGCAGAGCAGACTCATAAGCGGCTAGAGCAGTGCCTCCAATTACGTCACCTCCAGGCTGAAGTCAAA CAGGTTCTGGGATGGATCCGCAATGGAGAGTCAATGCTCAACGCCAGCCTGGTCAATGCCAGCTCTTTGTCGGAAGCAGAGCAGCTGCAGCGGGAGCACGAGCAGTTCCAAC TGGCCATCGAGTCCCTCTTTCATGCCACTTCCTTGCAGAAGACGCACCAGAGTGCCCTGCAGGTACAGCAGAAAGCCGAGGTGCTΑCTCCAGGCCGGCCACTACGATGCCGA TGCCATCCGGGAATGTGCTGAGAAGGTGGCCCTCCACIGGCAGCAGCTCATGCTGAAGATGGAAGACCGGCTAAAAT'IGGTCAATGCCTCTGTGGCCTTTTACAAAACTTCT GAACAGGTGTGTAGTGTCCTGGAGAGCTTAGAGCAAGAATACCGGAGAGATGAGGACTGGTGTGGTGGACGAGATAAGCTGGGGCCAGCAGCAGAGATCGACCATGTCATTC CCCTCATCAGCAAACATTTGGAACAAAAGGAGGCCTTTCTTAAGGCCTGCACCCTGGCTCGGCGGAATGCTGAGGTGTTTCTCAAGTACATCCACAGGAACAACGTCAGCAT GCCCAGTGTCGCCAGCCACACTCGGGGACCCGAGCAACAAGTGAAAGCCATCCTGAGTGAGCTCCTGCAGAGGGAGAATCGCGTGCTGCATTTCTGGACCTTGAAGAAGCGG CGGTTAGACCAATGCCAGCAATATGTGGTGTTCGAGCGCAGCGCTAAGCAGGCGCTTGACTGGATCCAAGAAACAGGTGAATTTTACCTCTCAACACATACCTCCACTGGAG AGACCACAGAGGAGACTCAGGAACTGCTGAAAGAATATGGGGAATTCAGGGTGCCTGCCAAGCAAACAAAGGAGAAGGTGAAGCTTCTGATTCAGCTGGCCGATAGCTTTGT GGAAAAAGGCCACATTCATGCCACGGAGATAAGGAAA'IGGGTGACCACGGTGGACAAGCACTACAGAGATTTCTCCCTGAGGATGGGAAAGTACCGATACTCACTGGAGAAA GCCCTAGGAGTCAACACAGAGGATAATAAGGACCTGGAGCTGGATATTATCCCAGCAAGCCTTTCGGATCGGGAGGTCAAGCTGCGGGACGCCAACCACGAAGTCAATGAAG AGAAGCGGAAGTCAGCCCGGAAGAAAGAATTTATTATGGCTGAACTACTCCAGACAGAGAAGGCTTATGTAAGGGATT'IGCATGAGTGCTTAGAGACCTACCTGTGGGAAAT GACCAGTGGTGTGGAGGAGATCCCCCCTGGGATCCTCAATAAAGAGCATATCATCTTTGGCAACATCCAAGAGA'ICTACGATTTCCATAACAACATCTTCCTCAAAGAGCTG GAGAAGTACGAGCAACTGCCTGAGGATGTGGGACACTGCTTTGTTACCTGGGCAGACAAATTTCAGATGTATGTCACCTACTGTAAAAACAAGCCTGATTCCAACCAGCTTA TCCTGGAGCATGCGGGCACCTTCTTTGATGAGATACAACAGCGGCATGGTCTGGCCAACTCCATCTCTTCCTACCTAATTAAGCCTGTCCAAAGGATCACCAAATATCAACT GCTCCTGAAGGAACTTTTAACTTGCTGTGAAGAAGGGAAAGGGGAGCTCAAGGATGGCCTGGAGGTGATGCTCAGTG'ICCCAAAGAAAGCCAATGATGCCATGCATGTCAGC ATGCTGGAAGGGTTCGACGAGAACCTGGATGTGCAGGGGGAGTTGATTCTCCAGGATGCCTTTCAAGTGTGGGACCCGAAGTCGCTGATCCGGAAGGGGCGGGAGCGGCACT TGTTCCTCTTTGAGATCTCCTTGGTTTTTAGCAAGGAGATCAAAGATTCTTCAGGACACACGAAATATGTTTACAAGAACAAGCTACTGACCTCAGAGCTGGGTGTGACCGA GCACGTGGAGGGCGATCCCTGCAAATTCGCCTTGTGGTCTGGGCGCACCCCATCCTCAGACAATAAAACAGTGCTGAAAGCCTCCAACATTGAAACCAAGCAGGAGTGGATC AAGAACATTCGAGAAGTGATTCAAGAAAGGATCATTCACCTGAAAGGAGCTTTAAAGGAGCCACTTCAGCTCCCCAAAACACCAGCCAAACAGAGGAACAATAGTAAGAGGG ATGGAGTGGAGGATATTGACAGCCAGGGGGATGGGAGCAGCCAACCAGACACCATCTCCATTGCTTCTAGGACCTCTCAGAACACAGTGGACAGTGACAAGGATGGCAACCT TGTTCCTCGGTGGCACCTGGGACCTGGAGATCCTTTCTCCACTTACGTTTAGCGCGCATCCTGGGACTTGTCCCTGCAGCTCACCGGGTTAGCCGTGGCACCGTTGGGACCT CCCACCAGGACTCCAATCACCCACCTCTCTTGAGACTTCTCTGGCAGGGCTGGTGTGGGGTGCAGCCTTTGCTCAGAGGGCAACATGTTCCAAGCAAAATCTCCCCGCCTGG GCCATGGGCTCACCCTCGGGGCTCCCTTCTTCTCTACTGGGTGCAATTCGAGGTTGCTGAGCTTCTCTCCAAAGTCTAAAATGGTGGGGCAGTAGGGACCTGTGAGAGGCCC AATGGCCCAATGTACTTCCCCCAGATCCCACTCAGAACAGCAGGTACGCCCAGGCTCCTGCTGCCCTAGAGGTCTGCAACATGAGTGAAGAGGTTAATTAGAGGGACACACT TATCTCTGAAGTTTTTCTCCAGGCTGAACATT'ICTA-RTATCAGTGGCCCCTAATCTGGAAAAACCCATCATTCTAATCTAGCTTGTATCCCCACATCATGAGAAAGAGGGAA GAAGAAGAAGGGATGATGTGTGGTAGAGAAGATGAGGGTTAACTTTAGCCTTTCCCAAACACTGGCAACAACCACTTCCTCAACAATTTTTCTATTTGCTTCAGCCTACTCA GATTTTTTCAGGTTTTTCTAGCTCCTCCATAACCTCACTCCCTCCCGAGGTCTCTGGTTCAAAGACCACCCTACCAGCCCCTATTTGCTTCAGGTTATCCTGTTGAGGGTGG GTGGGAAGAGTGAGAAGATATAAATGAAAAACTGGCCACATGTTGATAATTGTTGAAACTAGATGATGGTACGTGGACATTCATTATACCATTCTCCCCACTTCTGTATTTG TTTGCAATTTTTCATAATAAAAAAGTTTTAAAAGTCCTCCAGTTTCCAACACACTCAAGAGAGAGCCCCAACCCCAAACACAGAGTTTCATGGAAACCCCACACCAAGGCAA GAGGCAGAGATGATGATTCCATTTCATATATACACTCATTTTCTAACTTTTTTTAAAGGCCCACTGCTTTATTTTCAATAGATTAAACCTGATTTCTGAGAGGTCCTGAAGT TGGGCTTATTTCCCTGGCTGGGTTATGGGGGAGGGCAGGGTAAAGGGATCCTTAAAAAAGTTTACACTTCTATGTATCTCACAATCTTATTGTGAGGATGTGACTTGTTCAG TGTTCTGAACTTTTCGAAΣΣAATCGTGCTCTCAATGCAAAGTGTCATTCTCTGGAATTGCACCTGGCTCAGGAAAGGACTGTCTTTGTACTTGAATTTAAATCCAATGGAGA ACTTTAACACGGGCATTTGCATGACTGAGAATTGCTGCTGTCTTTTTTCCGTATGTCACTTTCTTGAATGTGTTCTAATAAAATG
89
^ClYSFDTTAEDP^nRISDCIKNLFSPIMSENHGH PLQPNAS EEEGTQGHPDG PPK DTA GTPKVYKSADSSTVKKGPPV PKPA F QSLKG RNRASEPRGLPDPA
LSTQPAPASREHLGSHIRASSSSSSIRQRISSFETFGSSQLPDKGAQRLSLQPSSGEAAKPLGKHEEGRFSGLLGRGAAPTLVPQQPEQVLSSGSPAASEARDPGVSESPPP
GRQPNQKTFPPGPDPLLRLLSTQAEESQGPVLKNPSQRARSFPLTRSQSCETK LDEKTSKLYSISSQVSSAVMKSLLCLPSSISCAQTPCIPKEGASPTSSSNEDSAANGS
AETSALDTGFSLNLSELREYTEGLTEAKEDDDGDHSSLQSGQSVISLLSSEELKKLIEEVKVLDEAT KQLDGIHVTILHKEEGAGLGFSLAGGAD ENKVITVHRVFPNGL
ASQEGTIQKGNEVLSINGKSLKGTTHHDALAILRQAREPRQAVIVTRKLTPEAMPDLNSSTDSAASASAASDVSVESTAEATVCTVTI.EKMSAGLGFSLEGGKG8LHGDKPL
TINRIFKGAASEQSETVQPGDEILQLGGTA QGLTRFEAWNIIKALPDGPVTIVIRRKSLQSKETTAAGDS
90
TGCTTAAAAAAACACAACΛGGATTTTCGAAGAATCCTTTCTTAGAAAACAAACAAAAAAACCAAACAAAAACGTACTTTCTCCCCACTAGTTTACACCACAGGAAGCGAGAG AGCTGCTGCCACTGCTGCTACCACAGGAAGACACAGCAGGGAGAAGCCCTAGTGCCTCTGCCGGCTGCCCAGGACCTGGTATCGGCCCACAGACCAAGTCCTCCACAGAGGG CGAGCCAGGGTGGAGAAGAGCCAGCCCAGTGACCCAAACATCCCCGATAAAACACCCACTGCTTAAGAGGCAGGCTCGGATGGACTATAGCTTTGATACCACAGCCGAAGAC CCT GGGTTAGGATTTCTGACTGCATCAAAAACTlATTTAGCCCCATCATGAG'rGAGAACCATGGCCACATGCCTCTACAGCCCAATGCCAGCC GAATGAAGAAGAAGGGA CACAGGGCCACCCAGATGGGACCCCACCAAAGCTGGACACCGCCAATGGCACTCCCAAAGTTTACAAGTCAGCAGACAGCAGCACTGTGAAGAAAGGTCCTCCTGTGGCTCC CAAGCCAGCCTGGTTTCGCCAAAGCTTGAAAGGTTTGAGGAATCGTGCTTCAGAGCCAAGAGGGCTCCCTGATCCTGCCTTGTCCACCCAGCCAGCACCTGCTTCCAGGGAG CACCTAGGATCACACATCCGGGCCTCCTCCTCCTCCTCCTCCATCAGGCAGAGAATCAGCTCCTTTGAAACCTTTGGCTCCTCTCAACTGCCTGACAAAGGAGCCCAGAGAC TGAGCCTCCAGCCCTCCTCTGGGGAGGCAGCAAAACCTCTTGGGAAGCATGAGGAAGGACGGTTTTCTGGACTCTTGGGGCGAGGGGCTGCACCCACTCTTGTGCCCCAGCA GCCTGAGCAAGTACTGTCCTCGGGGTCCCCTGCAGCCTCCGAGGCCAGAGACCCAGGTGTGTCTGAGTCCCCTCCCCCAGGGCGGCAGCCCAATCAGAAAACTTTCCCCCCT GGCCCGGACCCGCTCCTAAGGCTGCTGTCAACACAGGCTGAGGAATCTCAAGGCCCAGTGCTCAAGATGCCTAGCCAGCGAGCACGGAGCTTCCCCCTGACCAGGTCCCAGT CCTGTGAGACGAAGCTACTTGACGAAAAGACCAGCAAACTCTATTCTATCAGCAGCCAAGTGTCATCGGCTGTCATGAAATCCTTGCTGTGCCTTCCATCTTCTATCTCCTG TGCCCAGACTCCCTGCATCCCCAAGGCAGGGGCATCTCCAACATCATCATCCAACGAAGACTCAGCTGCAAATGGTTCTGCTGAAACATCTGCCTTGGACACGGGGTTCTCG CTCAACCTTTCAGAGCTGAGAGAATATACAGAGGGTCTCACGGAAGCCAAGGAAGACGATGATGGGGACCACAGTTCCCTTCAGTCTGGTCAGTCCGTTATCTCCCTGCTGA GCTCAGAAGAATTAAAAAAACTCATCGAGGAGGTGAAGGTTC GGATGAAGCAACATTAAAGCAATTAGACGGCATCCATGTCACCATCTTACACAAGGAGGAAGGTGCTGG TCTTGGGTTCAGCTTGGCAGGAGGAGCAGATCTAGAAAACAAGGTGATTACGGTTCACAGAGTGTTTCCAAATGGGCTGGCCTCCCAGGAAGGGACTATTCAGAAGGGCAAT GAGGTTCTTTCCATCAACGGCAAGTCTCTCAAGGGGACCACGCACCATGATGCCTTGGCCATCCTCCGCCAAGCTCGAGAGCCCAGGCAAGCTGTGATTGTCACAAGGAAGC TGACTCCAGAGGCCATGCCCGACCTCAACTCCTCCACTGACTCTGCAGCCTCAGCCTCTGCAGCCAGTGATGTTTCTGTAGAATCTACAGCAGAGGCCACAGTCTGCACGGT GACACTGGAGAAGATGTCGGCAGGGCTGGGCTTCAGCCTGGAAGGAGGGAAGGGCTCCCTACACGGAGACAAGCCTCTCACCATTAACAGGATTTTCAAAGGAGCAGCCTCA GAACAAAGTGAGACAGTCCAGCCTGGAGATGAAATCTTGCAGCTGGGTGGCACTGCCATGCAGGGCCTCACACGGTTTGAAGCCTGGAACATCATCAAGGCACTGCCTGATG GACCTGTCACGATTGTCATCAGGAGAAAAAGCCTCCAGTCCAAGGAAACCACAGCTGCTGGAGACTCCTAGGCAGGACATGCTGAAGCCAAAGCCAATAACACACAGCTAAC ACACAGCTCCCATAACCGCTGATTCTCAGGGTCTCTGCTGCCGCCCCACCCAGATGGGGGAAAGCACAGGTGGGCTTCCCAGTGGCTGCTGCCCAGGCCCAGACCTTCTAGG ACGCCACCCAGCAAAAGGTTGTTCCTAAAATAAGGGCAGAGTCACACTGGGGCAGCTGATACAAATTGCAGACTGTGTAAAAAGAGAGCTTAATGATAATATTGTGGTGCCA CAAATAAAATGGATTTATTAGAATTCCATATGACATTCATGCCTGGCTTCGCAAAATGTTTCAAGTACTGTAACTGTGTCATGATTCACCCCCAAACAGTGACATTTATTTT TCTCATGAATCTGCAATGTGGGCAGAGATTGGAATGGGCAGCTCATCTCTGTCCCACTTGGCATCAGCTGGCGTCATGCAAAGTCATGCAAAGGCTGGGACCACCTGAGATC ATTCACTCATACATCTGGCCGTTGATGTTGGCTGGGAACTCACCTGGGGCTGCTGGCCTGAATGCTTATAGGTGGCCTCTCCTTGTGGCCTGGGCTCCTCACAACATGGTGT CTGGATTCCCAGGATGAGCATCCCAGGATCGCAAGAGCCACGTAGAAGCTGCATCTTGTTTATACCTTTGCCTTGGAAGTTGCATGGCATCACCTCCACCATACTCCATCAG TTAGAGCTGACACAAACCTGCCTGGGTTTAAGGGGAGAGGAAATATTGCTGGGGTCATTTATGAAAAATACAGTTTGTCACATGAAACATTTGCAAAATTGTTTTTGGTTGG ATTGGAGAAGTAATCCTAGGGAAGGGTGGTGGAGCCAGTAAATAGAGGAGTACAGGTGAAGCACCAAGCTCAAAGCGTGGACAGGTGTGCCGACAGAAGGAACCAGCGTGTA TATGAGGGTATCAAATAAAATTGCTACTACTTACCTACC
91
MAEVPKLASEMMAYYSGNEDDLFFEADGPKQMKCSFQDLDLCPLDGGIQLRISDHHYSKGFRQAASVWAMDKLRKMLVPCPQTFQENDLSTFFPFIFEEEPIFFDTWDNEA YVHDAPVRS NCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQWFSMSFVQGEESNDKIPVALGLKEKN YLSCVLKDDKPTLQLESVDP NYPKKKNEKRFVFNKIEINN KLEFESAQFPN YISTSQAENMPVFLGGTKGGQDITDFTNQFVSS
92
ACCAACCTCTTCGAGGCACAAGGCACAACAGGCTGCTCTGGGATTCTCTTCAGCCAATCTTCATTGCTCAAGTGTCTGAAGCAGCCATGGCAGAAGTACCTGAGCTCGCCAG
TGAAATGATGGCTIATTACAGTGGCAATGAGGATGACTTGTTCTTTGAAGCTGATGGCCCTAAACAGATGAAGTGCTCCTTCCAGGACCTGGACCTCTGCCCTCTGGATGGC
GGCATCCAGCTACGAATCTCCGACCACCACTACAGCAAGGGCTTCAGGCAGGCCGCGTCAGTTGTTGTGGCCATGGACAAGCTGAGGAAGATGCTGGTTCCCTGCCCACAGA
CCTTCCAGGAGAATGACCTGAGCACCTTCTTTCCCTTCATCTTTGAAGAAGAACCTATCTTCTTCGACACATGGGATAACGAGGCTTATGTGCACGATGCACCTGTACGATC
ACTGAACTGCACGCTCCGGGACTCACAGCAAAAAAGCTTGGTGATGTCTGGTCCATATGAACTGAAAGCTCTCCACCTCCAGGGACAGGATATGGAGCAACAAGTGGTGTTC
TCCATGTCCTTTGTACAAGGAGAAGAAAGTAATGACAAAATACCTGTGGCCTTGGGCCTCAAGGAAAAGAATCTGTACCTGTCCTGCGTGTTGAAAGATGATAAGCCCACTC
TACAGCTGGAGAGTGTAGATCCCAAAAATTACCCAAAGAAGAAGATGGAAAAGCGATTTGTCTTCAACAAGATAGAAATCAATAACAAGCTGGAATTTGAGTCTGCCCAGTT
CCCCAACTGGTACATCAGCACCTCTCAAGCAGAAAACATGCCCGTCTTCCTGGGAGGGACCAAAGGCGGCCAGGATATAACTGACTTCACCATGCAATTTGTGTCTTCCTAA
AGAGAGCTGTACCCAGAGAGTCCTGTGCTGAATGTGGACTCAATCCCTAGGGCTGGCAGAAAGGGAACAGAAAGGTTTTTGAGTACGGCTATAGCCTGGACTTTCCTGTTGT
CTACACCAATGCCCAACTGCCTGCCTTAGGGTAGTGCTAAGAGGATCTCCTGTCCATCAGCCAGGACAGTCAGCTCTCTCCTTTCAGGGCCAATCCCCAGCCCTTTTGTTGA
GCCAGGCCTCTCTCACCTCTCCTACTCACTTAAAGCCCGCCTGACAGAAACCACGGCCACATTTGGTTCTAAGAAACCCTCTGTCATTCGCTCCCACATTCTGATGAGCAAC
CGCTTCCCTATTTATTTATTTATTTGTTTGTTTGTTTTATTCATTGGTCTAATTTATTCAAAGGGGGCAAGAAGTAGCAGTGTCTGTAAAAGAGCCTAGTTTTTAATAGCTA
TGGAATCAATTCAATTTGGACTGGXGTGCTCTCTTTAAATCAAGTCCTTTAATTAAGACTGAAAATATATAAGCTCAGATTATTTAAATGGGAATATTTATAAATGAGCAAA
TATCATACTGTTCAATGGTTCTGAAATAAACTTCTCTGAAG
93
MRLTVLCAVCL PGSLALPLPQEAGGMSE QWEQAQDYLKRFYLYDSETKNANSLEAKLKEMQKFPGLPITGM NSRVIEIMQKPRCGVPDVAEYSLFPNSPKWTSKWTYR
IVSYTRDLPHITVDR VSKALNMWGKEIPLHFRKWWGTADIMIGFARGAHGDSYPFDGPGNTLAHAFAPGTGLGGDAHFDEDER TDGSSLGINFLYAATHELGHSLGMGH
SSDPNAVMYPTYGNGDPQNFKLSQDDIKGIQKLYGKRSN8RKK
94
ACCAAATCAACCATAGGTCCAAGAACAATTGTCTCTGGACGGCAGCTATGCGACTCACCGTGCTGTGTGCTGTGTGCCTGCTGCCTGGCAGCCTGGCCCTGCCGCTGCCTCA GGAGGCGGGAGGCATGAG GAGCTACAGTGGGAACAGGCTCAGGACTATCTCAAGAGATTTTATCTCTATGACTCAGAAACAAAAAATGCCAACAGTTTAGAAGCCAAACTC AAGGAGATGCAAAAATTCTTTGGCCTACCTATAACTGGAATGTTAAACTCCCGCGTCATAGAAATAATGCAGAAGCCCAGATGTGGAGTGCCAGATGTTGCAGAΔTACTCAC TATTTCCAAATAGCCCAAAATGGACTTCCAAAGTGGTCACCTACAGGATCGTATCATATACTCGAGACTTACCGCATATTACAGTGGATCGATTAGTGTCAAAGGCTTTAAA CATGTGGGGCAAAGAGATCCCCCTGCATTTCAGGAAAGTTGTATGGGGAACTGCTGACATCATGATTGGCTTTGCGCGAGGAGCTCATGGGGACTCCTACCCATTTGATGGG CCAGGAAACACGCTGGCTCATGCCTTTGCGCCTGGGACAGGTCTCGGAGGAGATGCTCACTTCGATGAGGATGAACGCTGGACGGATGGTAGCAGTCTAGGGATTAACTTCC TGTATGCTGCAACTCATGAACTTGGCCATTCTTTGGGTATGGGACATTCCTCTGATCCTAATGCAGTGATGTATCCAACCTATGGAAATGGAGATCCCCAAAATTTTAAACT TTCCCAGGATGATATTAAAGGCATTCAGAAACTATATGGAAAGAGAAGTAATTCAAGAAAGAAATAGAAACTTCAGGCAGAACATCCATTCATTCATTCATTGGATTGTATA TCATTGTTGCACAATCAGAATTGATAAGCACTGTTCCTCCACTCCATTTAGCAATTATGTCACCCTTTTTTATTGCAGTTGGTTTTTGAATGTCTTTCACTCCTTTTATTGG TTAAACTCCTTTATGGTGTGACTGTGTCTTATTCCATCTATGAGCTTTGTCAGTGCGCGTAGATGTCAATAAATGTTACATACACAAATAAATAAAATGTTTATTCCATGGT AAATTTA
95
MKRLTCFFICFFLSEVSGFEIPING SEFVDYEDLVETΛPGKFQLVAENRRYQRSLPGESEE^ IEEVDQVTLYSYKVQε ITεR^IATTMIQεKVVNNεPQPQNVVFDVQIPK
GAFI8NF8MTVTX3KTFRSSIKEKTVGRALYAQARAKGKTAGLVR8SALDMENPRTEVNVLPGAKVQPELHYQEVKWR LGSYEHRIYLQPGRLAKHLEVDVWVIEPQGLRFL
HVPDTFEGHFDGVPVI8KGQQKAHVSFKPTVAQQRICPSCRETAVDGELWLYDVKREEKAGELEVFNGYFVHFFAPDNLDPIPKNILFVIDVSGSNWGVKNKQTVEAMKTI
LDD RAEDHFSVIDFNQNIRTWRNDLISATKTQVADAKRYIEKIQPSGGTNINEALLRAIFILNEANN G LDPNSVS I ILVSDGDPTVGELKLSKIQKNVKENIQDNISL.
FSLGMGFDVDYDFLKRLSNENHGIAQRIYGNQDTSSQLKKFYNQVSTPLLRNVQFNYPHTSVTDVTQNNFHNYFGGSEIWAGKFDPAKLDQIESVITATSANTQLVLETI-A
QMDDLQDFLSKDKHADPDFTRKLWAYLTINQLIAERSLAPTAAAKRRITRSILQMSLDHHIVTPLTSLVIENEAGDEPJ^LADAPPQDPSCCSGALYYGSKVVPDSTPSWANP
SPTPVISMIAQGSQVLESTPPPHV RVENDPHFI IYLPKSQKNICFNIDSEPGKILNLVSDPESGIVVNGQLVGAKKPNNGKLSTYFGKLGFYFQSEDIKIEISTETITLSH
GSSTFSL8WSDTAQVTNQRVQISVKKEKWTITLDKEMSFSVLLHRV KKHPVNVDFLGIYIPPTNKFSPKAHGLIGQFMQEPKIHIFNERPG KDPEKPEASMEVKGQKX.i l
TRGLQKDYRTDLVFGTDVTC FVHNSGKGFIDGHYKDYFVPQLYSF KRP
96
GAAAGAAGTGATATCCTCCCCAGACCATCTGCITTGGGGAGCTTGGCAAAACTGTCCAGCAAAATGAAAAGACTCACGTGCTTTTTCATCTGCTTCTTTCTTTCTGAAGTAT
CAGGCTTCGAAATCCCCATAAATGGACTTTCTGAATTTGTAGACTATGAAGATCTTGTGGAACTGGCCCCAGGCAAATTTCAATTGGTGGCAGAGAACCGGAGATATCAGAG
AAGCCTTCCAGGAGAATCGGAAGAAATGATGGAAGAGGTTGATCAAGTAACTCTTTA'rAGCTATAAAGTCCAGTCTACTATTACTTCTCGGATGGCCACCACCATGATCCAG
AGCAAAGTGGTGAACAATTCCCCGCAGCCTCAGAATGTCGTGTTTGATGTTCAGATCCCCAAAGGAGCATTCATTTCCAACTTCTCCATGACTGTGGACGGCAAGACATTTA
GGAGCTCTATTAAGGAGAAAACTGTGGGCCGAGCTCTTTATGCACAGGCCAGAGCAAAAGGCAAGACGGCTGGCTTGGTGAGGAGCAGCGCTCTTGATATGGAAAACTTCAG
AACGGAAGTAAATGTCCTCCCAGGAGCAAAGGTGCAGTTCGAACTTCACTACCAGGAGGTGAAGTGGAGGAAGCTGGGCTCCTATGAGCACAGGATCTATCTGCAACCTGGA
CGGCTGGCCAAACACTTAGAGGTAGATGTGTGGGTTATCGAACCACAGGGACTGAGATTTCTTCATGTTCCCGACACATTTGAAGGCCATTTCGATGGTGTTCCGGTCATTT
CTAAAGGACAACAGAAGGCGCACGTCTCCTTCAAGCCCACGGTAGCACAGCAGAGAATATGCCCTAGCTGCCGGGAGACTGCGGTAGATGGGGAACTGGTGGTGCTGTATGA
CGTGAAAAGAGAAGAGAAGGCTGGTGAACTGGAGGTGTTTAATGGATATTTTGTCCACTTCTTTGCTCCTGACAACCTGGACCCAATTCCCAAAAACATCCTCTTTGTCATC
GATGTGAGTGGCTCCATGTGGGGAGTTAAAATGAAACAAACTGTGGAAGCAATGAAGACCATATTGGATGACCTCAGAGCAGAAGACCATTTCTCTGTGATTGATTTCAACC
AGAACATTCGAACTTGGAGAAATGATTTATTTCAGCTACAAAAACACAGGTTGCAGATAGCCAAGAGGTATATTGAGAAAATCCAGCCCAGTGGAGGCACAAACATCAACGA AGCACTCCTACGGGCAATCTTCATTTTGAATGAAGCCAATAACTTGGGACTGTTAGACCCCAACTCCGTCTCGCTGA'ICATTTTGGTTTCTGATGGAGATCCAACAGTGGGC GAACTAAAACTGTCAAAAATTCAGAAAAACG'ITAAGGAGAACATCCAAGACAATATCTCCTTGTTCAGTTTGGGCATGGGATTTGATGTGGACTATGATTTTTTGAAGAGAC TGTCCAATGAAAACCATGGAATTGCACAAAGGATT'IATGGAAACCAGGACACGTCTTCCCAGCTTAAGAAATTCTACAACCAGGTCTCCACTCCATTGCTCCGGAATGTTCA GTTCAACTATCCCCATACATCAGTCACGGACGTCACTCAAAACAATTTCCATAACTACTTTGGAGGCTCAGAGATTGTGGTGGCAGGAAAATTTGACCCTGCTAAATTGGAT CAAATAGAGAGCGTTATCACGGCGACTTCGGCTAACACGCAGTTAGTCTTGGAGACCCTGGCCCAGATGGACGACTTGCAGGATTTTCTATCGAAAGACAAGCATGCAGATC CCGATTTCACCAGGAAACTGTGGGCCTATCTAACCATCAACCAACTGCTAGCTGAACGAAGCCTGGCTCCTACAGCTGCCGCCAAGAGAAGAATTACAAGATCGATCCTGCA GATGTCTCTAGACCACCACATTGTGACTCCGCTGACCTCGCTGGTGATCGAGAACGAGGCTGGGGATGAGCGCATGCTGGCGGATGCCCCACCGCAGGATCCCTCCTGCTGC TCAGGGGCCCTGTATTACGGCAGCAAAGTGGTTCCAGATTCCACCCCGTCTTGGGCCAATCCTTCACCAACGCCCGTGATCTCCATGCTGGCACAAGGATCTCAGGTGCTAG AGTCCACGCCACCCCCACATGTGATGAGAGTTGAAAATGACCCACATTTCATCATTTATCTACCAAAAAGCCAAAAGAACATTTGTTTCAATATTGACTCAGAACCTGGAAA AATCCTCAACCTGGTTTCTGACCCAGAATCAGGAATTGTAGTCAACGGTCAGCTTGTTGGTGCCAAGAAGCCCAACAATGGAAAACTAAGCACCTATTTTGGAAAACTGGGA TTTTATT CCAAAGTGAAGACATAAAAATAGAAATCAGCACTGAGACCATCACCCTGAGCCATGGTTCTAGCACATTCTCCTTGTCCTGGTCCGACACGGCTCAAGTCACGA ATCAGAGGGTGCAGATCTCAGTGAAGAAAGAAAAAGTGGTAACTATCACCCTGGATAAAGAGATGTCCTTTTCTGTTTTACTTCATCGTGTTTGGAAGAAGCATCCCGTCAA TGTTGACTTTCTGGGAATCTACATACCCCCTACAAACAAGTTCTCACCTAAAGCCCACGGACTAATAGGCCAGTTCATGCAGGAACCAAAGATACACATCTTCAATGAGAGA CCAGGAAAGGACCCTGAGAAGCCAGAGGCCAGCATGGAAGTGAAGGGGCAGAAGCTGATCATCACCAGGGGCTTACAGAAAGACTACAGAACGGATCTAGTGTTTGGAACGG ACGTTACCTGCTGGTTTGTGCACAACAGTGGAAAAGGATTCATTGACGGGCATTACAAGGATTACTTCGTGCCTCAGCTCTACAGCTTTCTCAAACGGCCTTAAAGGTTTAT AGTTTGGGAAATTATATATATTAATATACATCITTCCCCTGTCACTTTTGCAGATATTCTTCGGTTTGAATAATTAAAATGAACCAGATATCAGGGTGGTTAATTAAAATGA ACCAGATATCAGGGTGGTTTATAAAGCCTGTAAACACACCTAAGAAAATAAACATTTTACAAATG
97
MRHNWTPDLSPLWVLLLCAHWTLLVRATPVSQTTTAATASVRSTKDPCPSQPPVFPAAKQCPALEVTWPEVEVPLNGTLSLSCVACSRFPNFSILYWLGNGSFIEHLPGRL
WEGSTSRERGSTGTQLCKALVLEQLTPALHSTNFSCVLVDPEQWQRHW AQLWVRSPRRGLQEQEELCFHMWGGKGGLCQSSL
98
GCCAGAGGGGCTAGGATGAGAGACAGAGGGTGTGAIGGTGGGTGCTGGGAGATGTAGCCGACCTTGGGGCTGGTGGCTGGGGGAGTGGGTAGCCTGGGAAAGGCCAGGATGT GGACGGACTGGTATGGCATTGAGCCTGAAGTGGTCCAACTTGGGGTTCCCCAGTGCCTAGGAAAGTTGTCCCCTTGAATGTCAGTGTGAAGGTGAAGGAGGAAGCAGATGCC TGTTCATATGGAAACAAAGACCTGGCTGTGAAGAGGGGAGGCGGACACCAAAGTCCTGACACTTGGGCGGGACAGAATTGATCTGTGAGAGACTCATCTAGTTCATACCCTA GGTGACCCTGGGGGTGGCATGGGGGTAGATTAGAGATCCCAGTCTGGTATCCTCTGGAGAGTAGGAGTCCCAGGAGCTGAAGGTTTCTGGCCACTGAACTTTGGCTAAAGCA GAGGTGTCACAGCTGCTCAAGATTCCCTGGTTAAAAAGTGAAAGTGAAATAGAGGGTCGGGGCAGTGCTTTCCCAGAAGGATTGCTCGGCATCCTGCCCTTCCCAGAAGCAG CTCTGGTGCTGAAGAGAGCACTGCCTCCCTGTGTGACTGGGTGAGTCCATATTCTCTCTTTGGGTCTCAATTTTGCCTTCCCTAATGAAGGGGTAAGATTGGACTAGGTAAG CATCTTACAACCATTTGTGGTCΔTGAGAGCTGGGGTGGGGAAGGATTGTCACTTGACCCCCCCAGCTCTGTTTCTAAGTGCTGAAAGAGCTCCAGGCTATGCTACGGGAGGA GAAGCCAGCTACTGAGGAAAAGCCAGCTACTGAGAAAAAGCGGGAGTGGTTTACCATTCTCCTCCCCCACCTTTCACCAGAGAAGAGGACGTTGTCACAGATAAAGAGCCAG GCTCACCAGCTCCTGACGCATGCATCATGACCATGAGACACAACTGGACACCAGACCTCAGCCCTTTGTGGGTCCTGCTCCTGTGTGCCCACGTCGTCACTCTCCTGGTCAG AGCCACACCTGTCTCGCAGACCACCACAGCTGCCACTGCCTCAGTTAGAAGCACAAAGGACCCCTGCCCCTCCCAGCCCCCAGTGTTCCCAGCAGCTAAGCAGTGTCCAGCA TTGGAAGTGACCTGGCCAGAGGTGGAAGTGCCACTGAATGGAACGCTGAGCTTATCCTGTGTGGCCTGCAGCCGCTTCCCCAACTTCAGCATCCTCTACTGGCTGGGCAATG GTTCCTTCATTGAGCACCTCCCAGGCCGACTGTGGGAGGGGAGCACCAGCCGGGAACGTGGGAGCACAGGTACGCAGCTGTGCAAGGCCTTGGTGCTGGAGCAGCTGACCCC TGCCCTGCACAGCACCAACTTCTCCTGTGTGCTCGTGGACCCTGAACAGGTTGTCCAGCGTCACGTCGTCCTGGCCCAGCTCTGGGTGAGGAGCCCAAGGAGAGGCCTCCAG GAACAGGAGGAGCTCTGCTTCCATATGTGGGGAGGAAAGGGTGGGCTCTGCCAGAGCAGCCTGTGAACTAATGCCCAGCATTCCTCAAGGTCAGCCAGACAAAAAGGAACTT AGGTCTTGGGCAGAGGAGGTGTAGCCTGGGGCAAAGTGATGAGATGTCCCTCCTTTCCTTGGCCTGATCCTTGTCTGCCTTCACTTCCCTAGGCTGGGCTGAGGGCAACCTT GCCCCCCACCCAAGAAGCCCTGCCCTCCAGCCACAGCAGTCCACAGCAGCAGGGTTAAGACTCAGCACAGGGCCAGCAGCAGCACAACCTTGACCAGAGCTTGGGTCCTACC TGTCTACCTGGAGTGAACAGTCCCTGACTGCCTGTAGGCTGCGTGGATGCGCAACACACCCCCTCCTTCTCTGCTTTGGGTCCCTTCTCTCACCAAATTCAAACTCCATTCC CACCTACCTAGAAAATCACAGCCTCCTTATAATGCCTCCTCCTCCTGCCATTCTCTCTCCACCTATCCATTAGCCTTCCTAACGTCCTACTCCTCACACTGCTCTACTGCTC AGAAACCACCAAGACTGTTGATGCCTTAGCCTTGCACTCCAGGGCCCTACCTGCATTTCCCACATGACTTTCTGGAAGCCTCCCAACTATTCTTGCTTTTCCCAGACAGCTC CCACTCCCATGTCTCTGCTCATTTAGTCCCGTCTTCCTCACCGCCCCAGCAGGGGAACGCTCAAGCCTGGTCGAAATGCTGCCTCTTCAGTGAAGTCATCCTCTTTCAGCTC TGGCCGCATTCTGCAGACTTCCTATCTTCGTGCTGTATGTTTTTTTTTTCCCCCTTCACTCTAATGGACTGTTCCAGGGAAGGGATGGGGGCAGCAGCTGCTTCGGATCCAC ACTGTATCTGTGTCATCCCCACATGGGTCCTCATAAAGGATTATTCAATGGAGGCATCCTGACATCTGTTCATTTAGGCTTCAGTTCCACTCCCAGGAACTTTGCCTGTCCC ACGAGGGAGTATGGGAGAGAGGGACTGCCACACAGAAGCTGAAGACAACACCTGCTTCAGGGGAACACAGGCGCTTGAAAAAGAAAAGAGAGAACAGCCCATAATGCTCCCC GGGAGCAGAGGCCACTAATGGAGAGTGGGAAGAGCCTGGAAAGATGTGGCCTCAGGAAAAGGGATGAGAGAAAGGAGGTGGTATGGAAGACTCAGCAGGAACAAGGTAGGCT TCAAAGAGCCTATATTCCTCTTTTTCCCACACCGATCAAGTCAACTCAGTACTCACGGGAGAAAAATAGACTTTATTTACAAGTAATAACATTTAGAAAAGATCCATCCCCG GCCCTTAAAAACCTTCCCATCACTCCAAATCCCACCCCAGTGCAAGTCTGGGGAAGGTAGGGTGTGAGCTGCTGCTGAAGGCTGTCCCCCAACCCCACTCCTGAGACACAGG GCCCATCCGTCCTGGGAAAGAGCATCCTCTGGCAGGTGCTCCCACCAGGTCAGACCCAGTCCTGGACTTCAAGAGTGAGGGCCCCTGCTGGGCCCAGCCACCAGGACAGCAG GAACCAGGGCCTACTCCTCTTATGGTCCCTTCTAGATCCAGAGGCTAAGAGGAAGACTGGCCAGGCCCAAGGACCCAGCCATCAAAACCAGCCTCAAATCTGGTTGTGATGG AGAAGTGACTTTGCTTTAAGAAAAAAGGAGGCAAGGTAGGGAGAGCGCCCACACTGTCCATGCTCCAGGCCCCCTGGGCCAGCTCCGAGAAGGCGCCAGTGAAGGACCAGGG ACCAGGCCAGGGTGCGGGCAGGCATCACTGTCTCTAGGGGTTTGGCTACTGTTGGCCTGGGAGCTGAGAGAAGGCACTGAGAGGGACAGTAGGCGGAGGACCAGGTGACGGC AGCATCGGGGACACAGGTGGGGCCACTCACTGGTACTGGCCCTTTAGTGCTTTGCCTGAAAGAGACACAGTCACATGGCCAGATGAGAACTTGCGATACTAGCCTGCACCCA CTGGCTGGGAAGATCICTTCCTGCTCCCACGCCCCTGTCTGGATCCCCTCCCTTGTGAGCCCCAGGGTTATCAGTTGCTGGCTGTGCCTGAGCAGCTCTGGGTGCTCTCCAT GAGAATGGGGCCATCTGTCTTCTCTCCTTGGAGAGGAGCTACCAGG
99 EGGDQSEEEPRERSQAGGMGTLWSQESTPEERLPVEGSRPWAVARRVLTAILILGLLLCFSVLLFYNFQNCGPRPCETSVCLDLRDHYIASGNTSVAPCTDFFSFACGRAK ET NSFQELATKNKNRLRRILEVQN8WHPGSGEEKAFQFYNSCMDTLAIEAAGTGPLRQVIEELGGWRISGKWTSLNFNRTLRLLMSQYGHFPFFRAYLGPHPASPHTPVIQ IDQPEFDVPLKQDQECKIYAQIFREYLTYLNQLGTL GGDPSKVQEHSSLSISITERLFQFLRPLEQRRAQGKLFQMVTIDQLKEMAPAIDWLSCLQATFTPMSLSP8QS V VHDVEYLK M8QLVEEMLLKQRDFLQSHMILGLVVTLSPALDSQFQEARRKLSQKLRELTEQPPMPARPRWMKCVEETGTFFEPTLAALFVREAFGPSTRSAAMKX,FTAIRD A ITRLRNLPWrølEETQMlAQDKVAQLQVEMGASEWALKPEI-ARQEYNDIQ GSSFLQSVLSCVKSLRARIVQSFLQPHPQHRWKVSP DVNAYYSVSDHVVVFPAGI- QPP FFHPGYPRAVNFGAAGSIMAHELLHIFYQLLLPGGC ACDNHALQEAHLCLKRHYAAFPLPSRTSFNDSLTFLENAADVGGLAIALQAYSKRLLRHHGETVLPSLDLSPQQI FFRSYAQVMCRKPSPQDSHDTHSPPHLRVHGPLSSTPAFARYFRCARGAL NPSSRCQL
100
CGGGAAGTGCCCCTTCTCCAGGATCAAGGAACTGGGGCGGGGGGTGTTTCCTGGACCCCAGTCCTCCGAATCAGCTCCTAGAGTGGAACCAGGAAGGA'ITCTGGAGCCACAG AAGATAGACAGATGGAAGGTGGGGACCAAAGTGAGGAAGAGCCGAGGGAACGCAGCCAGGCAGGTGGAATGGGAACTCTCTGGAGCCAAGAGAGCACTCCAGAAGAGAGGCT GCCCGTGGAAGGGAGCAGGCCATGGGCAGTGGCCAGGCGGGTGCTGACAGCTATCCTGATTTTGGGCCTGCTCCTTTGTTTTTCTGTGCTTTTGTTCTACAACTTCCAGAAC TGTGGCCCTCGCCCCTGTGAGACATCTGTGTGTTTGGATCTCCGGGATCATTACCTGGCCτCTGGGAACACAAGTGTGGCCCCCTGCACCGACTTCTTCAGCTTTGCCTGTG GAAGGGCCAAAGAGACCAATAATTCTTTTCAGGAGCTTGCCACAAAGAACAAAAACCGACTTCGGAGAATACTGGAGGTCCAGAATTCCTGGCACCCAGGCTCTGGGGAGGA GAAAGCCTTCCAGTTCTACAACTCCTGCATGGATACACTTGCCATTGAAGCTGCAGGGACTGGTCCCCTCAGACAAGTTATTGAGGAGCTTGGAGGCTGGCGCATCTCTGGT AAATGGACTTCCTTAAACTTTAACCGAACGCTGAGACTTCTGATGAGTCAGTATGGCCATTTCCCTTTCTTCAGAGCCTACCTAGGACCTCATCCTGCCTCTCCACACACAC CAGTCATCCAGATAGACCAGCCAGAGTTTGATGTTCCCCTCAAGCAAGATCAAGAACAGAAGATCTATGCCCAGATCTTTCGGGAATACCTGACTTACCTGAATCAGCTGGG AACCTTGCTGGGAGGAGACCCAAGCAAGGTGCAAGAACACTCTTCCTTGTCAATCTCCATCACTTCACGGCTGTTCCAGTTTCTGAGGCCCCTGGAGCAGCGGCGGGCACAG GGCAAGCTCTTCCAGATGGTCACTATCGACCAGCTCAAGGAAATGGCCCCCGCCATCGACTGGTTGTCCTGCTTGCAAGCGACATTCACACCGATGTCCCTGAGCCCTTCTC AGTCCCTCGTGGTCCATGACGTGGAATATTTGAAAAACATGTCACAACTGGTGGAGGAGATGCTGCTAAAGCAGAGGGACTTTCTGCAGAGCCACATGATCTTAGGGCTGGT GGTGACCCTTTCTCCAGCCCTGGACAGTCAATTCCAGGAGGCACGCAGAAAGCTCAGCCAGAAACTGCGGGAACTGACAGAGCAACCACCCATGCCTGCCCGCCCACGATGG ATGAAGTGCGTGGAGGAGACAGGCACGTTCTTCGAGCCCACGCTGGCGGCTTTGTTTGTTCGTGAGGCCTTTGGCCCGAGCACCCGAAGTGCTGCCATGAAATTATTCACTG CGATCCGGGATGCCCTCATCACTCGCCTCAGAAACCTTCCCTGGATGAATGAGGAGACCCAGAACATGGCCCAGGACAAGGTTGCTCAACTGCAGGTGGAGATGGGGGCTTC AGAATGGGCCCTGAAGCCAGAGCTGGCCCGACAAGAATACAACGATATACAGCT'IGGATCGAGCTTCCTGCAGTCTGTCCTGAGCTGTGTCCGGTCCCTCCGAGCTAGAATT GTCCAGAGCTTCTTGCAGCCTCACCCCCAACACAGGTGGAAGGTGTCCCCTTGGGACGTCAATGCTTACTATTCGGTATCTGACCATGTGGTAGTCTTTCCAGCTGGACTCC TCCAACCCCCATTCTTCCACCCTGGCTATCCCAGAGCCX3TGAACTTTGGCGCTGCTGGCAGCATCATGGCCCACX3AGCTGTTGCACATCTTCTACCAGCTCTTACTGCCTGG GGGCTGCCTCGCCTGTGACAACCATGCCCTCCAGGAAGCΓCACCTGTGCCTGAAGCGCCATTATGCTGCCTTTCCATTACCTAGCAGAACCTCCTTCAATGACTCCCTCACA TTCTTAGAGAATGCTGCAGACGTTGGGGGGCTAGCCATCGCGCTGCAGGCATACAGCAAGAGGCTGTTACGGCACCATGGGGAGACTGTCCTGCCCAGCCTGGACCTCAGCC CCCAGCAGATCTTCTTTCGAAGCTATGCCCAGGTGATGΓGTAGGAAGCCCAGCCCCCAGGACTCTCACGACACTCACAGCCCTCCACACCTCCGAGTCCACGGGCCCCTCAG CAGCACCCCAGCCTTTGCCAGGTATTTCCGCTGTGCACGTGGTGCTCTCTTGAACCCCTCCAGCCGCTGCCAGCTCTGGTAACTTGGTTACCAAAGATGCCACAGCACAGAA ATATCGACCAACACCTCCCTGGTCACATCCATGGAATCAGAGCAAGATTTCCTTTCTGCTTCTGTTCCAAAAATAAAAGCTGGCACTTGGCTTCCGCCCG
101
MESTCVSASLPRSYRKTDTVRLTSVVTPRPFGSQTRGISSLPRSYTMDDAWKY GDIEDIKRTPNNVVSTPAPSPDASQLASSIJSSQKEVAATEEDVTRLPSPISPFSS SQ DQAATSKATLSSTSGLDLMSESGEGEISPQREVSRSQDQFSDMRISINQTPGKSLDFGFTIKWDIPGIFVASVEAGSPAEFSQLQVDDEIIAINNTKFSYNDSKE EEAMAK AQETGHLVMDVRRYGKAGSPETK IDATSGIYNSEKSSNLSVTTDFSESLQSSNIESKEINGIHDESNAFESKASESISLKNLKRRSQFFEQGSSDSWPDLPVPTISAPSR WV DQEEERKRQER QKEQDRLLQEKYQREQEKLREEHQRAKQEAEREN8KYLDEELMVLSεNSMSLTTREPεLATWEATWSEGSKεεDREGTRAGEEERRQPQEEWHEDQ GKKPQDQLVIERERK EQQLQΞEQEQKRLQAEAEEQ RPAEEQKRQAEIERETSV IYQYRRPVDSYDIPKTEEASSGFLPGDRNKSR8TTELDDYS NKNGNNKYLDQIGN TTSSQRR8KKEQVPSGAELERQQILQEMRKRTPLHNDNS IRQRSASVNKEPVSLPGIMRRGESLDNLDSPRSNSWRQPPWLNQPTGFYASSSVQDFSRPPPQLVSTSNRAY MR PSSSVPPPSAGSVKTSTTGVATTQSPTPRSHSPSASQSGSQLRNRSVSGKRICSYCN ILGKGAAMIIESLGLCYHLHCFKCVACECDLGGSSSGAEVRIRNHQLYCND CYLRFKSGRPTAM
102
AGGAGAGAAGAAATTGAAAAGCAGGCACTTGAGAAGΓCTAAGAGAAGCTCTAAGACGΓΓTAAGGAAATGCTGCAGGACAGGGAATCCCAAAATCAAAAGTCTACAGTTCCGT CAAGAAGGAGAATGTAΓTCTTTTGATGATGTGCTGGAGGAAGGAAAGCGACCCCCTACAATGACTGTGTCAGAAGCAAGTTACCAGAGTGAGAGAGTAGAAGAGAAGGGAGC AACTTATCCTTCAGAAATTCCCAAAGAAGATTCTACCACTTΓTGCAAAAAGAGAGGACCCGTGTAACAACTGAAATTCAGCTTCCTTCTCAAAGTCCTGTGGAAGAACAAAG CCCAGCCTCTTTGTCTRCTCTGCGTRCACGGAGCACACAAARGGAATCAACTTGTGTRRCAGCTTCTCTCCCCAGAAGTTACCGGAAAACTGATACAGTCAGGTTAACATCT GTGGTCACACCAAGACCCTTTGGCTCTCAGACAAGGGGAATCTCATCACTCCCCAGATCTTACACGATGGATGATGCTTGGAAGTATAATGGAGATATTGAAGACATTAAGA GAACTCCAAACAATGTGGTCAGCACCCCTGCACCAAGCCCGGACGCAAGCCAACTGGCΓTCAAGCTTATCTAGCCAGAAAGAGGTAGCAGCAACAGAAGAAGATGTGACAAG GCTGCCCTCTCCTACAΓCCCCCTTCTCATCTCTTTCCCAAGACCAGGCTGCCACTTCTAAAGCCACATTGTCTTCCACATCTGGTCTTGATTTAATGTCTGAATCTGGAGAA GGGGAAATCTCCCCACAAAGAGAAGΓCTCAAGATCCCAGGATCAGTTCAGTGATATGAGAATCAGCATAAACCAGACGCCTGGGAAGAGTCTTGACTTTGGGTTTACAATAA AATGGGATATTCCTGGGATCTTCGTAGCATCAGTTGAAGCAGGTAGCCCAGCAGAATTTTCTCAGCTACAAGTAGATGATGAAATTATTGCTATTAACAACACCAAGTTTTC ATATAACGATTCAAAAGAGTGGGAGGAAGCCATGGCRAAGGCTCAAGAAACTGGACACCTAGTGATGGATGTGAGGCGCTATGGAAAGGCTGGTTCACCTGAAACAAAGTGG AΓTGATGCAACTTCTGGAATTTACAACTCAGAAAAAΓCTTCAAATCTATCTGTAACAACTGATTTCTCCGAAAGCCTTCAGAGTTCTAATATTGAATCCAAAGAAATCAATG GAATTCATGATGAAAGCAATGCTTTTGAATCAAAAGCATCTGAATCCATTTCTTTGAAAAACTTAAAAAGGCGATCACAATTTTTTGAACAAGGAAGCTCTGATTCGGTGGT TCCTGATCTTCCAGTTCCAACCATCAGTGCCCCGAGΓCGCTGGGTGTGGGATCAAGAGGAGGAGCGGAAGCGGCAGGAGAGGTGGCAGAAGGAGCAGGACCGCCTACTGCAG GAAAAATATCAACGTGAGCAGGAGAAACTGAGGGAAGAGTGGCAAAGGGCCAAACAGGAGGCAGAGAGAGAGAATTCCAAGTACTTGGATGAGGAACTGATGGTCCTAAGCT CAAACAGCATGTCTCTGACCACACGGGAGCCCTCTCRRGCCACCTGGGAAGCTACCTGGAGTGAAGGGTCCAAGTCTTCAGACAGAGAAGGAACCCGAGCAGGAGAAGAGGA GAGGAGACAGCCACAAGAGGAAGTTGTTCATGAGGACCAAGGAAAGAAGCCGCAGGATCAGCTTGTTATTGAGAGAGAGAGGAAATGGGAGCAACAGCTTCAGGAAGAGCAA GAGCAAAAGCGGCTTCAGGCTGAGGCTGAGGAGCAGAAGCGTCCTGCGGAGGAGCAGAAGCGCCAGGCAGAGATAGAGCGGGAAACATCAGTCAGAATATACCAGTACAGGA GGCCTGTTGATTCCTATGATATACCAAAGACAGAAGAAGCATCΓΓCAGGTTTTCTTCCTGGTGACAGGAATAAATCCAGATCTACTACTGAACTGGATGATTACTCCACAAA TAAAAATGGAAACAATAAATATTTAGACCAAATTGGGAACACGACCTCTTCACAGAGGAGATCCAAGAAAGAACAAGTACCATCAGGAGCAGAATTGGAGAGGCAACAAATC CTTCAGGAAATGAGGAAGAGAACACCCCTTCACAATGACAACAGCTGGATCCGACAGCGCAGTGCCAGTGTCAACAAAGAGCCTGTTAGTCTTCCTGGGATCATGAGAAGAG GCGAATCTTTAGATAACCTGGACTCCCCCCGATCCAATTCTTGGAGACAGCCTCCTTGGCTCAATCAGCCCACAGGATTCTATGCTTCTTCCTCTGTGCAAGACTTTAGTCG CCCACCACCTCAGCTGGTGTCCACATCAAACCGTGCCΓACATGCGGAACCCCTCCTCCAGCGTGCCCCCACCTTCAGCTGGCTCCGTGAAGACCTCCACCACAGGTGTGGCC ACCACACAGTCCCCCACCCCGAGAAGCCATICCCCTΓCAGCTΓCACAGTCAGGCTCTCAGCTGCGTAACAGGTCAGTCAGTGGGAAGCGCATATGCTCCTACTGCAATAACA TRCTGGGCAAAGGAGCCGCCATGATCATCGAGTCCCTGGGTCRTTGTTATCATTTGCATTGTTTTAAGTGTGTTGCCTGTGAGTGTGACCTCGGAGGCTCTTCCTCAGGAGC TGAAGTCAGGATCAGAAACCACCAACTGTACTGCAACGACTGCTATCTCAGATTCAAATCTGGACGGCCAACCGCCATGTGATGTAAGCCTCCATACGAAAGCACTGTTGCA
AGAAGCATTGTAGTCTTGGTAGAACCΔGTATTTTTGTTGTTTATTTATAAGGTAATTGTGTGTGGGGAAAAGTGCAGTATTTACCTGTTGAATTCAGCATCTTGAGAGCACA AGGGAAAAAATAAGAACCTACGAATATTTTTGAGGCAGATAARGATCTAGTTTGACTTTCTAGTTAGTGGTGTTTTGAAGAGGGTATTTTATTGTTTTTTAAAAAAAGGTTC TTAAACATTATTTGAAATAGTTAATATAAATACATAATTGCAΓTTGCTCTGTTTATTGTAATGTATTCTAAATTAATGCAGAACCATATGGAAAATTTCATTAAAATCTATC CCCAAATGTGCTTTCTGTATCCTTCCTTCTACCTATTATTCTGATTTTTAAAAATGCAGTTAATGTACCATTTATTTGCTTGATGAAGGGAGCTCTATTTTCTTTACCAGAA ATGTTGCTAAGTAATTCCCAATAGAAAGCTGCTTATTTTCATΓAATGAAAAATAACCATGGTTTGTATACTAGAAGTCTTCTTCAGAAACTGGTGAGCCTTTCTGTTCAATT GCARTTGTAAATAAACTTGCTGATGCATTTAACGAGTGGGTCGTCTTTTTCTTAGGTGTATGTGTCTGACCTCAGGCCTTTTAGCCATATTTCAGTATGTGGCCTTTTTTGA TGTTATGTTTTATCCAGTAGCTTTACTAAGGTATAATTGATGΓAATAAACTGCATATATTTAAAGTGTATACTTTGACAAATTTTGACATGGTGTATACCTTCGAAACTATG CCACAGTCTGGATGTGTTTACTGAAACATTTTAATAAGGAAGRTTATTTTTGATAAAGTTATGTTTTTGGATACAATATATTTGTATGGTGAGAGTGATGAATTGTTGGATC TTTGAATAAAATCTTTTACTAACCCCATGATAAAAGGAGAAGACAACAGTGAGCTTAGAATATCTATAAAGCAAAAA
103
^WGSPTCLTLIYI QLTσSAASGPVKELVGS GG VTF LKSK KQVDεIV TFNTT LVTIQPEGGTIIV Q R lRER\rt)F DGGY8LKLSI KKNDSGI VGIYSεSL QQPSTQEYVLHVYEHLSKPKVTLGLQSNKNGTCVTNLTCCMEHGEEDVIYTWKALGQAA ESHNGSILPISWRWGESDWIFICVARNPVSRNFSSPILARKLCEGAADDPDS SMV LCLLLVP LLSLFV GLFLWF KRERQEEYIEEKKRVDICRETPNICPHSGE r^EYDTIPHτ RTI KEDPA TVYSTVEIPKKMENPHS T^1PDTPRLFAYENVI
104
GCGGCCGCGAATTCGGCACGAGCAGAGAGCAATATGGCTGGTTCCCCAACATGCCTCACCCTCATCTATATCCT'ITGGCAGCTCACAGGGTCAGCAGCCTCTGGACCCGTGA AAGAGCTGGTCGGTTCCGTTGGTGGGGCCGTGACTTTCCCCCTGAAGTCCAAAGTAAAGCAAGTTGACTCTATTGTCTGGACCTTCAACACAACCCCTCTTGTCACCATACA GCCAGAAGGGGGCACTATCATAGTGACCCAAAATCGTAATAGGGAGAGAGTAGACTTCCCAGATGGAGGCTAC'ICCCTGAAGCTCAGCAAACTGAAGAAGAATGACTCAGGG ATCTACTATGTGGGGATATACAGCTCATCACTCCAGCAGCCCTCCACCCAGGAGTACGTGCTGCATGTCTACGAGCACCTGTCAAAGCCTAAAGTCACATTGGGTCTGCAGA GCAATAAGAATGGCACCTGTGTGACCAATCTGACATGCTGCATGGAACATGGGGAAGAGGATGTGATTTATACCTGGAAGGCCCTGGGGCAAGCAGCCAATGAGTCCCATAA ΓGGGTCCATCCTCCCCATCTCCTGGAGATGGGGAGAAAGTGAΓAΓGACCTTCATCTGCGTTGCCAGGAACCCTGTCAGCAGAAACTTCTCAAGCCCCATCCTTGCCAGGAAG CTCTGTGAAGGTGCTGCTGATGACCCAGATTCCTCCARGGTCCTCCTGTGTCTCCTGTTGGTGCCCCTCCTGCTCAGTCTCTTTGTACTGGGGCTATTTCTTTGGTTTCTGA AGAGAGAGAGACAAGAAGAGTACATTGAAGAGAAGAAGAGAGTGGACATTTGTCGGGAAACTCCTAACATATGCCCCCATTCTGGAGAGAACACAGAGTACGACACAATCCC TCACACTAATAGAACAATCCTAAAGGAAGATCCAGCAAATACGGTTTACTCCACTGTGGAAATACCGAAAAAGATGGAAAATCCCCACTCACTGCTCACGATGCCAGACACA CCAAGGCTATTTGCCTATGAGAATGTTATCTAGACAGCAGTGCACTGCCCCTAAGTCTCTGCTCAAAAAAAAAACAATTCTCGGCCCAAAGAAAACATACAGG
105
MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIESRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHE SRD
KKKDTVPWFPRTIQELDRFANQILεYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKSLYKTHACYEYNHIFPLLEKYCGFHEDNI
PQLEDVSQFLQTCTGFRLRPVAGLLSSRDF GGLAFRVFHCTQYIRHGSKP YTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWFTVEFGLCKQ
GDSIKAYGAGL SSFGELQYC SEKPK PLELEKTAIQ^^T TEFQP YY AESF 3AKEKVRNFAATIPRPFSVRYDPYTQ IEV D^r^QQLKIIiADSINSEIGILCSAL
QKIK
106
CAGCTGGGGGTAAGGGGGGCGGATTATTCATATAATTGTTATACCAGACGGTCGCAGGCTTAGTCCAATTGCAGAGAACTCGCTTCCCAGGCTTCTGAGAGTCCCGGAAGTG CCRAAACCTGTCTAATCBACGGGGCTTGGGTGGCCCGRCGCTCCCRGGCTTCTTCCCTTTACCCAGGGCGGGCAGCGAAGTGGTGCCTCCTGCGTCCCCCACACCCTCCCTC AGCCCCTCCCCTCCGGCCCGTCCTGGGCAGGTGACCTGGAGCATCCGGCAGGCTGCCCTGGCCTCCTGCGTCAGGACAAGCCCACGAGGGGCGTTACTGTGCGGAGATGCAC CACGCAAGAGACACCCTTTGTAACTCTCTTCTCCTCCCTAGTGCGAGGTTAAAACCTTCAGCCCCACGTGCTGTTTGCAAACCTGCCTGTACCTGAGGCCCTAAAAAGCCAG AGACCTCACTCCCGGGGAGCCAGCATGTCCACLOCGGRCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGGACAGGAAACAAGCTATATTGAAGACAACTGCA AΓCAAAATGGTGCCATATCACTGATCTTCTCACTCAAAGAAGAAGTTGGTGCATTGGCCAAAGTATTGCGCTTATTTGAGGAGAATGATGTAAACCTGACCCACATTGAATC TAGACCTTCTCGTTTAAAGAAAGATGAGTATGAATTTΓTCACCCAΓTTGGATAAACGTAGCCTGCCTGCTCTGACAAACATCATCAAGATCTTGAGGCATGACATTGGTGCC CTGTCCATGAGCTTTCACGAGATAAGAAGAAAGACACAGTGCCCTGGTTCCCAAGAACCATTCAAGAGCTGGACAGATTTGCCAATCAGATTCTCAGCTATGGAGCGGAAC TGGATGCTGACCACCCTGGTTTTAAAGATCCTGTGTACCGTGCAAGACGGAAGCAGTTTGCTGACATTGCCTACAACTACCGCCATGGGCAGCCCATCCCTCGAGTGGAATA CATGGAGGAAGAAAAGAAAACATGGGGCACAGTGTTCAAGACTCTGAAGTCCT'RGTATAAAACCCATGCTTGCTATGAGTACAATCACATTTTTCCACTTCTTGAAAAGTAC TGTGGCTTCCATGAAGATAACATTCCCCAGCTGGAAGACGTTTCTCAATTCCTGCAGACTTGCACTGGTTTCCGCCTCCGACCTGTGGCTGGCC'IGC'RTTCCTCTCGGGATT TCTTGGGTGGCCTGGCCTTCCGAGTCTTCCACTGCACACAGTACATCAGACATGGATCCAAGCCCATGTATACCCCCGAACCTGACATCTGCCATGAGCTGTTGGGACATGT GCCCTTGTTTTCAGATCGCAGCTTTGCCCAGTTTTCCCAGGAAATTGGCCT'IGCCTCTCTGGGTGCACCTGATGAATACATTGAAAAGCTCGCCACAA'ITTACTGGTTTACT GTGGAGTTTGGGCTCTGCAAACAAGGAGACTCCATAAAGGCATATGGTGCTGGGCTCCTGTCATCCTTTGGTGAATTACAGTACTGCTTATCAGAGAAGCCAAAGCTTCTCC CCCTGGAGCTGGAGAAGACAGCCATCCAAAATTACACTGTCACGGAGTTCCAGCCCCTGTATTACGTGGCAGAGAGTTTTAATGATGCCAAGGAGAAAGTAAGGAACTTTGC RGCCACAATACCTCGGCCCTTCTCAGTTCGCTACGACCCATACACCCAAAGGATTGAGGTCTTGGACAATACCCAGCAGCTTAAGATTTTGGCRGATTCCATTAACAGTGAA ATTGGAATCCTTTGCAGTGCCCTCCAGAAAATAAAGTAAAGCCATGGACAGAATGTGGTCTGTCAGCTGTGAATCTGTTGATGGAGATCCAACTATTTCTTTCATCAGAAAA AGTCCGAAAAGCAAACCTTAATTTGAAATAACAGCCTTAAATCCTTTACAAGATGGAGAAACAACAAATAAGTCAAAATAATCTGAAATGACAGGATATGAGTACATACTCA GAGCATAATGGTAAATCTTTTGGGGTCATCTTTGATTTAGAGATGATAATCCCATACTCTCAATTGAGTTAAATCAGTAATCTGTCGCATTTCATCAAGATTAATTAAAAT TTGGGACCTGCTTCATTCAAGCTTCATATATGCTTTGCAGAGAACTCATAAAGGAGCATATAAGGCTAAATGTAAAACACAAGACTGTCATTAGAATTGAATTATTGGGCTT AATATAAATCGTAACCTATGAAGTTTATTTTCTATTTTAGTTAACTATGATTCCAATTACTACTTTGTTATTGTACCTAAGTAAATTTTCTTTAGGTCAGAAGCCCATTAAA ATAGTTACAAGCATTGAACTTCTTTAGTATTATATTAATATAAAAACATTTTTGTATGTTTTATTGTAATCATAAATACTGCTGTATAAGGTAATAAAACTCTGCACCTAAT TCAGGAAATGTTCACTGAATAAATAAGTAAATACATTATTGAAAAGCAAATCTGTATAAATGTGAAATTTT'IATT'IGTATTAGTAATAAAACATTAGTAGTTTA
107
MGA KKAσPGGPAGEσPGE^WLVVHGFPSSVA LRFE AWQHPHASRRI «VGPRLRGETAFAFH RV AHMLR PPWA LPLTLRWV PD RQD C PPPPHVPIJAFGPPP PQAPAPRRRAGPFDDAEPEPDQGDPGACCSLCAQTIQDEEGPLCCPHPGCLLRAHVICLAEEFLQEEPGQLLPLEGQCPCCEKSLIiWGDLIWLCQMDTEKEVEDΞELEEAHW TDLLET
108
CTTCTACACCCGCCTCCAGACAGGAGAGGGGCACGTACCGGCGCTACGGCTTCCTGCAGGCTGCCTCCGGATAGTCCCCGAGAGCTTGTTCCGAAGCAAGCACCCTGCAGCC
CTAGCGATCCAGCCCTCCCCTGGACCCTAGGTCACGGCAATCAACCCCCTGCTGTGGTTCCCGAACCCCAAGGCCCGATGGGTCCCGCGGGGGTCGCGGCGAGGCCAGGGCG
CTTTTTCGGCGTCTACCTGCTCTACTGCCTGAACCCCCGGTACCGGGGCCGCGTCTACGTGGGGTTCACTGTCAACACTGCTCGTCGGGTCCAGCAGCACAATGGGGGCCGC
AAAAAAGGCGGGGCCTGGCGGACCAGCGGGCGAGGGCCCTGGGGAGATGGTGCTCGTCGTGCACGGCTTCCCGTCCTCCGTGGCCGCCCTTCGGTTTGAGTGGGCTTGGCAG
CACCCGCACGCCTCGCGCCGCCTGGCGCACGTGGGGCCTCGCCTGCGAGGAGAGACAGCCTTCGCTTTCCACCTGCGCGTGCTGGCGCACATGCTGCGCGCACCGCCCTGGG
CTCGCCTCCCGCTCACGCTGCGCTGGGTGCGCCCAGACCTCCGCCAGGACCTCTGCCTCCCGCCGCCGCCGCACGTGCCTCTGGCCTTCGGGCCTCCACCGCCCCAGGCCCC
GGCCCCAAGGCGCCGCGCAGGTCCCTTTGATGACGCGGAGCCTGAGCCAGACCAGGGGGATCCAGGGGCCTGCTGCTCCCTGTGCGCCCAGACCATCCAGGATGAAGAGGGG
CCCTrGTGTTGCCCCCACCCTGGCTGCCTGCTAAGGGCCCATGTGATCTGCCTGGCAGAGGAGTTTCTTCAGGAAGAACCAGGGCAGCTTCTGCCCCTAGAGGGCCAATGCC
CTTGCTGTGAGAAGTCACTGCTTTGGGGAGACCTGATCTGGCTGTGCCAGATGGACACTGAGAAAGAAGTAGAAGACTCAGAATTAGAAGAGGCACACTGGACAGACCTGCT
GGAGACCTGATCCTCAGTGTCCTTACCCCCTCCTACCTCTTTTCTGTGCCACCTGCTGTGGGTCCAGCAGGTTTTTACTTGAGTACAATAAAAAGTCTGAGTC
109
MTTDGGMYVFQ FDYYSASGTTLLWQAF ECVVVV VYσADRFTDDIACMIGYRPCP MKWCHSFFTPLVCMGIFIFNVVYYKPLVYKNTNVYPWWGEAMG^^
PLHLLGCLLRAKGTMAECWKHLTQPI GLHHLEYRAQDADVRGLTTLTPVSESSKWWESVMGQLSSHHQLTSGSHSSPCFIPTPPLQGACLSLTLLGSAWERRGESTMSA
H
110
AGGTGTGTTCCTTATTCCCTGCATCCTGATAGCCCTGGTCGGAGGAATCCCCATTTTCTTCTTGGAGATCTCGCTGGGCCAGTTCATGAAGGCCGGCAGCATCAATGTCTGG AACATCTGTCCCTTGTTCΔAΔGGCCTGGGCTATGCCTCCATGGTGATCGTCTTCTACTGCAACACCTACTACATCΔTGGTGCTGGCCTGGGGCTTCTATTACCTGGTCAAGT CCΓTTAGCACCACGCTGCCCTGGGCCACATGTGGCCACACCTGGAACACTCCCGACTGTGTGGAGATCTTCCGCCATGAAGACTGTGCCAGTGCCAGCCTGGCCAACCTCAC TΓGTGACCAGCTTGCTGACCGCCAGTCCCCTGTCATCGAGTTCTGGGAGAACAAAGTCTTGAGGCTGTCTGGGGGACTGGAGGTGCCAGGGGCCCTCAACTGGGAGGTGACC CRRTGTCTGCTGGCCTGCTGGGTGCTGGTCTACTTCTGTGTCTGAAAGGGGGTCAAATCCATGGGAAAGATCGTGTACTTCACTGCTACATTCCCCTACGTGGTCCTGGTCG TGCTGCTTGTGCTTGGAGTGCTGCTGCCTGGCGCCCTGGACAGCATCATTTACTATCTCAAGCCTGACTGGTCAAAGCTGGGGTCCCCTCAGGTATGGATAGATGTGGGGAC CCAGATTTTCTTTTCTTATGCCATTGGCCTGGGGGCCCTCACAGCCCTGGGCAGCTACAACCGCTTCAACAACAACTGCTACAAGGACGCCATCATCCTGGCTGTCATCAAC AGRGGGACCAGCTTCTTTGCTGGCTTCGTGGTCTTCTCCATCCTGGGCTTCATGGCTGCAGAGCAGGGCATGCACATCTCCAAGGTGGCAGAGTCAGGGCCGGGCCTGGCCT TCATCGCCTACCCACAGGCTGTCACACTGATGCCAGTGGCCCCACTCTGGGCTGCCCTGTTCTTCTTCATGCTGTTGCTGCTTGGTCTCGACAACCAGATTTGTAGGTGTGG AGGGCTTCATCACCGGCCTCCTCAACCTCCTCCCAGCCTCCTACTACTTCTGTTTCCAAAGGGAGATCTCTGTGGCCCTCTGTTGTGCCCTCCGCTTTGTCATTGATCTCTC CARGGTGACTGATGGTGGGATGTATGTCTTCCAGCTGTTTGACTACTACTCAGCCAGTGGCACCACCCTGCTCTGGCAGGCCTTTTGGGAGTGCGTGGTGGTGGTCTGGGTG TAΓGGAGCTGACCGCTTCACGGACGACATTGCCTGTATGATCGGGTACCGACCTTGCCCCTGGATGAAATGGTGCTGGTCCTTCTTCACCCCGCTGGTTTGCATGGGCATCT TCATCTTCAACGTTGTGTACTACAAGCCGCTGGTCTACAAAAACACCAACGTGTACCCGTGGTGGGGTGAGGCCAGGGCTGGGCCTTCGTGCTGTCCTCCATGCTGTGCAT GCCACTGCACCTCCTGGGCTGCCTCCTCAGGGCCAAGGGCACCATGGCTGAGTGCTGGAAGCACCTGACCCAGCCCATCTGGGGCCTCCACCACTTGGAGTACCGAGCTCAG GARGCAGATGTCAGGGGCCTGACCACCCTGACCCCAGTGTCCGAGAGCAGCAAGGTCGTCGTGGTGGAGAGTGTCATGGGACAGCTCAGCTCACATCACCAGCTCACCTCTG GΓAGCCATAGCAGCCCCTGCTTCATCCCCACCCCACCCCTCCAGGGGGCCTGCCTTTCCCTGACGCTTTTGGGGTCTGCCTGGGAGAGGAGGGGAGAAAGCACCATGAGTGC TCACTAAAACAACTTTTTCCATTTTTAATAAAACGCCAAAAATATCACAACCCACCAAAAATAGATGCCTCTCCCCCTCCAGTCCTAGCCCAGCTGGTCCTAGGCCCCGCCT AGΓGCCCCACCCCCACCCACAGTGCTGCACTCCTCCTGCCCCTGCCACGCCCACCCCCTGCCCACCTCTCCAGGTTCTGCTCTGTAGCACACCCTTGGGTGACCCCTCACCC CAGAAGCAGCAGTGGCAGCTTGGGAAATGTGAGGAAGGGAAGGAGGGAGAGACGGGAGGGAGGAGAGAGAGGAGAAGGGAGGCAAGGGAGGGGCAGCAGAACCAAGACAAAT AΓΓTCAGCTGGGCTATACCCCTCTCCCCATCCCTGTTATAGAAGCTTAGAGAGCCAGCCAGCAGTGGAACCTTCTGGTTCCTGCGCCAATCACCACCAATATCAATTGTGTG AGCTTGGGTGCGAGTGCACGCGTGCGTGAGCACGTAGAGTATATATAGATOTCTATCTCTTAGCAAAGGTGAATACCAGATGTAAATGGTGCCTCTGGGCAAAGGAGGCTTG TAΓTTTGCACATTTTATAACAACT GAGAGAATGAGATTTCTGCTTGTATATTTCTAAAAAGAGGAAGGAGCCCAAACCATCCTCTCCTTACCACTCCCATTCCTGTGAGCC CΓACCTTACCCCTCTGCCCCTAGCCTAGGAGTGTGAATTTATAGATCTAACTTTCAGAGGCAAAACAAAAGCTTCGAGCTGTTGCATGTGCGAGTCTGTTGTGTGGATGTGT GRGTGTGGTCCCCAGACCCAGAATGGATTGGAAAAGTGCATGGTGGGGGCCTCGGGGCTGTCCCCACGCTGTCCCTTTGCCCACAGGTCTGTGGGGCAAGAGGCTGCAATAT TCCATCCTGGGTGTCTGGGCTGCTAACCTGGCCTGCTCAGGCTTCCCACCCTGTGCCCTGGGCTGGGCACACCCCCGGGAAGGGACCCCGGACACGGCTCCCACATCCAGGC TCAAGGCGGATGCACTTCCTGCACCTCCAGTCTTCTGTGTAGCGGCTTTAACCCACGTATGTCTGTCACGTCCAGTCCCGAGACGGCTGAGTGACCCCAAGAAAGGCTTCCC TGACACCCGGACAGAGGCTGGAGGGCTGGGGCTGGGTGAGGGTGGTGGGCCTGCGGGGACATTCTTACTGTGCTAAAAAGCCACTGCAAACATAGCAATAAAAACCTGTCAT TTTCC
111
MELIQDTSRPPLEYVKGVPLIKYFAEALGPLQSFQARPDDLLINTYPKSGTT VSQILDMIYQGGDLEKCNRAPIYVRVPFLEVNDPGEPSGLETLKDTPPPRLIKSHLPIiA
LLPQTLLDQKVKVVYVARNPKDVAVSYYHFHR EKAHPEPGTWDSFLEKFMAGEVSYGS YQHVQEWWELSRTHPVLYLFYED KENPKREIQKILEFVGRSLPEETMDFMV
QHrSFKEMKKNP TNYTTVPQELMDH8I8PFMRKGMAGDWKTTFTVAQNERFDADYAEKMAGCSLSFR8EL
112
GRGACGGGGAGGCGGTGCCCGGGGCATCTCCGCGGCGGAACTCAGCCTGTGAGAAGTCACTGCTTTGGGGAGACCTGATCTGGCTGTGCCAGATGGACACTGAGAAAGAAGT AGAAGACTCAGAATTAGAAGAGGAACATGGAGCTGATCCAGGACACCTCCCGCCCGCCACTGGAGTACGTGAAGGGGGTCCCGCTCATCAAGTACTTTGCAGAGGCACTGGG GCCCCTGCAGAGCTTCCAAGCCCGACCTGATGACCTGCTCATCAACACCTACCCCAAGTCTGGCACCACCTGGGTGAGCCAGATACTGGACATGATCTACCAGGGCGGCGAC CTAGAGAAGTGTAACGGGGCTCCCATCTACGTACGGGTGCCCTTCCTTGAGGTCAATGATCCAGGGGAACCCTCAGGGCTGGAGACTCTGAAAGACACACCGCCCCCACGGC TCATCAAGTCACACCTGCCCCTGGCTCTGCTCCCTCAGACTCTGTTGGATCAGAAGGTCAAGGTGGTCTATGTTGCCCGAAACCCAAAGGACGTGGCGGTCTCCTACTACCA TΓΓCCACCGTATGGAAAAGGCGCACCCTGAGCCTGGGACCTGGGACAGCTTCCTGGAAAAGTTCATGGCTGGAGAAGTGTCCTACGGGTCCTGGTACCAGCACGTGCAGGAG TGGTGGGAGC GAGCA3CACCCACCCTGTTCTCTACCTCTTCTATGAAGACTTGAAGGAGAACCCCAAAAGGGAGATTCAAAAGATCCTGGAGTTTGTGGGGCGCTCCCTGC CAGAGGAGACCATGGACTTCATGGTTCAGCACACGTCGTTCAAGGAGATGAAGAAGAACCCTATGACCAACTACACCACCGTCCCCCAGGAGCTCATGGACCACAGCATCTC CCCCTTCATGAGGAAAGGCATGGCTGGGGACTGGAAGACCACCTTCACCGTGGCGCAGAATGAGCGCTTCGATGCGGACTATGCGGAGAAGATGGCAGGCTGCAGCCTCAGC TTCCGCTCTGAGCTGTGAGAGGGGCTCCTGGAGTCACTGCAGAGGGAGTGTGCGAATCTACCCTGACCAATGGGCTCAAGAATAAAGTATGATTTTTGAGTCAGGCACAGTG GCTCATGTCTGCAATCCCAGCGATTTGGGAGGTTGAGCTGGTAGGATCACAATAGGCCACGAATTTGAGACCAGCCTGGTAAAATAGTGAGACCTCATCTCTACAAAGATGR AAAAAAATTAGCCACATGTGCTGGCACTTACCTGTAGTCCCAGCTACTTGGGAAGCAGAGGCTGGAGGATCATTTCAGCCCAGGAGGTTGTGGATACAGTGAGTTATGACAΓ GCCCATTCACTACAGCCTGGATGACAAGCAAGACCCTCCCTCCAAAGAAAATAAAGCTCAATTAAAAT
113
MDLTAIYESL SLSPDVPVPSDHGGTE8SPGWG8SGPWSLSPSDSSPSGVTSRLPGRSTSLVEGRSCGWVPPPPGFAPLAPRLGPELSPSPTSPTATSTTPSRYKTELCRTF SESGRCRYGAKCQFAHGLGELRQANRHPKYK'IELCKKFYLQGRCPYGSRCHFIHNPSEDLAAPGHPPVLRQSISFSGLPSGRRTSPPPPGLAGPSLSSSSFSPSSSPPPPGD PLSPSAFSAAPGTPLARRDPTPVCCPSCRRATPISVWGPLGGLVRTPSVQSLGSDPDEYASSGSSLGGSDSPVFEAGVFAPPQPVAAPRRLPIFIIRISVSE
114
GAGCCTGACTTCAGCGCTCCCACTCTCGGCCGACACCCCTCATGGCCAACCGTTACACCATGGATCTGACTGCCATCTACGAGAGCCTCCTGTCGCTGAGCCCTGACGTGCC CGTGCCATCCGACCATGGAGGGACTGAGTCCAGCCCAGGCTGGGGCTCCTCGGGACCCTGGAGCCTGAGCCCCTCCGACTCCAGCCCGTCTGGGGTCACCTCCCGCCTGCCΓ GGCCGCTCCACCAGCCTAGTGGAGGGCCGCAGCTGTGGCTGGGTGCCCCCACCCCCTGGCTTCGCACCGCTGGCTCCCCGCCTGGGCCCTGAGCTGTCACCCTCACCCACTΓ CGCCCACTGCAACCTCCACCACCCCCTCGCGCTACAAGACTGAGCTATGTCGGACCTTCTCAGAGAGTGGGCGCTGCCGCTACGGGGCCAAGTGCCAGTTTGCCCATGGCCΓ GGGCGAGCTGCGCCAGGCCAATCGCCACCCCAAATACAAGACGGAACTCTGTCACAAGTTCTACCTCCAGGGCCGCTGCCCCTACGGCTCTCGCTGCCACTTCATCCACAAC CCTAGCGAAGACCTGGCGGCCCCGGGCCACCCTCCTGTGCTTCGCCAGAGCATCAGCTTCTCCGGCCTGCCCTCTGGCCGCCGGACCTCACCACCACCACCAGGCCTGGCCG GCCCTTCCCTGTCCTCCAGCTCCTTCTCGCCCTCCAGCTCCCCACCACCACCTGGGGACCTTCCACTGTCACCCTCTGCCTTCTCTGCTGCCCCTGGCACCCCCCTGGCTCG AAGAGACCCCACCCCAGTCTGTTGCCCCTCCTGCCGAAGGGCCACTCCTATCAGCGTCTGGGGGCCCTTGGGTGGCCTGGTTCGGACCCCCTCTGTACAGTCCCTGGGATCC GACCCTGATGAATATGCCAGCAGCGGCAGCAGCCTGGGGGGCTCTGACTCTCCCGTCTTCGAGGCGGGAGTTTTTGCACCACCCCAGCCCGTGGCAGCCCCCCGGCGACTCC CCATCTTCAATCGCATCTCTGTTTCTGAGTGACAAAGTGACTGCCCGGTCAGATCAGCTGGATCTCAGCGGGGAGCCACGTCTCTTGCACTGTGGTCTCTGCATGGACCCCA GGGCTGTGGGGACTTGGGGGACAGTAATCAAGTAATCCCCTTTTCCAGAATGCATTAACCCACTCCCCTGACCTCACGCTGGGGCAGGTCCCCAAGTGTGCAAGCTCAGTAT TCATGATGGTGGGGGATGGAGTGTCTTCCGAGGTTCTTGGGGGAAAAAAAATTGTAGCATATTTAAGGGAGGCAATGAACCCTCTCCCCCACCTCTTCCCTGCCCAAATCΓG TCTCCTAGAATCTTATGTGCTGTGAATAATAGGCCTTCACTGCCCCTCCAGTTTTTATAGACCTGAGGTTCCAGTGTCTCCTGGTAACTGGAACCTCTCCTGAGGGGGAATC CTGGTGCTCAAATTACCCTCCAAAAGCAAGTAGCCAAAGCCGTTGCCAAACCCCACCCATAAATCAATGGGCCCTTTATTTATGACGACTTTATTTATTCTAATATGATTTT ATAGTATTTATATATATTGGGTCGTCTGCTTCCCTTGTATTTTTCTTCCTTTTTTTGTAATATTGAAAACGACGATATAATTATTAΓAAGTAGACTATAATATATTTAGTAA
TATATATTATTACCTTAAAAGTCTATTTTTGTGTTTTGGGCATTTTTAAATAAACAAT'CTGAGTGT 115
MRFAWTVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGA RQQIQWENNGQVFSLLSLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTAAGRTRTAGSSGV TAGRPRPTARHWFQAGYSTSRAREAGPSRAENQTAPGEVPALSNLRPPSRVDGMVGDDPYNPYKYSDDNPYYNYYDTYERPRPGGRYRPGYGTGYFQYGLPDLVADPYYIQA STYVQKMSMYN RCAAEENCIΛSTAYPJΩVRDYDHRVL RFPQRVKNQGTSDFLPSRPRYS E HSCHQHYHSMDEFSHLYLI IANTQRRWAEGHKASFCLEDTSCDYGYHR RFACTAHTQGLSPGCYDTYGADIDCQWIDITDVKPGNYILKVSVNPSYLVPESDYTNNWRCDIRYTGHHAYASGCTISPY
116
GGGCCAGGACTGAGAAAGGGGAAAGGGAAGGGTGCCACGTCCGAGCAGCCGCCTTGACTGGGGAAGGGTCTGAATCCCACCCTTGGCATTGCTTGGTGGAGACTGAGATACC CGTGCTCCGCTCGCCTCCTTGGTTGAAGATTTCTCCTTCCCTCACGTGATTTGAGCCCCGTTTTTATTTTCTGTGAGCCACGTCCTCCTCGAGCGGGGTCAATCTGGCAAAA GGAGTGATGCGCTTCGCCTGGACCGTGCTCCTGCTCGGGCCTTTGCAGCTCTGCGCGCTAGTGCACTGCGCCCCTCCCGCCGCCGGCCAACAGCAGCCCCCGCGCGAGCCGC CGGCGGCTCCGGGCGCCTGGCGCCAGCAGATCCAATGGGAGAACAACGGGCAGGTGTTCAGCTTGCTGAGCCTGGGCTCACAGTACCAGCCTCAGCGCCGCCGGGACCCGGG CGCCGCCGTCCCTGGTGCAGCCAACGCCTCCGCCCAGCAGCCCCGCACTCCGATCCTGCTGATCCGCGACAACCGCACCGCCGCGGGGCGAACGCGGACGGCCGGCTCATCR GGAGTCACCGCTGGCCGCCCCAGGCCCACCGCCCGTCACTGGTTCCAAGCTGGCTACTCGACATCTAGAGCCCGCGAAGCTGGGCCCTCGCGCGCGGAGAACCAGACAGCGC CGGGAGAAGTTCCTGCTCTCAGTAACCTGCGGCCGCCCAGCCGCGTGGACGGCATGGTGGGCGACGACCCTTACAACCCCTACAAGTACTCTGACGACAACCCTTATTACAA CTACTΔCGATACTTATGAAAGGCCCAGACCTGGGGGCAGGTACCGGCCCGGATACGGCACTGGCTACTTCCAGTACGGTCTCCCAGACCTGGTGGCCGACCCCTACTACATC CAGGCGTCCACGTACGTGCAGAAGATGTCCATGTACAACCTGAGATGCGCGGCGGAGGAAAACTGTCTGGCCAGTACAGCATACAGGGCAGATGTCAGAGATTATGATCACA GGGTGCTGCTCAGATTTCCCCAAAGAGTGAAAAACCAAGGGACATCAGATTTCTTACCCAGCCGACCAAGATATTCCTGGGAATGGCACAGTTGTCATCAACATTACCACAG TATGGATGAGTTTAGCCACTTGTACCTGCTTGATGCCAACACCCAGAGGAGATGGGCTGAAGGCCACAAAGCAAGTTTCTGTCTTGAAGACACATCCTGTGACTATGGCTAC CACAGGCGATTTGCATGTACTGCACACACACAGGGATTGAGTCCTGGCTGTTATGATACCTATGGTGCAGACATAGACTGCCAGTGGATTGATATTACAGATGTAAAACCTG GAAACTATATCCTAAAGGTCAGTGTAAACCCCAGCTACCTGGTTCCTGAATCTGACTATACCAACAATGTTGTGCGCTGTGACATTCGCTACACAGGACATCATGCGTATGC CTCAGGCTGCACAATTTCACCGTATTAGAAGGCAAAGCAAAACTCCCAATGGATAAATCAGTGCCTGGTGTTCTGAAGTGGGAAAAAATAGACTAACTTCAGTAGGATTTAT GTATTTTGAAAAAGAGAACAGAAAACAACAAAAGAATTTTTGTTTGGACTGTTTTCAATAACAAAGCACATAACTGGATTTTGAACGCTTAAGTCATCATTACTTGGGAAAT TTTTAATGTTTATTATTTACATCACTTTGTGAATTAACACAGTGTTTCAATTCTGTAATTACATATTTGACTCTTTCAAAAAAAAAAAAAAAAAAAAAAA
117
MKFLLILLLQATASGALPLNSETSLEKNNVLFGERYLEKFYG EINKLPV KNKYSGNLMKEKIQEMQHFLGLKV GQLDTSTLEMMHTAPRCGVPDVHHFREMPGGPVWRKH YITY I RYTPD^MREDVD AI KAFQVWS Λ^TPL FSKINTGMADILVVFARGAHGDFHAFDG GGILAHAFGPGSGIGGDAHFDEDEFW THSGGT LFLTAVHEIGHS GLGHSSDPKAVMFPTYKYVDINTFRLSADDIRGIQSLYGDPKENQRLPNPDNSEPALCDPNLSFDAVTTVGNKIFFFKDRFFWLKVSERPKTSVNLISSLWPTLPSGIEAAY EIEARNQVFLFKDDKYWLISNLRPEPNYPKSIHSFGFPNFVKKIDAAVFNPRFYRTYFFVDNQYWRYDERRQMMDPGYPKLITKNFQGIGPKIDAVFYSKNKYYYFFQGSNQ FEYDFLLQR I KTLKSNSWFGC
118
TAGAAGTTTACAATGAAGTTTCTTCTAATACIGCTCCTGCAGGCCACTGCTTCTGGAGCTCTTCCCCTGAACAGCTCTACAAGCCTGGAAAAAAATAATGTGCTATTTGGTG AGAGATACTTAGAAAAATTTTATGGCCTTGAGATAAACAAACTTCCAGTGACAAAAATGAAATATAGTGGAAACTTAATGAAGGAAAAAATCCAAGAAATGCAGCACTTCTT GGGTCTGAAAGTGACCGGGCAACTGGACACATCTACCCTGGAGATGATGCACGCACCTCGATGTGGAGTCCCCGATCTCCATCATTTCAGGGAAATGCCAGGGGGGCCCGΓA TGGAGGAAACATTATATCACCTACAGAATCAATAATTACACACCTGACATGAACCGTGAGGATGTTGACTACGCAATCCGGAAAGCTTTCCAAGTATGGAGTAATGTTACCC CCTTGAAATTCAGCAAGATTAACACAGGCATGGCTGACATTTTGGTGGTTTTTGCCCGTGGAGCTCATGGAGACTTCCATGCTTTTGATGGCAAAGGTGGAATCCTAGCCCA TGCTTTTGGACCTGGATCTGGCATTGGAGGGGATGCACATTTCGATGAGGACGAATTCTGGACTACACATTCAGGAGGCACAAACTTGTTCCTCACTGCTGTTCACGAGATT GGCCATTCCTTAGGTCTTGGCCATTCTAGTGATCCAAAGGCTGTAATGTTCCCCACCTACAAATATGTCGACATCAACACATTTCGCCTCTCTGCTGATGACATACGTGGCA TTCAGTCCCTGTATGGAGACCCAAAAGAGAACCAACGCTTGCCAAATCCTGACAATTCAGAACCAGCTCTCTGTGACCCCAATTTGAGTTTTGATGCTGTCACTACCGTGGG AAATAAGATCTTTTTCTTCAAAGACAGGTTCTTCTGGCTGAAGGTTTCTGAGAGACCAAAGACCAGTGTTAATTTAATTTCTTCCTTATGGCCAACCTTGCCATCTGGCATT GAAGCTGCTTATGAAATTGAAGCCAGAAATCAAGTTTTTCTTTTTAAAGATGACAAATACTGGTTAATTAGCAATTTAAGACCAGAGCCAAATTATCCCAAGAGCATACATT
CTTTTGGTTTTCCTAACTTTGTGAAAAAAATTGA'IGCAGCTGTTTTTAACCCACGTTTTTATAGGACCTACTTCTTTGTAGATAACCAGTATTGGAGGTATGATGAAAGGAG ACAGATGATGGACCCTGGTTATCCCAAACTGATTACCAAGAACTTCCAAGGAATCGGGCCTAAAATTGATGCAGTCTTCTATTCTAAAAACAAATACTACTATTTCTTCCAA GGATCTAACCAATTTGAATATGACTTCCTACTCCAACGTATCACCAAAACACTGAAAAGCAATAGCTGGTTTGGTTGTTAGAAATGGTGTAATTAATGGTTTTTGTTAGTTC ACTTCAGCTTAATAAGTATTTATTGCATATTTGCTATGTCCTCAGTGTACCACTACTTAGAGATATGTATCATAAAAATAAAATCTGTAAACCATAGGTAATGATTATATAA AATACATAATATTTTTCAATTTTGAAAACTCTAATTGTCCATTCTTGCTTGACTCTACTATTAAGTTTGAAAATAGTTACCTTCAAAGCAAGATAATTCTATTTGAAGCATG CTCTGTAAGTTGCTTCCTAACATCCTTGGACTGAGAAATTATACTTACTTCTGGCATAACTAAAATTAAGTATATATATTTTGGCTCAAATAAAATTG
119
MVISLNSCLSFICLLLCHWIGTASPLNLEDPNVCSHWESYSVTVQESYPHPFDQIYYTSCTDILNWFKCTRHRVSYRTAYRHGEKTMYRRK8QCCPGFYESGEMCVPHCADK
CVHGRCIAPNTCQCEPG GGTNCSSACDGDHWGPHCTSRCQCKNGALCNPITGACHCAAGFRGWRCEDRCEQGTYGNDCHQRCQCQNGATCDHVTGECRCPPGYTGAFCEDL
CPPGKHGPQCEQRCPCQNGGVCHHVTGECSCPSGWMGTVCGQPCPEGRFGKNCSQECQCHNGGTCDAATGQCHCSPGYTGERCQDECPVGTYGVLCAETCQCVNGGKCYHVS
GACLCEAGFAGERCEARLCPEGLYGIKCDKRCPCHLENTHSCHPMSGECACKPG SGLYCNETCSPGFYGEACQQICSCQNGADCDSVTGKCTCAPGFKGIDCSTPCPLGTY
GINCSSRCGCKNDAVCSPVDGSCTCKAGWHGVDCEIRCPSGTWGFGCN TCQCLNGGACNTLDGTCTCAPGWRGEKCELPCQDGTYGLNCAERCDCSHADGCHPTTGHCRCL
PGWSGVHCDSVCAEGR GPNCSLPCYCKNGASCΞPDDGICECAPGFRGTTCQRICSPGFYGHRCSQTCPQCVHSSGPCHHITGLCDCLPGFTGALCNEVCPSGRFGKNCAGI
CTCT^mGTCNPIDRSCOC PGWIGSDCSQPCPPAHWGPNCIHTCNCHNGAFCSAYDGECKCTPG TGLYCTQRCPLGFYGKDCA ICQCQNGADCDHISGQCTCRTGFMGRH CEQKCPSGTYGYGCRQICDCLNNSTCDHITGTCYCSPGWKGARCDQAGVIIVGNLNSLSRTSTA PADSYQIGAIAGIIILVLWLFLLALFIIYRHKQKGKESSMPAVTYT
PAMRVVNAD TISGTLPHSNGGNANSHYFTNP8YHTLTQCATSPHVNNRDRMTVTKSKNNQLFVNLKNVNPGKRGPVGDCTGTLPADWKHGGYLNELGAFGLDRSYMGKSLK
DLGKNSEYNSSNCSLSSSENPYATIKDPPVLIPKSSECGYVEMKSPARRDSPYAEINNSTSANRNVYEVEPTVSWQGVFSNNGRLSQDPYDLPKNSHIPCHYDLLPVRDSS
SSPKQED8GGSSSNSSSSSE
120
AAAGATTΑCTTTCTTCTΑGGACGCTGCTTGAACGCTAACCGCGTTGATTGGAACAGATTTTGTGTCTTGGCTGGCTTTGGGTGAAGACCGGGGAGAAAAGGTTGCGCTGCGA RTCRCAAGATCTCTGGACCTGGATTATCATTGCAAATCCATTAAAGAAGGAGAAGCAAGCGGATTTCAGAGAGGTTGTTCTTCAGAAAAAAATGG'ITATTTCTTTGAACTCA RGCCTGAGCTTTATTTGTTTATTGTTATGCCACTGGATTGGGACAGCATCACCTCTGAATCTTGAAGACCCTAATGTGTGTAGCCACTGGGAAAGCTACTCAGTGACTGTGC AAGAGTCATACCCACATCCCTTTGATCAAATTTACTACACGAGCTGCACTGACATTCTAAACTGGTTTAAATGCACGCGGCACAGAGTCAGCTATCGGACAGCCTATCGACA RGGGGAGAAGACTATGTATAGGCGCAAGTCTCAGTGTTGTCCTGGATTTTATGAAAGCGGGGAAATGTGTGTCCCCCACTGTGCTGATAAATGTGTCCATGGTCGCTGTATT GCTCCAAACACCTGTCAGTGTGAGCCTGGCTGGGGAGGGACCAACTGCTCCAGTGCCTGCGATGGTGATCACTGGGGTCCCCACTGCACCAGCCGGTGCCAGTGCAAAAATG GGGCTCTGTGCAACCCCATCACCGGGGCTTGCCACTGTGCTGCGGGCTTCCGGGGCTGGCGCTGCGAGGACCGCTGTGAGCAGGGCACCTATGGTAACGACTGTCATCAGAG ATGCCAGTGCCAGAATGGAΣCCACCTGCGACCACGTCACΣGGΒGAATGCCΣCTGCCCACCAGGATACACCGGAGCCTTCTGTGAGGATCTTTGTCCTCCTGGTAAACATGGT CCACAGTGTGAGCAGAGATGCCCTTGTCAAAATGGAGGAGTGTGTCATCACGTCACTGGAGAATGCTCTTGCCCTTCTGGCTGGATGGGCACAGTGTGTGGTCAGCCTTGCC CCGAGGGTCGCTTTGGAAAGAACTGTTCCCAAGAATGCCAGTGCCATAATGGAGGGACGTGTGATGCTGCCACAGGCCAATGTCATTGCAGTCCAGGATACACAGGGGAACG GTGCCAGGATGAGTGTCCTGTTGGGACCTATGGCGTTCTCTGTGCTGAGACCTGCCAGTGTGTCAACGGAGGGAAGTGTTACCACGTGAGCGGCGCATGCCTCTGTGAAGCA GGCTTTGCTGGCGAGCGCTGCGAAGCACGCCTGTGTCCTGAGGGGCTCTACGGCATCAAATGTGACAAACGGTGTCCCTGCCACTTGGAAAACACTCATAGCTGTCACCCCA TGTCTGGAGAGTGTGCCTGCAAGCCGGGCTGGTCAGGACTCTACTGTAATGAGACATGTTCTCCTGGATTCTACGGGGAAGCTTGCCAGCAGATCTGCAGCTGCCAAAATGG GGCAGACTGTGACAGTGTGACTGGAAAGTGCACCTGTGCCCCAGGATTCAAAGGAATTGACIGCTCTACCCCATGCCCTCTGGGAACCTATGGGATAAACTGTTCCTCTCGC TGTGGCTGTAAAAATGATGCAGTCTGCTCTCCTGTGGACGGGTCTTGTACTTGCAAGGCAGGCTGGCACGGGGTGGACTGCTCCATCAGATGTCCCAGTGGCACATGGGGCT TTGGCTGTAACTTAACATGCCAGTGCCTCAACGGGGGAGCCTGCAACACCCTGGACGGGACCTGCACGTGTGCACCTGGATGGCGCGGGGAGAAATGCGAACTTCCCTGCCA GGATGGCACGTACGGGCTGAACTGTGCTGAGCGCTGCGACTGCAGCCACGCAGATGGCTGCCACCCTACCACGGGCCATTGCCGCTGCCTCCCCGGATGGTCAGGTGTCCAC TGTGACAGCGTGTGTGCTGAGGGACGCTGGGGCCCCAACTGCTCCCTGCCCTGCTACTGTAAAAATGGGGCTTCATGCTCCCCTGATGATGGCATCTGCGAGTGTGCACCAG GCTTCCGAGGCACCACTTGTCAGAGGATCTGCTCCCCTGGTTTTTATGGGCATCGCTGCAGCCAGACATGCCCACAGTGCGTTCACAGCAGCGGGCCCTGCCACCACATCAC CGGCCTGTGTGACTGCTTGCCTGGCTTCACAGGCGCCCTCTGCAATGAAGTGTGTCCCAGTGGCAGATTTGGGAAAAACTGTGCAGGAATTTGTACCIGCACCAACAACGGA ACCTGTAACCCCATTGACAGATCTTGTCAGTGTTACCCCGGTTGGATTGGCAGTGACTGCTCTCAACCATGTCCACCTGCCCACTGGGGCCCAAACTGCATCCACACGTGCA ACTGCCATAATGGAGCTTTCTGCAGCGCCTACGATGGGGAATGTAAATGCACTCCTGGCTGGACAGGGCTCTACTGCACTCAGAGATGTCCTCTAGGGTTTTATGGAAAAGA TTGTGCACTGATATGCCAATGTCAAAACGGAGCTGACTGCGACCACATTTCTGGGCAGTGTACTTGCCGCACTGGATTCATGGGACGGCACTGTGAGCAGAAGTGCCCTTCA GGAACATATGGCTATGGCTGTCGCCAGATATGTGATTGTCTGAACAACTCCACCIGCGACCACATCACTGGGACCTGTTACTGCAGCCCCGGATGGAAGGGAGCGAGATGTG ATCAAGCTGGTGTTATCATAGTTGGAAATCTGAACAGCTTAAGCCGAACCAGTACTGCTCTCCCTGCTGATTCCTACCAGATCGGGGCCATTGCAGGCATCATCATTCTTGT CCTAGTTGTTCTCTTCCTACTGGCATTGTTCATTATTTATAGACACAAGCAGAAGGGAAAGGAATCAAGCATGCCAGCAGTTACCTACACCCCTGCTATGAGGGTCGTCAAT GCAGATTATACCATTTCAGGAACCCTTCCTCACAGCAATGGTGGAAACGCTAATAGCCACTACTTCACCAATCCCAGTTACCACACGCTCACCCAGTGTGCCACATCCCCTC ACGTCAACAACAGGGACAGGATGACTGTCACGAAGTCAAAAAACAATCAACTGTTTGTGAATCTTAAAAATGTGAACCCTGGGAAGAGAGGCCCTGTGGGGGACTGCACTGG GACATTGCCGGCTGACTGGAAACATGGCGGCTACCTCAACGAGCTCGGTGCTTTTGGACTTGACAGAAGCTATATGGGAAAATCCTTAAAAGACCTGGGAAAGAATTCTGAA RATAATTCAAGTAACTGCTCCCTAAGCAGTTCTGAGAACCCATATGCCACTATTAAAGACCCACCTGTACTTATCCCGAAAAGCTCAGAGTGTGGTTATGTGGAGATGAAAT CGCCGGCACGAAGAGATTCCCCATATGCAGAGATCAATAACTCAACTTCAGCCAACAGGAATGTCTATGAAGTTGAACCTACAGTGAGTGTTGTCCAAGGAGTATTCAGCAA ΓAATGGGCGTCTCTCCCAGGATCCATATGACCTCCCAAAGAACAGTCACATCCCTTGTCATTATGACCTGCTGCCAGTCCGAGACAGTTCATCCTCCCCTAAGCAAGAGGAC AGTGGAGGTAGCAGCAGCAACAGCAGCAGCAGCAGTGAATGACACCAAAGGACCGCTTGGTAGCCACTGGAACCCTTTCCAGAACTGCTGTTTGGTTCTTCTCCATCCTCAA RRTTGCCACTTTCATGTGAATGTTAGTCAATTCGGTGGGCAATTTTTGGACATGAACCAGAAAGCTGAAAGCTGAGGCTGACACGGACTGTAGGTGCTTTTTGTTCAGGTGG ARRCGAAGGAGTTAGAGATGTGATTTGCCATTGCTGTTAGTTTTAGAACTATACCCGTGAAGCATGACTTATTGTAAGATGTTGGCTGAAAGCATGAACTTGCAGAACTCCC RCGGAGACGCAGGTTGCAGTGGACATTGGGATTGTTGCTTGAAAAATTAAAATTTGAATATTTTCTCTCTCATTTGCATCATACAGCTCTACCTAGGATTGTACAGTTTACC AΓAAAATTTACTTCATGAAAGTGGGAATCACTGAACATGTAGAAGACAAGGAACA'IATTGTTAACTCCTGATTCTTAACTTTATTCAACTGGACTCAGAATTGTAGGGATAA RARGAATGCAGGAGGAAACATTCTGTCAGGCGGTATGACTGGACAGACTTTGAATATACTCTAAAAGTGGACAGAAAATTTACGAAAATCTTAGATTTTGTTTAGAATGAGA AAATATACAATTAGAATTATTTTAGAAATAGTAGGAAGTATTGCAGAAGTCAATACACAAATGTGCCAGGCAGAGGTGGTTTTCTCTGTTTGACTCTCAACCAACTTCAGAT CRATGACATTATTCTGATCACTGGCTCCATCATACATATTCACCACTTGAGATTCATAACATATCAATAGTTATTTCATAAATATAGAAATGAAATAATTTTATTTTTGACA GACTGGATGGAATGAGTGTGTAATGATTGATAAAGGTTGTAAATTTTAAATGCAAGATGACGCTTACGTTCTGTAAACCATTAGTAATACATGCTGTAATATAGAATTAGTG GAACATTTTGATTAATCTTTCCCTAGAAGTGACTGAAATATTTTTGTGCATATTTGAGAAAGGGAACTTTCCTTTTATTAATTGTCAATTTAGAGAAACTATGCTTAAGCTG GRCTTTTGCATTGCTAATGTGACATGTACCCAACTTTTCATTAATTTGTATTTCCATTTTTAAATTGCATATTCTATGTTTTGTAGTGTTTGGATTGTTAATGAAAAAATAT RATATGTTCGTTATTCCTTGTATTATTGCCACTTATCTTTTGCTTGATAAAAATGCGTTGTTCTTTTTTCTTTTGGAGGGACAAGATGAAAATATATAATTTGAATTGATTA AAATTGGTCGTTACTAAAATAGTATAGTAACCACAAGTGATTGGCTTATAAATGAAGTAGAAATGCTTTTTAATATTCCAAAATAGAGTTCCTTTTGATCTGTTGGTGCTGA GCCTTGGTTAAACCAGGGAGAAGGGGAGCAGAAAGGAAACGTTGTTACTGATGAGTACCACAGACTCATCTTAAAAAAAACTCTCATTATGGTGATCATAGAATTGACCATC CAAACTGGGACACTCTTGAGAGTAAATGGAGGGCATTATTAATAATTATCTTGTAATGAΔCTTAAATCTGGACTGTTCCAGGCAAACCAGACTTA'ICTTGCAATATGAGAAT GCTGACACAATGCAGGAAAGCCAGTTTCCCTTTTGTTGATCTACTTGACCAAGCAAAGGGGCTGAAAAACTGAATAAGGAAACAACTTTATAAGAGAAACAGTGGTCTTCAA TCTTTRAAAGACATGAAATCCTATATGGCATTCTGTCTCAGTGAGTCAGTTAACAAATACGTATGTGCAACCCTTCTGCTAGTAGTGCACATAAGTGATTATCCCTGCCAGG TATCGAGTTGGAATATCCAGTTATTTCATGTCACACATCGGCACGTATGATGGTGGTTTGGTCAGATGGATAATACAGCAGACACACTTAGAACACTCACTGCACTGGTGGC TGTTCATTTTGAGGAACTCCAAAGTCAATTCAAGGAAATAAGGAATGACCTGGAACAGGCCTTAGAAACAATTGATTTATTCCAATAGTTAACCACTGGCTGGCTCCCAACT CΓAGGTGATAGGCATCTAATTGAGACATGTGTGAGTCAATAGCCATCGGGGTCCTTTTTGGTGAGAAGAAATAAGACATTTTCTCCCTTTTAAAGATCATCTCTTCAGAGCT GCATGGTAAATTTGAATTTCCCCATTGTTCTCTAGAGATAGGTCAAAAAAACAACTGTTTCTTTTCTTATTCCACTATTAATAAATTGAAAGCTTGCTGTACAAAGGCAACA GCAACΓTAAAAAAGAAAATCTGGACAATAGATGTGGACTCCAAGGGGCCACTGCCATCCCTTCCTGTGTGCTCTTTTTGACAAGTAAATCACTCCAGTTAGCTGATGTCCTG AAATGACATTTGTACCTGAGGCAATTCTTATTAGAGCTTACTCAGGACTTTTCAAACATCAGGACACACATAGCAATTTGGATGTTGTAAAACTACGTGTTACATTTGGAGA GGTCΓΓGTTGAGAAGGCAAAATTTTCTAAATATTTTGATATCAATTTGGGTAAAGAAAGGAATACTTTTGTTAGAATGAGAATTAAAGAGAAAACAAAAGAATCTTGGCAAA ATTTTCCCTCTGAΔΔTTACAAACTTTAGGAACTTTTCCAGATGTATCGAATTTAATTTGACATTGATGTCACTCTTCATACCAAGTGAATCTATTCTCATGAACTTTGAACC CATGTΓAATTTTGGACCCTATAACTAATTTCCTTTCTGTATCCCATGGTGGTCAAAGCAGTAAAGGAGTTTAGAGATACTTAGCAAATGCCATTCATATAGTATTGTTAGCC AAACTATTATTCCTTCCTTAGAAGTTGATGTATCAGAAAATTTATAAGTTATTTGTATTTATATATAAGTACATCAGAACTTGCCCACATGATAACTCATGTTTGCTTTAAT AAGGAAAATATGTTATTTGAGGTTAATTATATGATAGTGAGGAACATTTTACAATTATTTACAGTGTTTGACATTAATTGCTGTCCTATGATACAGTAGTAATGTTAACAGA GAGTTTAATATGTTTAGCATTATCTTTATGGAATTTATATTCACCAATTTCAGGAAAACCAACCATAGAACTTTΆTAATAGGACAGTTATAACCTGACTGAACCAAATCCAT CAGCATAATGACTGTGTGTTCTGAGAAATGCAAACAACTTTATGAAAGTGTGGTCATCTTGACCCCCAAAGAGCCACAGTAGCTGTCAATTATTGAGATTTTTAAATGGTAA
ATATTGCAAAAGTTAAACAAGGGTACCACAATATCATTTATAATTGATGTCAATATTAGTAGTCCACTTTATGCT'IAAAATAAAATCATAAAAAATCAAGTTTTAAGGTTAT ATTTTTTAAAATAATGAATTTTCTATCTCTAGGCAACATGTCTTTATTATTCAAGCTGAATGTTTAAGAGAGAT'I'ITGGTCTTAAAGGCTTCATCATGAAAGTGTACATGCA
TATGCAAGTGTGAATTACGTGGTATGGATGGTIGCT GTTTATTAACTAAAGATGTACAGCAAACTGCCCGTTTAGAGTCCTGTTAATATTGATGTCCTAACACTGGGTCTG CTTATGCTAGTTCAGTATTTGGTCTAGGCTTCATTTTGATATGACTGAATTGCAATCTATATTTTTAAAAAGAAAAATCAAAATACATTAGGGTTTACTTGGTTGTGGCAAA CAAACAAAAAATGCTTTCAGTGTTGAAATATCTCTATTTTCCAAAGATGATAAACTTTCATCGTTCTTAGCCTACATTGTCATTTATATCACCAAATGAGTTTATAGATTAA TGCAATAAACTTTCTAAT
121
MFPSSQIPSWKDWAKPGPYDQPLVNTLQRRKEKREPDPNGGGPTTASGPPAAAEEAQRPRSMTVSAATRPGEEMEACEE ALALSRGLQLDTQRSSRDSLQCSSGYSTQTTT PCCSEDTIPSQVSDYDYFSVSGDQEADQQEFDKSSTIPRNSDISQSYRRMFQAKRPASTAGLPTTLGPAMVTPGVATIRRTPSTKPSVRRGTIGAGPIPIKTPVIPVKTPTV
PDLPGVLPAPPDGPEERGEHSPESFSVGEGPQGVTSMPSSMWSGQASVNPPLFGPKPSIPEEHRQAIPESEAEDQEREPPSATVSPGQIPESDPADLSPRDTPQGEDMLNAI
RRGVK KKTTTNDRSAPRFS
122
CGTCCACCGTGGAGTCTCTCCTTGCTTTGGGTCCACTGAGCCCCACACATTGTTGAGTGTCTGATTGTCTCCTTGCCCTTACAGGACAGGAAAGCGAAATCTCTGTTCCTTT GTAGGGACCTTTCTTTTGTAGGTGAAAGGGACAGAAATATGATTCTGGCCTCCTTGATGGTGAATACAGGAACACTTTCAGATAAATTACAATAGAGAGGAGTCAGCTTATT TAAACAAACTGAGGTTAAGCCAGAGATTGCAGTTAACAGTGAAAAAATTTAAAGCAAGTACCTGGATGGATGCAAAGCAGTGCCCAGGAGACCCAACTTACGTGACAGAGAT GAΓCATTGTCACTCATTCATTATGTTTTGAGCACCAGCCATGTGCCAGGTCCAGAACTAGAAGAAACTTGGGTGTAGGTGAGATCATAGGAACAGTCCCTGCCCCAGCTGAA CATCAGGAAGCCAGACTGGGAGCACATGCCGTGGCTGACTAGGACTCCAGCAGGGACCTGGGGTTCCATCAGATCAGTGTAAAGCGATGGTTTCCCAAATGAGACCTCTCCA GAGATGGTTCATTCCACCCCGCAATGGCCACCAGAAACATTGTGCTGACCAGAGGGCTTCACTGCCCCAAACCCCAAAATCACACΤCCAGGATGAGAAACCTAAAAGTCTAT CTTGATGAGGCTTCATAGCTGGAAACCACCCCTCATGGATCCACAGGCTGCATTTGATGAAAGGAGACTCCAGGAAGTCGAGCCATTCCAGGCAGACATGTAGCAAAAGCCC GAGCTGGGGTCCGCCCTCATGCAATAAATAACACCTGTGCACATAAGAGAGGTGACAGGCAGGGCATCCCTGGGGACCTGGGCCTGTGGCACGTGAAGAAACACCCAAGAGA GCACGAAGTCCCAATGCCATGACCAGATATTTCGGTGCCAGGCATGCTTCTGGGTCCCAGCAAAAGACACACAAATCCGTGTCCTTGGGGACCCACAGTCTAGTGACCTAGG GCTGGCCGGGTCGCACGCTΓCTTTTCAAGGGCTCGAAAGCCTCTGCATGGATGCAACTTTGGGGGAAAAGTAACCCTAACCCTCTGCTTCTCTCATCCTCCCCTCTTCTGTG TATATGTCTGTCTCTTTGTCTCTGTGTGTGCCCTTCCCCACTCCCATCCCCATTCCTTTTTTTATTTATTATATTTTGGTGGTGTGTGGCTCGGTTTCTGTTGGTCCCCTCG TGTGGCCCCTCCCCTGCTGCAGAACTCGTCCAGCTCGGCCTCCTCCGAAGCCTCGGAAACCTGCCAGTCAGTGAGCGAGTGCAGCTCCCCCACCTCTGTCΔGCTCGGGCTCC CCATGGGTGCCTGGGTGTCCACAGAGAAGGTGACCGCCCGGGTGGCAGCCACAGCGGCCCCACTCTCCCTGGTCCCCCTGCCTGCTGCTCAGACAGCCCTCACAGCCGCGG CAACCTGGAAGCTCAGAATCGACACCAAGAGTGGGGCTCCTCTTGGGGACAGAGGGTGGGACAAGGCTGAGAGCATTTTCTAGAATGAGTGCCTGGCTGCTGGACAATGACC ACARGGTTGTCTCAAGGGAGAGGAAGGGGTATGGGGAATTTGGAGGTGTGAAGGCTTTCTCCCAGACCAGGTGTTGCGTGCCTGTCCATCCTCCTCCCTCCCTTCCCGAGCC ACCCACCAGACCGTTGGATGAGCCATGTCACTGTGTCAGAGGCTGTGTGCTTTTCCGCTTTTTAGTTTGCACCCCCACCCCCCTGCCCTTGATTGAGAATGTGCTCCTGAGC AAΓGCGACGATTTTGGAAACCTAGAATGAACAGATTCATTTGAAGATGCTTTGGAATTTTTAAATTTGCATAATGAAATGAGCAAATCACTATCACCATTAAATGAGGCTTC ATTAGTTACATTATCAAAAACCATTGACAAGGCCACAAATTGAGGGCACTGATCAATTTCCAAACTTCTAAAACGTAGGTCAAACATAGATGCTTATTTGCTGTCAAACTCA
TGTGCATTCTTTGCACCCCGGCTCTTTTCTCTTGCATCACAGATCATCCGTGAGCAGCAGAGCCCCAATGTTTGTTTTATTTATAAATATTCAGGT'ITCCCCTCCCTTGAAT
ATCAAGTGAGTCCCACGTGGGGCCCACGGGTGCAGGCCTTTTCCCTCATTGCCTGCCTGCCTCCCGCCTGCTCCCTCGGGTCACCTCTGTCCACCTTCCAGACTACGCTCAT TATΓACACCATTGGGCCCGGCATGTTCCCGTCATCTCAGATCCCTAGCTGGAAGGACTGGGCTAAGCCTGGGCCCTATGACCAGCCTCTGGTGAACACCCTGCAGCGCCGCA AGAGAAGCGAGAACCGGACCCCAACGGGGGAGGACCCACTACCGCCAGCGGCCCACCTGCAGCAGCTGAGGAGGCTCAGAGACCACGGAGCATGACTGTATCGGCTGCCAC CAGGCCTGGTGAGGAGAΓGGAGGCTTGTGAGGAGCTGGCCCTGGCCCTGTCTCGGGGCCTGCAGCTGGACACCCAGAGGAGCAGCCGGGACTCGCTTCAGTGCTCCAGCGGC TACAGCACCCAGACAACCACCCCCTGCTGCTCTGAGGACACCATCCCTTCCCAAGTTTCAGATTATGATTATTTCTCTGTAAGTGGTGACCAGGAGGCAGATCAGCAGGAGT TCGACAAGTCCTCCACCATTCCAAGAAACAGCGACATCAGCCAGTCCTACCGACGGATGTTCCAAGCCAAGCGTCCAGCCTCAACTGCTGGCCTCCCCACCACCCTGGGACC TGCTATGGTCACTCCAGGGGTTGCAACTATCCGACGGACCCCTTCCACCAAGCCTTCTGTCCGCCGGGGAACCATTGGAGCTGGTCCCATCCCCATCAAGACACCCGTGATC CCTGTCAAGACCCCAACCGTCCCAGACCTCCCAGGGGTGTTGCCAGCCCCTCCAGA GGGCCAGAAGAGCGGGGGGAGCACAGCCCTGAGTCGCCA'RCTGTGGGTGAGGGCC CCCAAGGTGTCACCAGCATGCCCTCCTCAATGTGGAGCGGCCAAGCTTCCGTTAACCCTCCACTTCCAGGCCCGAAGCCCAGTATCCCTGAGGAGCACAGACAGGCAATTCC AGAAAGTGAAGCTGAAGACCAGGAACGGGAACCCCCAAGTGCCACTGTCTCCCCAGGCCAGATTCCAGAGAGTGACCCTGCAGACCTGAGCCCAAGGGATACTCCACAAGGA GAAGACATGCTGAACGCCATCCGAAGGGGCGTGAAACTGAAGAAGACCACGACAAACGATCGCTCAGCCCCTCGCTTTTCTTAGGTTCACAAGAAATGCGCCGGTGGGGAAT GAACTGTTTCATTAAΓAAAACCTAATTTGTCTTGATCCATTCCACTCTATAATAAAACAAAAGATTTTGTAGGCAACTCGGAATATAGCTCTTTTGAAAGTACTCGACACCT
TTAGATAAGAATTAAAACCAACCTATGTAACTGACATAATCTTGATCTTTTAATTTGTAAATATTGACAATTTTCTTTCTGCACATTTTAATCT'IAGTTTCCCTTTTGATTT
TTCTGAAGGTGCCAAAΓTCCATTTAACTTTTTTACAAGTCTTTGTAAAATTTTAAATGCATAAAGGGGGTTGGGGCAGGGGAACCACGAAGTAGTTAATTTTAGAAAAGGAT
GAGGTAAAATCTTCARRTAAATATACTATGTTCTGGATGAAAAGAGCAGGAGTAACAATTGATGAGCAATATTCAGAGTGAAGTAAATCTGGAAATGGTAGACTGTGTTGGG ATTGGGGGGAGGGCCARGGGAGGGGTACATCGTCAACATAGCCGATCCTGTTACATTTAAGAGTAGCCTCGTAGGTTGAATTTCTTCTGGTAGCTTCATGGTAAATGCATCC GAATAAGCCATACTGGATΓGCAGTGTTTGTTTCTGTAGGGTGTTTAAGGACTTGACTTCCTTTCTCCCATGATTCCTCTGGACTGCACACAGCACCCACAACCAGCCCCATG CATGCTGCTGCCTCTGGGCAGTCGTAGAATCTCCCACTTCAGTTTCTCGTTGATTGTACTCACCTTTATGGAATCCAAATACATCCAAAAGGGTAAGGCAGTTTTAAAAATG TGAAAACATTTAAAAARGATAATAGCAGGGAATTCTTAGATTATAGTAAATGCCTTTTACTTAACTGTGCCCAGCAGGCTGGGTGCGTTAAAAAGCCCAAGTATTTTGAAAA AACTCGAACAGATTTGACAAGGGTAGCCAGCTTGGAGTCTAGCAACTTGCCAATGTGTTTACCAATCTGGGGGCTTGTTTTTCTTTTCTTCTTTCAAATAAATGGCAGTTAA CTGGCTTTACAGTAAACAΓTGAAGAGAGGAGGATTTGTTTATTGTCACTGGGAATCTGACCACTATACTGTCCTTTTTTTGTATTCTGGGTAATGTTTTTTGGAAAAGATTT GTCTTTTCTAAGTGGAAGΓTAAATTTGTTATACTGCCCATCCCCTAAAGCCAACAGAGATTTGTAGATTTAAAGGGATCACATTTGAAGACAATAG'IGTTTAAGAAAGCAAG CAAGTCCCTTAGCAGRCAGGTCATAACAGGGCACATTTCTGACCGAACCCTCTCAAGGCAGAGGAGGAGTTTGGTGGGTTTCATACACCCTGCAGATTCCTGTTGGCTCTAA CCCTCAATTACCTAARCTRATGCTTTAACACATAACTGCATTGGATGTGAGAGTAACGTACCGTATGGTCATTGTTCTATATATTAACATTGAACACTGCTGCGATTGCTCA
GTGGTTTAGCCCACCAATCTTGATGACTAAAAGTAGCTGATGCATTGTGCATATGATGCTTGAGATGGTTTTTGCAAAAGCAGAAATCGCTGCAAGGTAATCACAATAGATA AAAGTGGTATTTTAAACCΓTTGAAATAAATGGATGTAACTGTACCTTGGTACAGCTTTTCACTTGTTTAGTTTTTAAACGTTAGTATAATCTGAATAAATAAAATGTTGCCA AATTCAATGTAGAAAGAAΓGTGACAACACACCTTGGGTAGTTCTGCTTGTGTTTTTGCATATTGTAAAAGCAGTGTCACAGCTAAAAAGAAAGAAATCGTTTCTAACAGTAA ATTATTGTGCTTTAGRRGCTAGTTTGTACTGAGAGTTGACCTCTCCCTGTGCAGTTTTTTGTTCTAAACTTGTATAAATAACAATTGTGTAATGTGTCTCCCTCCTACATTG ΓAACAATTGCTTCAGCCTACGTTATAAATAAAGAACCACTAGATT
123
MGLGPVFLLLAGIFPFAPPGAAAEPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRD TGNGKD RMTLAHIKDQKEGLHS QEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMISRVF-SIFLK^^
CRASGFYPWNITLSWRQDGVSIISHDTQQ GDVLPDGNGTYQT VATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSH QTFHVSAVAAAAIFVIIIFYVRCCKKKTS AAEGPE VSLQVL.DQHPVGTSDHRDATQLGFQPLMSDLGSTGSTEGA
124
CACTGCTTGAGCCGCΓGAGAGGGTGGCGACGTCGGGGCCATGGGGCTGGGCCCGGTCTTCCTGCTTCTGGCTGGCATCTTCCCTTTTGCACCTCCGGGAGCTGCTGCTGAGC CCCACAGTCTTCGTTAΓAACCTCACGGTGCTGTCCTGGGATGGATCTGTGCAGTCAGGGTTTCTCACTGAGGTACATCTGGATGGTCAGCCCTTCCTGCGCTGTGACAGGCA GAAATGCAGGGCAAAGCCCCAGGGACAGTGGGCAGAAGATGTCCTGGGAAATAAGACΛTGGGACAGAGAGACCAGAGACTTGACAGGGAACGGAAAGGACCTCAGGATGACC CTGGCTCATATCAAGGACCAGAAAGAAGGCTTGCATTCCCTCCAGGAGATTAGGGTCTGTGAGATCCATGAAGACAACAGCACCAGGAGCTCCCAGCATTTCTACTACGATG GGGAGCTCTTCCTCTCCCAAAACCTGGAGACTAAGGAATGGACAATGCCCCAGTCCTCCAGAGCTCAGACCTTGGCCATGAACGTCAGGAATTTCTTGAAGGAAGATGCCAT GAAGACCAAGACACACΓAΓCACGCTATGCATGCAGACTGCCTGCAGGAACTACGGCGATATCTAAAATCCGGCGTAGTCCTGAGGAGAACAGTGCCCCCCATGGTGAATGTC ACCCGCAGCGAGGCCTCAGAGGGCAACATTACCGTGACATGCAGGGCTTCTGGCTTCTATCCCTGGAATATCACACTGAGCTGGCGTCAGGATGGGGTATCTTTGAGCCACG ACACCCAGCAGTGGGGGGATGTCCTGCCTGATGGGAATGGAACCTACCAGACCTGGGTGGCCACCAGGATTTGCCAAGGAGAGGAGCAGAGGTTCACCTGCTACATGGAACA CAGCGGGAATCACAGCACΓCACCCTGTGCCCTCTGGGAAAGTGCTGGTGCTTCAGAGTCATTGGCAGACATTCCATGTTTCTGCTGTTGCTGCTGCTGCTATTTTTGTTATT ATTATTTTCTATGTCCGTΓGTTGTAAGAAGAAAACATCAGCTGCAGAGGGTCCAGAGCTCGTGAGCCTGCAGGTCCTGGATCAACACCCAGTTGGGACGAGTGACCACAGGG ATGCCACACAGCTCGGATΓTCAGCCTCTGATGTCAGATCTTGGGTCCACTGGCTCCACTGAGGGCGCCTAGACTCTACAGCCAGGCAGCTGGGATTCAATTCCCTGCCTGGA ΤCTCACGAGCACTTTCCCRCTTGGTGCCTCAGTTTCCTGACCTATGAAACAGAGAAAATAAAAGCACTTATTTATTGTTGTTGGAGGCTGCAAAATGTTAGTAGATATGAGG CGTTTGCAGCTGTACCATATT
125
MVGYDPKPDGRNNTKFQVAVAGSVSGLVTRALISPFDVIKIRFQLQHERLSRSDPSAKYHGILQASRQILQEEGPTAFWKGHVPAQI SIGYGAVQFLSFEMLTELVHRGSV YDAREFSVHFVCGKSLAAC ΛTLTVHPVDVLRTRFAAQGEPKVYNTIiRHAVGTMYRSEGPQVFYKGLAPT IAIFPYAGLQFSCYSSLKHLYK AIPAEGKKNENLQNLLCGS GAGVISKTLTYPLDLFKKRLQVGGFEHARAAFGQVPJIYKGLMDCAKQVLQKEGALGFFKGLSPSLLKAALSTGFMFFSYEFFCNVFHCMNRTASQR
126
ATGGTTGGCTATGACCCCAAACCAGATGGCAGGAATAACACCAAGTTCCAGGTGGCAGTGGCTGGGTCTGTGTCTGGACTTGTTACTCGGGCGCTGATCAGTCCCTTCGACG ΓCATCAAGATCCGTTTCCAGCTTCAGCATGAGCGCCTGTCTCGCAGTGACCCCAGCGCAAAGTACCATGGCATCCTCCAGGCCTCTAGGCAGATTCTGCAGGAGGAGGGTCC GACAGCTTTCTGGAAAGGACACGTCCCAGCTCAGATTCTCTCCATAGGCTATGGAGCTGTCCAATTCTTGTCATTTGAAATGCTGACGGAGCTGGTCCACAGAGGCAGCGTG RACGACGCCCGGGAATRCTCAGTGCACTTTGTATGTGGTGGCCTGGCTGCCTGTATGGCCACCCTCACTGTGCACCCCGTGGATGTTCTGCGCACCCGCTTTGCAGCTCAGG GΓGAGCCCAAGGTCTAΓAATACGCTGCGCCACGCCGTGGGGACCATGTATAGGAGCGAAGGCCCCCAGGTTTTCTACAAAGGCTTGGCTCCCACCTTGATCGCCATCTTCCC CTACGCO3GGCTGCAGΓTCTCTTGCTACAGCTCCTTGAAGCACCTGTACAAGTGGGCCATACCAGCCGAAGGAAAGAAAAATGAGAACCTCCAAAACCTGCTTTGTGGCAGT GGAGCTGGTGTCATCAGCAAGACCCTGACATATCCGCTGGACCTCTTCAAGAAGCGGCTACAGGTTGGAGGGTTTGAGCATGCCAGAGCTGCCTTTGGCCAGGTACGGAGAT ACAAGGGCCTCATGGACTGTGCCAAGCAGGTGCTACAAAAGGAAGGCGCCCTGGGCTTCTTCAAGGGCCTGTCCCCCAGCTTGCTGAAGGCTGCCCTCTCCACAGGCTTCAT GTTCTTCTCGTATGAATTCTTCTGTAATGTCTTCCACTGCATGAACAGGACAGCCAGCCAGCGCTGA
127
MERASCLLLLLLPLVHVSATTPEPCELDDEDFRCVCNFSEPQPDWSEAFQCVSAVEVEIHAGGLNLEPFLKRVDADADPRQYADTVKALRVRR TVGAAQVPAQL VGALRV IAYSRLKE TLEDLKITGTMPPLPLEATGLALSSLRLRNVS ATGRSWLAELQQWLKPGLKVLSIAQAHSPAFSYEQVRAFPALTSLDLSDNPGLGERGLMAALCPHKFPAI QNLALRNTG ETPTGVCAALAAAGVQPHSLDLSH SLRATVNPSAPRC1VMSSALNSLNLSFAGLEQVPKG PAK RVLDLSCNRLNRAPQPDELPEVDNLTLDGNPFLVPGT A PHEGSMNSGWPACARSTLSVGVSGTLVLLQGARGFA
128
CCGGCCGGCCGAAGAGTTCACAAGTGTGAAGCCTGAAGCCGCCGGGTGCCGCTGTGTAGAAAGAAGCTAAAGCACTTCCAGAGCCTGCTGAGCTCAGAGG'TTCGGAAGACTT ATCGACCATGGAGCGCGCGTCCTGCTTGTTGCTGCTGCTGCTGCCGCTGGTGCACGTCTCTGCGACCACGCCAGAACCTTGTGAGCTGGACGATGAAGATTTCCGCTGCGTC RGCAACTTCTCCGAACCTCAGCCCGACTGGTCCGAAGCCTTCCAGTGTGTGTCTGCAGTAGAGGTGGAGATCCATGCCGGCGGTCTCAACCTAGAGCCGTTTCTAAAGCGCG RCGATGCGGACGCCGACCCGCGGCAGTATGCTGACACGGTCAAGGCTCTCCGCGTGCGGCGGCTCACAGTGGGAGCCGCACAGGTTCCTGCTCAGCTACTGGTAGGCGCCCT GCGTGTGCTAGCGTACTCCCGCCTCAAGGAACTGACGCTCGAGGACCTAAAGATAACCGGCACCATGCCTCCGCTGCCTCTGGAAGCCACAGGACTTGCACTTTCCAGCTTG CGCCTACGCAACGTGTCGTGGGCGACAGGGCGTTCTTGGCTCGCCGAGCTGCAGCAGTGGCTCAAGCCAGGCC1CAAGGTACTGAGCATTGCCCAAGCACACTCGCCTGCCT ΓTTCCTGCGAACAGGTTCGCGCCTTCCCGGCCCTTACCAGCCTAGACCTGTCTGACAATCCTGGACTGGGCGAACGCGGACTGATGGCGGCTCTCTGTCCCCACAAGTTCCC GGCCATCCAGAATCTAGCGCTGCGCAACACAGGAATGGAGACGCCCACAGGCGTGTGCGCCGCACTGGCGGCGGCAGGTGTGCAGCCCCACAGCCTAGACCTCAGCCACAAC ΓCGCTGCGCGCCACCGTAAACCCTΔGCGCTCCGAGATGCATGTGGTCCAGCGCCCTGAACTCCCTCAATCTGTCGTTCGCTGGGCTGGAACAGGTGCCTAAAGGACTGCCAG CCAAGCTCAGAGTGCTCGATCTCAGCTGCAACAGACTGAACAGGGCGCCGCAGCCTGACGAGCTGCCCGAGGTGGATAACCTGACACTGGACGGGAA'ICCCTTCCTGGTCCC RGGAACTGCCCTCCCCCACGAGGGCTCAATGAACTCASGCGTGGTCCCAGCCTGTGCACGTTCGACCCTGTCGGTGGGGGTGTCGGGAACCCTGGTGCTGCTCCAAGGGGCC CGGGGCTTTGCCTAAGATCCAAGACAGAATAATGAATGGACTCAAACTGCCTTGGCTTCAGGGGAGTCCCGTCAGGACGTTGAGGACTTTTCGACCAATTCAACCCTTTGCC CCACCTTTATTAAAATCTTAAAC
129
MAPMGIRLSPLGVAVFCLLGLGVLYHLYSGFIΛGRFSLFGLGGEPGGβAAGPAAAArXMTVDLREMIΛV8VI_AAVRGGDEVRRVRESNVLHEKSKGKTREGAEDKMTSGDVL SNRKWFYLLKTAFPSVQINTEEHVDAADQEVILVmHKIPEDILKEVTTPKEVPAESVTVWIDPLDATQEYTED RKYVTTMVCVAVNGKPM GVIHKPFΞEYTA AMλ/DGGS VKARSSYNEKTPRIV SRSHSGWKQVA QTFG QTTIIPAGσAGYKVLA LDVPDKSQEKAD YIHVTYIKKWDICAG AILKALGGHMTTLSGEEISYTσSDGIEGGLL ASI MNHQALVRKLPDLEKTGHK
130
CACCTCGCGGCCGTAGGCTAACGTGGAAGTCGGACCAGCCGGCCGGCGGAAGAACCTAGAGCGCGCTGCCTGGCGAGTCAGGCGCGCGGGGCGGCGTTGGTGGTCTTCGCGG CGTAACTCGGCCTTTCCTGGGAGGGAGTGATGGGGCGCACCGGGGCCGGGGAGCGGGCGCCAGTGTAGCCCGCGCGGCGCCTGGCCCGGAGCGCGGCGGCTGCGGCGGCGGC GGCGGCGGGCGCTGGAGGCCTGTGAGAGCCGCAGCCCGGAGCGCCCGGCTTCCCACGCCATGGCCCCCATGGGCATCCGCCTTTCCCCACTGGGGGTGGCAGTGTTTTGTCT GCTGGGGCTCGGCGTGCTCTACCACCTCTACTCGGGCTTCTTGGCCGGCCGCTTCAGCCTCTTCGGCCTGGGCGGCGAGCCTGGCGGCGGCGCGGCGGGGCCCGCGGCCGCG GCCGATGGGGGCACCGTHGACΓTGCGCGAGATGCTGGCTGTGΓCAGTGCTGGCCGCAGTCCGCGGCGGCGACGAGGTGAGGCGCGTCCGCGAGAGCAACGTCCTCCACGAGA AGTCCAAGGGGAAGACGCGCGAGGGAGCCGAGGACAAGATGACCAGCGGCGACGTGCTGTCCAACCGCAAGATGT"ICTACCTGCTCAAGACCGCCTTCCCCAGCGTCCAGAT RAATACTGAGGAACACGTGGATGCAGCTGATCAGGAGGTTATCTTGTGGGATCATAAGATTCCTGAGGATATCCTAAAGGAAGTAACTACTCCTAAAGAGGTACCAGCAGAA AGTGTTACTGTCTGGATTGACCCACTTGATGCTACACAGGAATATACAGAGGATCTTCGAAAGTACGTCACTAC'IA'RGGTGTGTGTGGCTGTAAATGGTAAACCCATGCTAG GAGTTATACATAAGCCATTTTCCGAATATACAGCTTGGGCAARGGTAGATGGTGGTTCAAATGTGAAAGCCCGCTCTTCCTACAATGAGAAGACCCCAAGGATCGTTGTGTC RCGTTCCCATTCAGGGATGGTCAAACAGGTCGCTCTTCAGACRTTTGGAAACCAGACTACAATTATCCCAGCTGGTGGTGCTGGTTATAAAGTTTTAGCACTTTTGGATGTG CCTGATAAGAGTCAAGAAAAAGCTGATTTATACATCCATGTGACATACATCAAAAAGTGGGATATATGTGCTGGTAATGCCATCTTAAAAGCCCTAGGGGGGCATATGACTA CCCTGAGTGGTGAAGAAATCAGTTACACTGGTTCAGACGGCAΓTGAAGGGGGACTCCTTGCTAGCATCAGAATGAACCACCAGGCCCTGGTCAGAAAACTCCCAGATCTAGA AAAGACAGGACATAAATGAGCAΓAACTGATTACAGGGTACAGΓTCTTCACAGCTGAAATGGTTAGCCTGAGATGCTGGAAGCTTCAAAGGATTGGTGGAGACTATGCATGGT ΓAAGGCCATCCCGAACΓTTTTAAAGTATTTATGAAGCATCAGAGACTTATTTT'CCCTGTAATAGAATGCAAAATCAGGGAAAATGGGTTGCTTTGTGTCTCAAGTATTGTCT ΓTATTTTTGAGACTATΓTTCAΓACAGTTGTCATACACAAGGCGCATATATATATTTGTGAATTAAAATCTGTAGCTGAGTCTAAAAAAAAAAAAAAAAAA
131
MAPMGIRLSPLGVAVFCLLGLGVLYHLYSGFIΛGRFSLFGLGGEPGGGAAGPAAAADGGTVDLREMLAV8VLAAVRGGDEVRRVRESNVLHEKSKGKTREGAEDKMTSGDV
SNRKMFYLLKTAFPSVQINTEEHVDAADQEVIL DHKIPEDILKEVTTPKEVPAESVTV IDPLDATQEYTEDLRKYVTTMVCVAVNGKPMLGVIHKPFSEYTA AMVDGGS n KA SSYNEKTPRIVVSRSHSGMVKQVA QTFG QTTIIPA^GAGYKVLALLDVPDKSQEKADLYIHV IKKWDICAGNAI KALGGHM T SGEEISYTGSDGIEGG L
AS I RMNHQAL VRKLPDL.EKTGHK
132
CACCTCGCGGCCGTAGGCTAACGTGGAAGTCGGACCAGCCGGCCGGCGGAAGAACCTAGAGCGCGCTGCCTGGCGAGTCAGGCGCGCGGGGCGGCGTTGGTGGTCTTCGCGG CGTAACTCGGCCTTTCCΓGGGAGGGAGTGATGGGGCGCACCGGGGCCGGGGAGCGGGCGCCAGTGTAGCCCGCGCGGCGCCTGGCCCGGAGCGCGGCGGCTGCGGCGGCGGC GGCGGCGGGCGCTGGAGGCCTGTGAGAGCCGCAGCCCGGAGCGCCCGGCTTCCCACGCCATGGCCCCCATGGGCATCCGCCTTTCCCCACTGGGGGTGGCAGTGTTTTGTCT GCTGGGGCTCGGCGTGCΓCTACCACCTCTACTCGGGCTTCTTGGCCGGCCGCTTCAGCCTCTTCGGCCTGGGCGGCGAGCCTGGCGGCGGCGCGGCGGGGCCCGCGGCCGCG GCCGATGGGGGCACCGRGGACRRGCGCGAGATGCTGGCTGTGRCAGTGCTGGCCGCAGTCCGCGGCGGCGACGAGGTGAGGCGCGTCCGCGAGAGCAACGTCCTCCACGAGA AGTCCAAGGGGAAGACGCGCGAGGGAGCCGAGGACAAGATGACCAGCGGCGACGTGCTGTCCAACCGCAAGATGTTCTACCTGCTCAAGACCGCCTTCCCCAGCGTCCAGAT TAATACTGAGGAACACGΓGGAΓGCAGCTGATCAGGAGGTTATCTTGTGGGATCATAAGATTCCTGAGGATATCCTAAAGGAAGTAACTACTCCTAAAGAGGTACCAGCAGAA AGTGTTACTGTCTGGAΓΓGACCCACTTGATGCTACACAGGAAΓATACAGAGGATCTTCGAAAGTACGTCACTACTATGGTGTGTGTGGCTGTAAATGGTAAACCCATGCTAG GAGTTATACATAAGCCAΓTTΓCCGAATATACAGCTTGGGCAAΓGGTAGATGGTGGTTCAAATGTGAAAGCCCGCTCTTCCTACAATGAGAAGACCCCAAGGATCGTTGTGTC TCGTTCCCATTCAGGGARGGRCAAACAGGTCGCTCTTCAGACTTTTGGAAACCAGACTACAATTATCCCAGCTGGTGGTGCTGGTTATAAAGTTTTAGCACTTTTGGATGTG CCTGATAAGAGTCAAGAAAAAGCTGATTTATACATCCATGTGACATACATCAAAAAGTGGGATATATGTGCTGGTAATGCCATCTTAAAAGCCCTAGGGGGGCATATGACTA CCCTGAGTGGTGAAGAAATCAGΓTACACTGGTTCAGACGGCATTGAAGGGGGACTCCTTGCTAGCATCAGAATGAACCACCAGGCCCTGGTCAGAAAACTCCCAGATCTAGA AAAGACAGGACATAAAΓGAGCAΓAACTGATTACAGGGTACAGTTCΓTCACAGCTGAAATGGTTAGCCTGAGATGCTGGAAGCTTCAAAGGATTGGTGGAGACTATGCATGGT TAAGGCCATCCCGAACΓΓTTΓAAAGTATTTATGAAGCATCAGAGACTTATTTTCCCTGTAATAGAATGCAAAATCAGGGAAAATGGGTTGCTTTGTGTCTCAAGTATTGTCT TΓATTTTTGAGACTATΓΓTCAΓACAGTTGTCATACACAAGGCGCATATATATATTTGTGAATTAAAATCTGTAGCTGAGTCTAAAAAAAAAAAAAAAAAA
133
MSVKEAGSSGRREQAAYHLHIYPQL8TTESQASCRVTATKDεrTSDVIKDAIASLRLDGTKCYVLVEVKESGGEEWVLDANDSPVHRVLLWPRRACDEHPQEDGYYFL QER
NADGTIKYVHMQLVAQArATRRLVERGLLPROQADFDDLm,PELTEGNLLKN^
TMLRKEVNQCIVYPGESGSGKTQSTNFLIHCLTALSQKGYASGVERTII^ACPVLEAFGNAKTAHNNNSSRFGKFIQVSYLESGIVRGAVVEKYLLEKSRLVSQEKDERNYH
VFYYLLLGVSEEERQEFQLKQPEDYFYLNQHNLKIELX3EDLKHDFERLKQAME1WGFLPATKKQIFAVLSAILYLGNVTYKKRATGREEGLEVGPPEVLDTLSQLLKVKREI
LVEV TKRKTVTV ^KIJIIJP SLSEAITARDS^®KS SA FDWIVIiRINHA NKKDVEEAVSCLSIGV DIFGFEDFER SFEQFCINANEQLQ YF QHIFKLEQEEY
QGEGITHHNIGYTDNVGCIH ISKKPTGLFYLLDEESNFPHATSQTLIiAKFKQQHEDNKYFLGTPVMEPAFIIQHFAGKVKYQIKDFREKNMDYMRPDIVALLRG8DSSYVR
ELIGMDPVAVFRWAVLRAAIRAMAVLREAGRLRAERAEKAAGMSSPGAQSHPEELPRGASTPSEKLYRDLHNQMIK8IKGLPWQGEDPR8LLQ8L8RLQKPRAFILK8KGIK
QKQIIPKNLLDSKSLKLIISMTLHDRTTKSLLHLHKKKKPPεiSAQFQTSLNKLLEALGKAEPFFIRCIRSNAEKKELCFDDELVLQQLRYTGMLETVRIRRSGYSAKYTFQ
DF EQFQVLLPKDAQPCREVIS^L EKMKIDKRrYQIGKTKVFLKETE QALQETIJ^REVVRKI LLQSWFR^^VLERPJ^FLQMKRAAVTIQACWRS VRRALERTQAAVYL
QAAWRGYWQRKLYRHQKQSIIRLQSLCRGHLQRKSFSQMISEKQKAEEKEREALEAARAGAEEGGQGQAAGGQQVAEQGPEPAEDGGHLASEPEVQPSDRSPLEHSSPEKEA
PSPEKTLPPQKTVAAESHEKVPSSREKRESRRQRGLEHVKFQNKHIQSCKEESALREPSRRVTQEQGVSL EDKKEΞREDETLLWETEAENTSQKQPTEQPQAMAVGKVSE
ETEKT PSGSPRPGQLERPTSLALDSRVSPPAPGSAPETPED SKPCGSPRVQEKPDSPGGSTQIQRYLDAERLASAVELWRGKKLVAAASPSAM SQSLDLSDRHRATGAA
LTPTEERRTSFSTSDVSKLLPSLAKAQPAAETTDGERSAKKPAVQKKKPGDASSLPDAGLSPGSQVDSKSTFKRLFLHKTKDKKYSLEGAEELENAVSGHWLEATTMKKGL
EAPSGQQHRHAAGEKRTKEPGGKGKKNRNVKIGKITVSEKWRESVFRQITNANELKYLDEFLLNKINDLRSQKTPIESLFIEATEKFRSNIKTMYSVPNGKIHVGYKDLMEN YQIWSNLATERGQKDTNLVLNLFQSLLDEFτRGYTKNDFEPVKQSKAQKKKRKQERAVQEHNGHVFASYQVεiPQεCEQCLSYIVJLMDKALLCSVCKMTCHKKCVHKIQSH CSYTYGRKGEPGAEPGHFGVCVDSLTSDKASVPIVLEKLLEHVEMHGLYTEGLYRKSGAANRTRELRQA QTDPAAVKLENFPIHAITGVLKQWLRELPEPLMTFAQYGDFL PΛVELPEKQEQLAAIYAVLEHLPEANHNSLERLIFHLVKVAL EDVNRM8PGALAIIFAPC LRCPDNSDPLTSMKDVLKITTCVEMLIKEQMRKYKVKMEEISQLEAAE8I AFRRLSLLRQNAPWPLKLGFSSPYEGVLNKSPQVPRDIQEEELEVLLEEEAAGGDEDREKEILIERIQSIKEEKEDITYRLPELDPRGSDEENLDSETSASTES LEERAGR GASEGPPAPA PCPGAPTPSPLPTVAAPPRRRPSSFVTVRVKTPRRTPIMPTANIKLPPGLPSHLPR APGAREAAAPVRRREPPARRPDQIHSVYITPGADLPVQGALEPL EEDGQPPGAKRRYSDPPTYCLPPASGQTNG
134
ATGAGTGTGAAAGAGGCAGGCAGCTCGGGCCGCCGGGAGCAGGCGGCCTACCACC GCACATCTACCCCCAGCTGTCCACCACCGAGAGCCAGGCCTCGTGCCGCGTGACTG CCACCAAGGACAGCACCACCTCGGACGTCATCAAGGACGCCATTGCCAGCCTGCGGCTGGACGGCACCAAATGTTATGTGCTGGTGGAGGTCAAAGAGTCGGGAGGCGAGGA ATGGGTGCTGGACGCCAACGACTCGCCTGTGCACCGGGTGCTGCTATGGCCCCGGCGGGCACAGGACGAGCACCCTCAGGAGGATGGCTACTACTTCCTGCTGCAGGAGCσC AACGCAGATGGAACCATCAAGTACGTGCATATGCAGCTGGTGGCGCAGGCCACAGCCACCCGGCGCCTAGTGGAGCGTGGCCTCCTGCCACGGCAGCAGGCGGACTTTGATG ACCTGTGTAACCTTCCTGAGCTAACCGAGGGCAACCTCCTGAAGAACCTCAAGCACCGCTTCCTGCAACAAAAGATCTACACGTACGCGGGGAGCATCCTGGTGGCCATCAA CCCCTTTAAGTTCCTGCCCATCTACAACCCCAAGTACGTGAAGATGTATGAGAACCAGCAGCTGGGCAAGCTGGAGCCACACGTCTTCGCGCTGGCCGACGTGGCCTACTAC ACCATGCTCAGGAAGCGCGTGAACCAGTGCATCG'IGTATCCGGGTGAGAGCGGCTCCGGCAAGACCCAGAGCACCAACTTCCTCATCCACTGCCTCACCGCCCTCAGCCAGA AGGGCTACGCCAGCGGCGTCGAGAGGACCATCCTGGGTGCCTGTCCTGTGCTGGAAGCTTTTGGAAATGCCAAGACAGCCCACAACAACAACTCCAGCCGGTTTGGGAAATT CATCCAAGTCAGCTACCTAGAGAGTGGCATCGTGAGAGGAGCTGTCGTCGAGAAATATCTGCTTGAAAAGTCTCGCCTGGTGTCTCAGGAGAAGGATGAGAGGAACTACCAT GTGTTTTATTATTTGTTACTTGGGGTCAGCGAGGAAGAGCGCCAAGAATTTCAGCTCAAGCAGCCTGAAGATTATTTCTACCTCAACCAGCATAACTTGAAGATTGAAGATG GGGAGGACCTGAAGCATGACTTTGAGAGGCTCAAGCAGGCCATGGAGATGGTGGGCTTCCTCCCCGCCACCAAGAAGCAGATTTTTGCCGTCCTCTCGGCCATCCTGTACCT GGGCAACGTCACTTATAAGAAGAGAGCTACAGGCCGAGAGGAAGGGTTGGAGGTCGGGCCACCCGAGGTGCTGGACACCCTGTCGCAGCTTCTGAAGGTGAAGCGAGAAATC TTGGTGGAGGTTCTGACCAAAAGAAAAACGGTGACCGTCAACGACAAGCTTATCCTTCCCTACAGCCTCAGCGAGGCCATCACTGCCCGCGACTCCATGGCCAAGTCrcrGT ACAGCGCCCTGTTCGACTGGATTGTGCTGCGGATCAACCACGCACTCCTCAACAAGAAGGACGTGGAAGAGGCAGTCTCGTGCCTGTCCATTGGGGTCCTGGACATCTTCGG GTTTGAAGACTTCGAGAGGAACAGCTTTGAGCAGTTCTGCATCAACTACGCCAATGAGCAGCTGCAGTATTACTTCAACCAGCACATCTTCAAGCTGGAGCAGGAGGAATAT CAGGGCGAGGGGATCACGTGGCACAACATCGGCTACACAGACAATGTCGGCTGCATCCATCTCATCAGCAAGAAACCCACGGGCCTCTTCTACCTGCTGGACGAGGAGAGCA ACTTCCCCCACGCCACGAGCCAGACCCTGCTGGCCAAGTTCAAACAGCAACATGAGGACAATAAGTACTTCCTGGGCACCCCGGTCATGGAGCCAGCTTTCATCATCCAGCA CTTCGCAGGGAAGGTGAAATATCAGATCAAGGACTTCCGGGAGAAGAACATGGACTACATGCGGCCAGACATCGTGGCCCTGCTGCGGGGCAGTGACAGCTCCTACGTGCGG GAGCTCATCGGCΛTGGACCCCGTGGCCGTGTTCCGCTGGGCCGTGCTCCGGGCTGCTATCCGGGCCATGGCAGTGCTTCGGGAGGCCGGACGCCTGCGGGCCGAGAGGGCCG AAAAGGCTGCAGGTATGAGCAGCCCTGGTGCCCAAAGTCACCCAGAAGAGCTGCCAAGAGGAGCCAGCACCCCTTCGGAAAAACTTTACCGCGATTTGCATAACCAAATGAT CAAGAGCATCAAAGGATTGCCCTGGCAGGGCGAGGACCCCCGTAGCCTTCTCCAGTCCCTCAGTCGGCTCCAGAAACCCCGCGCCTTCATCCTGAAAAGTAAAGGTATCAAA CAAAAGCAGATCATTCCAAAGAACCTACTGGACTCCAAGTCCCTGAAACTCATCATCAGCATGACTCTGCACGACCGCACCACCAAGTCCCTACTGCACCTGCACAAGAAGA AAAAGCCACCAAGCATCAGCGCCCAGTTCCAGACATCCCTTAACAAGCTCTTGGAGGCACTGGGGAAGGCGGAGCCCTTCTTTATCCGCTGCATCCGTTCCAATGCTGAAAA GAAAGAGCTGTGCTTTGACGACGAGCTGGTCCTGCAGCAGCTGCGCTACACCGGCATGCTGGAGACCGTGCGCATCCGGAGGTCAGGGTACAGCGCCAAGTACACGTTCCAG GATTTCACCGAGCAGTTCCAGGTGCTCCTGCCCAAGGATGCCCAGCCCTGCAGGGAGGTCATCTCCACCCTCCTGGAGAAAATGAAGATAGACAAGAGGAACTACCAGATCG GGAAGACCAAGGTCTTCCTGAAGGAGACGGAGCGGCAAGCCCTGCAGGAGACGCTGCACCGGGAGGTGGTGCGGAAAATCCTGCTGCTGCAGAGCTGGTTCCGGATGGTGCT GGAGCGTCGGCACTTCCTGCAGATGAAGCGGGCCGCCGTCACCATCCAGGCCTGCTGGCGGTCCTACCGGGTCCGGAGGGCGCTGGAGAGGACGCAGGCTGCCGTGTACCTC CAGGCCGCATGGAGGGGCTACTGGCAGCGGAAGCICTACCGGCACCAGAAACAGAGCATCATCCGCCTGCAGAGCCTGTGTCGGGGGCACCTGCAGCGCAAGAGCTTCAGCC AGATGATCTCGGAGAAGCAGAAGGCAGAAGAGAAGGAGAGGGAAGCCCTGGAAGCCGCAAGAGCAGGCGCTGAGGAGGGCGGACAGGGTCAGGCGGCTGGAGGGCAGCAGGT AGCTGAGCAGGGGCCGGAGCCAGCGGAGGATGGCGGGCACCTGGCATCGGAGCCTGAGGTGCAGCCAAGTGACAGGTCCCCCCTAGAGCACTCCTCACCTGAGAAGGAGGCC CCAAGCCCAGAGAAGACTCTCCCACCCCAGAAAACCGTGGCGGCTGAAAGTCACGAGAAAGTCCCCAGCAGCCGGGAGAAGCGTGAGTCGCGTCGGCAAAGAGGGCTGGAGC ACGTCAAGTTCCAGAACAAACACATCCAGTCCTGCAAGGAGGAGAGTGCCCTCAGAGAACCTTCCAGAAGGGTCACCCAGGAGCAAGGGGTGAGTCTCCTGGAAGACAAAAA GGAGAGCAGAGAAGATGAAACCCTTCTAGTCGTAGAGACGGAGGCTGAGAACACATCTCAAAAGCAGCCCACAGAGCAACCCCAGGCCATGGCAGTTGGCAAGGTCTCTGAA GAAACTGAGAAGACGCTGCCCAGTGGGAGCCCCAGGCCTGGCCAGTTGGAGCGGCCGACCAGCCTGGCCCTGGACAGCAGGGTCAGCCCACCGGCCCCCGGCAGCGCCCCCG AGACCCCCGAGGACAAGAGCAAACCATGTGGCAGCCCAΔGGGTTCAGGAAAAGCCCGACAGCCCCGGAGGCTCCACGCAGATCCAGCGGTACCTGGACGCCGAGCGGCTGGC CAGCGCCGTGGAACTGTGGCGGGGCAAGAAGCTGGTGGCCGCCGCCAGCCCTAGTGCCATGCTCAGCCAGTCCCTGGACCTCAGCGACAGACACCGGGCCACAGGGGCCGCC CTCACGCCCACAGAGGAGAGGCGCACCTCCTTCTCCACGAGCGACGTCTCCAAGCTCCTCCCGTCCCTGGCCAAGGCTCAGCCTGCAGCAGAAACCACGGACGGAGAGCGAA aTGCGAAAAAGCCAGCTGTCCAGAAGAAGAAGCCAGGCGACGCATCCTCCCTCCCAGACGCAGGGCTGTCCCCGGGCTCTCAGGTCGACTCTAAATCCACGTTTAAGAGGCT TTTTCTGCATAAAACCAAGGATAAAAAATACAGCCTGGAGGGAGCAGAGGAGCTGGAGAATGCAGTGTCCGGGCACGTGGTGCTGGAAGCCACCACCATGAAGAAGGGCCTG GAAGCCCCCTCCGGACAGCAGCATCGCCACGCTGCAGGTGAGAAGCGCACCAAGGAACCAGGAGGCAAAGGGAAGAAGAACCGAAATGTCAAGATTGGGAAGATCACAGTGT CAGAGAAGTGGCGGGAATCGGTGTTCCGCCAGATCACCAACGCCAATGAGCTCAAGTACCTGGACGAGTTCCTGCTCAACAAGATAAATGACCTCCGTTCCCAGAAGACGCC CATTGAGAGCTTGTTTATCGAAGCCACCGAGAAGTTCAGGAGCAACATCAAAACGATGTACTCTGTCCCGAACGGGAAGATCCACGTGGGCTACAAGGATCTGATGGAGAAC TACCAGATCGTTGTCAGCAACCTGGCCACTGAGCGTGGCCAGAAGGACACCAACCTGGTCCTCAACCTCTTCCAGTCACTGCTAGATGAGTTCACCCGTGGCTACACCAAGA ACGACTTCGAGCCAGTGAAGCAGAGCAAAGCTCAGAAGAAGAAGCGGAAGCAGGAGCGTGCTGTCCAGGAGCACAACGGGCACGTGTTCGCCAGCTACCAGGTTAGCATCCC GCAGTCGTGCGAGCAGTGCCTCTCCTATATCTGGCTCATGGACAAGGCCCTGCTCTGCAGCGTGTGCAAGATGACCTGCCACAAGAAGTGCGTGCACAAGATTCAGAGCCAC TGCTCCTACACCTACGGGAGGAAGGGCGAGCCAGGCGCTGAGCCTGGCCACTTCGGCGTGTGCGTAGACAGCCTGACCAGCGACAAGGCCTCGGTGCCCATCGTGCTGGAGA AGCTCCTGGAACACGTGGAGATGCACGGCCTGTACACCGAGGGCCTCTACCGCAAG'ICGGGTGCTGCCAACCGCACTCGGGAGCTCCGGCAGGCGCTGCAGACAGACCCCGC AGCAGTCAAGCTGGAGAACTTCCCCATCCACGCCATCACAGGGGTGCTGAAGCAGTGGCTGCGGGAGCTGCCCGAGCCCCTCATGACCTTCGCACAGTACGGCGACTTCCTC CGAGCCGTCGAGCTGCCGGAGAAGCAGGAGCAGCTGGCTGCCATCTATGCCGTCCTGGAGCACCTTCCAGAAGCCAACCACAACTCCCTGGAGAGACTCATCTTCCACCTTG TCAAGGTGGCCCTGCTCGAGGATGTCAACCGCATGTCACCTGGGGCGCTGGCCATTATCTTCGCACCCTGCCTCCTGCGCTGCCCTGACAACTCGGACCCGCTGACCAGCAT GAAGGACGTCCTCAAGATCACCACGTGCGTGGAGATGCTGATCAAGGAGCAGATGAGGAAATACAAAGTGAAGATGGAGGAGATCAGCCAACTGGAGGCTGCAGAGAGTATC GCCTTCCGCAGGCTTTCGCTCCTGCGACAAAATGCTAACAAGAGCCCCAAGACCCGAGAGCCTGCTGGAGGAGCGGGCCGGCTCTTGACGACCTCCAGGGTCTCCCCGAGCC CCAGCACGCGAAACCTGGCCCTCGGAAGCTGGCGGAGCGCGGCCCTCAGGACTCGGGGGACAGGGCGGCCAGCCCGGCCGGGCCGCGCAAGAGCCCTCAGGAGGCGGCCGCC GCGCCCGGCACGAGAGAGCCCTGCCCAGCCGCCCAGGAGCCGGCCCCGAGTGAGGACAGAAACCCCTTCCCCGTTAAGCTCCGGTCCACCTCCCTCTCGCTCAAATACAGGG ATGGCGCCTCTCAGGAGGTGA
135
M LP ALLLL VPGCFALSKCRTVAGPVGGSLSVQCPYEKEHRTLNKYWCRPPQIFLCDKIVETKGSAGKRNGRVSIRDSPAN SFTVT ENLTEEDAGTY CGVDTP LQD
FHDPWEVEVSVFPASTSMTPASITAAKTSTITTAFPPVSSTTLFAVGATHSASIQEETEEW SQ PLLLSLLALLLLLLVGASLLAWRMFQKWIKAGDHSELSQNPKQAA
TQSELHYANLELLMWPLQEKPAPPREVEVEYSTVASPREELHYASWFDSNTNRIAAQRPREEEPDSDYSVIRKT
136
GACCCACGCGTCCGGCTACGGAGTCACTACAGGGAGAGGTCTCATCACTAGAAATAGCCGAAGAACCTGCAGCCTCAACCAGCGTTAAGGAGGACGTGCCGTTTCTAGGGAG TCTTAGTCGGGGCTCACCAGCTTCCTGCATTTTCTGACCX3GCTCCAGGAATAGAACCAAAAGAAGCTGAACAAGGAAGCAGCGCGGCACCAAGAAAAGCAGAAGTCGGGGCC TTGGAGGCGTGACTTTCCCCTCGGGTCCAGGTAGGGCCTGGAGCTGCTGCAAGTGCCGCCTGTGCTGGGGAAGGGACCATGTGGCTGCCTTGGGCTCTGTTGCTTCTCTGGG TCCCAGGATGTTTTGCTCTGAGCAAATGCAGGACCGTGGCGGGCCCCGTGGGGGGATCCCTGAGTGTGCAGTGTCCCTATGAGAAGGAACACAGGACCCTCAACAAATACTG GTGCAGACCACCACAGATTTTCCTATGTGACAAGATTGTGGAGACCAAAGGGTCAGCAGGAAAAAGGAACGGCCGAGTGTCCATCAGGGACAGTCCTGCAAACCTCAGCTTC ACAGTGACCCTGGAGAATCTCACAGAGGAGGATGCAGGCACCTACTGGTGTGGGGTGGATACACCGTGGCTCCGAGACTTTCATGATCCCGTTGTCGAGGTTGAGGTGTCCG TGTTCCCGGCATCAACGTCAATGACACCTGCAAGTATCACTGCGGCCAAGACCTCAACAATCACAACTGCATTTCCACCTGTATCATCCACTACCCTGTT'IGCAGTGGGTGC CACCCACAGTGCCAGCATCCAGGAGGAAACTGAGGAGGTGGTGAACTCACAGCTCCCGCTGCTCCTCTCCCTGCTGGCATTGTTGCTGCTTCTGTTGGTGGGGGCCTCCCTG CTAGCCTGGAGGATGTTTCAGAAATGGATCAAAGCTGGTGACCATTCAGAGCTGTCCCAGAACCCCAAGCAGGCTGCCACGCAGAGTGAGCTGCACTACGCAAATCTGGAGC TGCTGATGTGGCCTCTGCAGGAAAAGCCAGCACCACCAAGGGAGGTGGAGGTGGAATACAGCACTGTGGCCTCCCCCAGGGAAGAACTTCACTATGCCTCGGTGGTGTTTGA TTCTAACACCAACAGGATAGCTGCTCAGAGGCCTCGGGAGGAGGAACCAGATTCAGATTACAGTGTGATAAGGAAGACATAGGCTTTTGTCCTGCCTCGCCATCGGAGCTCT CATGGGCCCCAGGAAGTCCAGGGACAGCTCCCTTATACCTGGCCCACGTCCTTCTCAGCCTGCCCTCGACAACAGTGACCAACAGACAGGCAGCTGGGTTTCCCAGGCCATC CCTCTGTTGCCATCAGCTTGATTGGCTTCCCCGAGGGCCAGCAGGGCTGGGGGCTCCX3GAGAGCAGCAGGAAGCACTCCCAGCCACCAGTGCCTGTCGCCTCTTTCCCCTTT GCCCCTGCTTCATCCCAGCTCTGTGTGTGGAGGACAAAGCTTCTTCCTGCGTGGCTCCAGGAAAAGATGTGGCTCACGTAGGTGGCACCTGCCAATAGCTTTGTCAATCACA GCCCCATAGGAACGTCTGGAATTGCTTGGGAGTTGGGGAGAACTGTCAAGAAGAGTGAAGAGAGTGCCAAAGCGGAGATCTGTTCACCTGGGGGCCATGGAGGGGGGACCCA CTAAAGATCAAGATCAAAGATTCTCCCCATCTCACAGACAAGGAAACTGAGGCCAGAGGGAGGAGAGAATTGCTCATGGCTCCAGAACTGGTGGCAAGTTTCTCTGGACTCT
TAGGΓTTATTTTTAATATGAAATATAAAAACAGTTTCAAATATCTTAAAAAAAAAAAAAAAAAAA
137 MTKHKKCFIIVGVLITTNIITLIVKLTRDSQSLCPYDWIGFQNKCYYFSKEEGDWNSSKYNCSTQHADLTIIDNIEEMNFLRRYKCSSDHWIGLKMAKNRTGQWVHGATFT KSFGMRGSEGCAYLSDDGAATARCYTERKWICRKRIH
138
CrGTGCTGTAAAAACAAGAGTAACATTTTTATATTAAAGTTAAATAAAGTTACAACTTTGAAGAGAGTTTCTGCAAGACATGACACAAAGCTGCTAGCAGAAAATCAAAACG CΓGATTAAAAGAAGCTACGGTATGATGACCAAACATAAAAAGTGTTTTATAATTGTIGGTGTTTTAATAACAACTAATATTATTACTCTGATAGT'TAAACTAACTCGAGATTC TCAGAGTTTATGCCCCTATGATTGGATTGGTTTCCAAAACAAATGCTATTATTTCTCTAAAGAAGAAGGAGATTGGAATTCAAGTAAATACAACTGTTCCACTCAACATGCC GACCTAACTATAATTGACAACATAGAAGAAATGAATTTTCTTAGGCGGTATAAATGCAGTTCTGATCACTGGATTGGACTGAAGATGGCAAAAAA'ICGAACAGGACAATGGG TACATGGAGCTACATTTACCAAATCGTTTGGCATGAGAGGGAGTGAAGGATGTGCCTACCTCAGCGATGATGGTGCAGCAACAGCTAGATGTTACACCGAAAGAAAATGGAT TrGCAGGAAAAGAATACACTAAGTTAATGTCTAAGATAATGGGGAAAATAGAAAATAACATTATTAAGTGTAAAACCAGCAAAGTACTTTTTTAATTAAACAAAGTTCGAGT TTTGTACCTGTCTGGTTAATTCTGCTTACGTGTCAGGCTACACATAAAAGCCACTTCAAAGATTGGCAAAAAAAAAAAAAAAAAAAA
139
MNGRADFREPNAEVPRPIPHIGPDYIPTEEERRVFAECNDESFWFRSVPliAATSMLITQGLISKGILSSHPKYGSIPKlILACIMGYFAGKLSYVKTCQEKFKKLENSP GE
ALRSGQARRSSPPGHYYQKSKYDSSVSGQSSFVTSFAADNIEMLPHYEPIPFSSSMNESAPTGITDHIVQGPDPNLEESPKRKNITYEELRNKNRESYEVSLTQKTDPSVRP
MHERVPKKEVKVNKYGDTWDE
140
GAGCCCCTGTCTGGATGACTTCTTGCGGCTGTTCTACCCCTCCCCCTCCCCGCGGTACCTTGCACTTTTCTCCCTCCCTGCCCCCTCTCGAGTCCACCCTCCGGGCCTTCTG CCCCTGATCGCTTGGTTTTCCTTGCAGTCGCCTGCTGCTGTCGTCGGGAGGAAAGATGAATGGGAGGGCTGA'ITTTCGAGAGCCGAATGCAGAGGTTCCAAGACCAATTCCC CACATAGGGCCTGATTACATTCCAACAGAGGAAGAAAGGAGAGTCTTCGCAGAATGCAATGATGAAAGCTTCTGGTTCAGATCTGTGCCTTTGGCIGCAACAAGTATGTTGA TTACTCAAGGATTAATTAGTAAAGGAATACTTTCAAGTCATCCCAAATATGGTTCCATCCCTAAACTTATACITGCTTGTATCATGGGATACTTTGCTGGAAAACTTTCTTA TGTGAAAACTTGCCAAGAGAAATTCAAGAAACTTGAAAATTCCCCCCTTGGAGAAGCTTTACGATCAGGACAAGCACGACGATCTTCACCACCTGGGCACTATTATCAAAAG TCAAAATATGACTCAAGTGTGAGTGGTCAATCATCTTTTGTGACATCCCCAGCAGCAGACAACATAGAAATGCTTCCTCATTATGAGCCAATTCCATTCAGTTCTTCTATGA ATGAATCTGCTCCCACTGGTATTACTGATCATATTGTCCAAGGACCTGATCCCAACCTTGAAGAAAGTCCTAAAAGAAAAAATATTACATATGAGGAATTAAGGAATAAGAA CAGAGAGTCATATGAAGrATCTTTAACACAAAAGACTGACCCCTCAGTCAGGCCTATGCATGAAAGAGTGCCAAAAAAAGAAGTCAAAGTAAACAAGTATGGAGATACTTGG GATGAGTGAAAAATTACATCATTGGACATGAAGGAGTTTCAACATCCAGCTTCATCTAGGTGGTCATGATTACCTGCATGCTTTGAGCTCAGCAGCAGTCTTCATAAACACA TTTAAAACAAGATCCTGGGTTTTTGTGGTTTGACTTCTATGGTGTTTTAAAAAAACACAGATTTTTAGTGTTAATATTGTGTAAATGTACTCACCTTAGGGATTCATTTGAA TGATGGTATTATACCATGATTGTATACAGTTTGTGAAATTGTTGCAAGGGCAAAGATAACTCTTAAAAAACCGTCGAGATTACAATGCTCTAGAATCAGCATATAAGAAAAT AAATGATATCTGCATGTrGAATTGGGGTGGATGGGGGGAGCAAGCATAATTTTTAAGTGTGAAGCTTTGCATCAAGAAATTATTAAAAAGCTTTTTTTCTCCAGTATTTTCT GTATTATCTTAATGTTTATGGCAAATAAAATGTAAAGGAACATGCCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
141
IRHERVATSSASGRLPRNARRRGRAI-ARSRRERPRCGAGQGSREAGPARACPCRAGTPSTMSSPASTP8RRG8RRGRATPAQTPR8EDARSSPSQRRRGEDSTSTGELQPMP TSPGVDLQSTAAQDVLFSSPPQMHSSAIPLDFDVSSPLTYGTPSSRVEGTPRSGVRGTPVRQRPDLGSAQKGLQVDLQSDGAAAEDIVASEQSLGQKLVI GTDVNVAACKE NFQRFLQRFIDPLAKEEENVGIDITEPLYMQR GEINVIGEQFLNVNCEHIKSFDKNLYRQLISYPQEVIPTFDMAV EIFFDRYPDSILEHQIQVRPFNALKTKNMRNLNP EDIDQLITISGMVIRTSQLIPEMQEAFFQCQVCAHTTRVEMDRGRIAEPSVCGRCHTTHSMALIHNRSLFSDKQMIKLQESPEDMPAGQTPHTVILFAHND VDKVQPGDRV NVTGIYPAVPIRVNPRVSNOTCSVYKTHIDVIHYRKTDAKRLHGIiDEEAEQKLFSEKRVELLKELSRKPDIYERLASALAPSIYEHEDIKKGILLQLFGGTRKDFSHTGRGKF RAEINILLCGDPGTSKSQLLQYVYNLVPRGQYTSGKGSSAVGLTAYVMKDPETRQLVLQTGALVLΞDNGICCIDEFDKMNESTRSVLHEVMEQQTLSIAKAGIICQL ARTS VIJVAANPIESQWNPKKrTIENIQLPHTLLSRFDLIFLMLDPQDEAYDRRLAHHLVALYYQSEΞQAEEELLDMAVLKDYIAYAHSTIMPRL8EEASQALIEAYVDMRKIGSSR GMVSAYPRQ ESLIRIAEAHAKVRLSNKVEAIDVEEAKRLHREA KQSATDPRTGIVDISILTTGMSATSRKRKEELAEALKK ILSKGKTPALKYQQLFEDIRGQSDIAIT KDMFEEALRALADDDFLTVTGKTVRL
142
CGCTGGCCGATCCCGGCCCGGATGCGCATGTTCGACTGGCTCAAGCGCTATCACGAATGCGGCAATCCCTGCCAGACCTGCGCCCGGCAATGTCCGGTCCAGTCGATCCATC CGACGGGCGAGATCAACCCCAACGAATGCATCAACTGCCTGCATTGCCAGGTGCTCTACCAGTCCGAAACCACCTGCCCGGTGGTCATCAAGAAGTTGAAGCGGCGCGAGGC CGTGGCCGCCGGCAGCARGCCCAAGCTGGGCCAGCCACCGGCCGGCCATCCCAACGCCGGCCCGCAAGATTGAAGCTTAACCAGAAGGAGTTCGATCATGGAATCGAAACAG GAAAAGGGTCTCAGCCSCCGCGCGCTTTTGGGCGCGACAGCCGGGGGCGCGGCCGTGGCCGGCGCGTTCGGCGGACGGCTGGCGCTGGGGCCGGCGGCGCTCGGCCTGGGCA CGGCGGGGGTCGCGACCGΓCGCCGGCAGTGGTGCGGCGCTGGCCGCCAGCGGCGACGGCTCGGTCGCGCCGGGGCAACTGGACGACTACTACGGCTTCTGGTCCTCGGGCCA GAGCGGCGAGATGCGCATCCTTGGCATTCCCTCGATGCGCGAGCTGATGCGGGTTCCGGTCTTCAACCGCTGCTCGGCCACCGGCTGGGGCCAGACCAACGAATCCGTGCGC ATCCATGAGCGCACCATGAGCGAGCGGACGAAGAAGTTCCTTGCCGCCAATGGCAAGCGCATCCACGACAACGGCGACCTGCACCACGTCCACATGTCCTTTACCGAGGGCA AATATGACGGCCGCTTCCRGRTCATGAACGACAAGGCCAATACCCGCGTGGCGCGGGTGCGCTGCGACGTGATGAAATGCGACGCCATCCTGGAGATCCCCAACGCCAAGGG CATCCACGGCCTGCGGCCGCAGAAATGGCCGCGCAGCAACTATGTCTTCTGCAATGGCGAGGACEAGACGCCGCTGGTCAACGACGGCACCAACATGGAGGACGTGGCGAAT TACGTGAACGTCTTCACCGCCGTCGATGCCGACAAGTGGGAGGTCGCCTGGCAGGTGCTCGTCTCGGGCAACCTGGACAACTGCGATGCCGATTACGAGGGCAAATGGGCCT TTTCGACCTCCTACAACTCGGAAAAGGGGATGACCCTGCCCGAGATGACGGCGGCCGAGATGGACCATATCGTCGTCTTCAACATCGCCGAGATCGAAAAGGCCATCGCTGC CGGCGACTATCAGGAACTGAACGGCGTCAAGGTCGTGGATGGCCGGAAAGAGGCAAGCAGCCTGTTCACCCGCTATATCCCCATCGCCAACAACCCGCATGGCTGCAACATG GCGCCGGACAAGAAGCACCTGΓGCGTCGCGGGCAAGCTGTCGCCCACGGCGACGGTGCTGGACG GACCCGGTTCGACGCGGTGTTCTATGAGAACGCCGATCCGCGCAGCG CCGTGGTGGCCGAGCCGGAACΓGGGCCTTGGCCCGCTGCACACCGCCTTCGACGGGCGCGGCAACGCCTATACCTCGCTATTCCTCGACAGCCAGGTGGTCAAGTGGAACAT CGAGGATGCCATCCGCGCCTAΓGCCGGCGAGAAGGTCGACCCGATCAAGGACAAGCTGGACGTGCATTACCAGCCCGGCCACCTCAAGACCGTGATGGGCGAGACGCTGGAC GCCACCAACGACTGGCRGGTCRGCCTGTCCAAGTTCTCGAAGGACCGCTTCCTGAACGTCGGGCCGCTGAAGCCGGAGAACGACCAGCTGATCGACATCTCGGGCGACAAGA TGGTGCTGGTCCATGACGGCCCCACCTTTGCCGAGCCGCACGACGCCATCGCCGTGCACCCCTCGATCCTGTCCGACATCAAGTCGGTCTGGGACCGCAACGACCCGATGTG GGCCGAGACCCGCGCΓCAGGCCGAGGCCGATGGCGTCGACATCGACAACTGGACCGAAGAGGTGATCCGCGACGGCAACAAGGTGCGGGTCTACATGTCCAGCGTGGCGCCG GCTTCTCGATCGAGAGCTTTACCGTCAAGGAGGGCGACGAGGTCACGGTGATCGTCACCAACCTGGACGAGATCGACGATCTGACGCATGGCTTCACCATGGGCAACTACG GCGTCGCCATGGAGARCGGGCCGCAGATGACCAGCTCGGTCACCTTCGTCGCCGCCAATCCCGGGGTCTATTGGTATTATTGCCAATGGTTCTGCCATGCGCTGCACATGGA GATGCGCGGCCGCATGCΓGGTCGAGCCGAAGGAGGCCTGAGTCCCATGCGCAGCCTGCTGACCCCTGTCCTCGCCCTTCTGCTTGCCTGGCCCGCGCTTGCGGTCGGAGGCA ATGCCGTGGCGCCGGGCGAGGGCAGCCTTGCCGATGCCACΓGGGCTGCCCCGGCGATGTGCTGCG
143
MAPTIQTQAQREDGHRPNSHRTLPERSGWCRVKYCNSLPDIPFDPKFITYPFDQNRFVQYKATSLEKQHKHDLLTEPDLGVTIDLINPDTYRIDPNVLLDPADEKLLEEEI
QAPTSSKRSQQHAKVVP MRKTEYISTEFNRYGISrffiKPEVKIGVSVKQQFTEEEIYKDRDSQITAIEKTFEDAQKSISQHYSKPRVTPVEVMPVFPDFKM INPCAQVIFD
SDPAPKOTSGAAALEIWSQAMIRGMIrøEEGNQFVAYFLPVEETLKKRKKDQEEEMDYAPDDVYDYKIAREYN^
AKAGVQSGTNALLWKHRD NEKELEAQEARKAQLENHEPEEEEEEEMETEEKEAGGSDEEQEKGSSSEKEGSEDEHSGSESEREEGDRDEASDKSGSGEDESSEDEARAAR
DKEEI FGSDADSEDDADSDDEDRGQAQGGSDNDSDSGSNGGGQRSRSHSRSASPFPSGSEHSAQEDGSEAAASDSSEADSDSD
144
AGTTGGTGGAACCGGAGCTΓCGAGTCCGTCCCCGGTGCΓGCCΓGCGCGTTCACCTGAGΓCTCGCTGGAGCTCTTCTCGCCCGCCCACCTCATCTCAACCCACTTTCCGCGGG GAGCGGCGCCAAGCTGGGCCRTCCTCGGATCAGGA3TCCCCRGAAGTCGGCACGCCCCRCTGCGTCCCCCTTCGGTCCCGCTAGGACCCCGTCCGGGCTGCCGTCGCCTCGT CGCTATGGCGCCCACCATCCAGACCCAGGCCCAGCGGGAGGATGGCCACAGGCCCAATRCCCACCGGACTCTGCCTGAGAGGTCTGGAGTGGTCTGCCGAGTCAAGTACTGC AATAGCCTCCCTGAΓAΓCCCCTTCGACCCCAAGTTCAΓCACCTACCCCTTCGACCAGAACAGGATCGTCCAGTACAAAGCCACTTCCTTGGAGAAACAGCACAAACATGACC TCCTGACTGAGCCAGACCTGGGGGTCACCATCGATCTCATCAATCCTGACACCTACCGCATCGACCCCAATGTTCTTCTAGATCCAGCTGATGAGAAACTTT GGAAGAGGA GATTCAGGCCCCCACCAGCΓCCAAGAGATCCCAGCAGCACGCGAAGGTGGTGCCATGGATGCGAAAGACAGAGTACATCTCCACTGAGTTCAACCGTTATGGCATCTCCAAT GAGAAGCCTGGGGTCAAGATTGGGGTTTCTGTGAAGCAGCAGTTTACCGAGGAAGAAATATACAAAGACAGGGATAGCCAGATCACAGCCATTGAGAAGACTTTTGAGGATG CCCAGAAATCAATCTCACAGCATTACAGCAAACCCCGAGTCACACCGGTGGAGGTCATGCCTGTCTTCCCAGACTTTAAGATGTGGATCAATCCATGTGCTCAGGTGATCTT TGACTCAGACCCAGCCCCCAAGGACACGAGTGGTGCAGCTGCGTTGGAGATGATGTCTCAGGCCATGATTAGGGGCATGATGGATGAGGAAGGGAACCAGTTTGTGGCCTAT TTCCTGCCTGTAGAAGAGACGTTGAAGAAACGAAAGCGGGACCAGGAGGAGGAGATGGACTATGCACCAGATGATGTGTATGACTACAAAATTGCTCGGGAGTACAACTGGA ACGTGAAGAACAAAGCTAGCAAGGGCTATGAGGAAAACTACTTCTTCATCTTCCGAGAGGGTGACGGGGTTTACTACAATGAGTTGGAAACCAGGGTCCGCCTTAGTAAGCG CCGGGCCAAGGCTGGGGTTCAGTCAGGCACCAACGCCCTGCTTGTGGTCAAACATCGAGACATGAATGAGAAGGAACTGGAAGCTCAGGAGGCACGGAAGGCCCAGCTAGAA AACCACGAACCGGAGGGGGAAGAGGAAGAGGAGATGGAGACAGAAGAGAAAGAAGCTGGGGGCTCAGATGAGGAGCAGGAGAAGGGCAGCAGCAGTGAGAAGGAGGGCAGTG AAGATGAGCACTCGGGCAGCGAGAGTGAACGGGAGGAAGGTGACAGGGACGAGGCCAGTGACAAGAGTGGTAGTGGTGAGGACGAGAGCAGCGAGGATGAGGCCCGGGCTGC CCGTGACAAAGAGGAGATCTTTGGCAGTGATGCTGATTCTGAGGACGATGCCGACTCTGATGATGAGGACAGAGGACAGGCCCAAGGTGGCAGTGACAATGATTCAGACAGC GGCAGCAATGGGGGTGGCCAGCGGAGCCGGAGCCACAGCCGCAGCGCCAGTCCCTTCCCCAGTGGCAGCGAGCACTCGGCCCAGGAGGATGGCAGTGAAGCTGCAGCTTCTG ATTCCAGTGAAGCTGATAGTGACAGTGACTGAGTCCCAGGGCATTCAGGGCTGGTTCAGACACCATTATTGTGAGCAGCAAAGCACTTTTCTAGTGGTCTGTTTGTGAGCCT TTCACTTGTTTGTTCCCCACCCCCAAACCTTTGCTGTTAATAAAGTCAACTTCTCTTTAAAG
145
MIKRF EDTTDDGELSKFVKDFSGNASCHPPEAKTWASRPQVPEPRPQAPDLYDDDLEFRPPΞRPQSSDNQQYFCAPAPLSPΞARPRSPWGKLDPYDSSEDDKEYVGFATLP NQVHRKSVKKGFDFTI-MVAGESGLGKETLVNSLFLTDLYRDRKLLGAEERIMQTVEITKHAVDIEEKGVRLRLTIVDTPGFGDAVNNTECWKPVAEYIDQQFEQYFRDESGL NRKNIQDNRVHCCLYFISPFGHGYGPSLRLLAPPGAVKGTGQEHQGQGCH
146
CGGCGGTGCTGCGAGGTCGGCGCGCACGTCCGCCGCGGGTCGCTCGGGCGCTGTCCAGGCGGAGCCGGCCCCGCCCGGGCTGCAGCCATGATCAAGCGTTTCCTGGAGGACA
CCACGGATGATGGAGAACTGAGCAAGTTCGTGAAGGATTTCTCAGGAAATGCGAGCTGCCACCCACCAGAGGCTAAGACCTGGGCATCCAGGCCCCAAGTCCCGGAGCCAAG
GCCCCAGGCCCCGGACCTCTATGATGATGACCTGGAGTTCAGACCCCCCTCGCGGCCCCAGTCCTCTGACAACCAGCAGTACTTCTGTGCCCCAGCCCCTCTCAGCCCATCT
GCCAGGCCCCGCAGCCCATGGGGCAAGCTTGATCCCTATGATTCCTCTGAGGATGACAAGGAGTATGTGGGCTTTGCAACCCTCCCCAACCAAGTCCACCGAAAGTCCGTGA
AGAAAGGCTTTGACTTTACCCTCATGGTGGCAGGAGAGTCTGGCCTGGGCAAATCCACACTTGTCAATAGCCTCT'ICCTCACTGATCTGTACCGGGACCGGAAACTTCTTGG
TGCTGAAGAGAGGATCATGCAAACTGTGGAGATCACTAAGCATGCAGTGGACATAGAAGAGAAGGGTGTGAGGCTGCGGCTCACCATTGTGGACACACCAGGTTTTGGGGAT
GCAGTCAACAACACAGAGTGCTGGAAGCCTGTGGCAGAATACATTGATCAGCAGTTTGAGCAGTATTTCCGAGACGAGAGTGGCCTGAACCGAAAGAACATCCAAGACAACA
GGGTGCACTGCTGCCTGTACTTCATCTCACCCTTCGGCCATGGGTATGGTCCAAGCCTGAGGCTCCTGGCACCACCGGGTGCTGTCAAGGGAACAGGCCAAGAGCACCAGGG
GCAGGGCTGCCACTAGCAGGTGGTCACAGGTTCCTGTTCCCCAGGCTCCGGCCATTGGATGTTGAATTCATGAAGGCCCTGCATCAGCGGGTCAACATCGTGCCTATCCTGG
CTAAGGCAGACACACTGACACCTCCCGAAGTGGACCACAAGAAACGCAAAATCCGGGAGGAGATTGAGCATT'rTGGAATCAAGATCTATCAATTCCCAGACTGTGACTCTGA
TGAGGATGAGGACTTCAAATTGCAGGACCAAGCCCTAAAGGAAAGCATCCCATTTGCAGTAATTGGCAGCAACACTGTAGTAGAGGCCAGAGGGCGGCGAGTTCGGGGTCGA
CTCTACCCCTGGGGCATCGTGGAAGTGGAAAACCCAGGGCACTGCGACTTTGTGAAGCTGAGGACAATGCTGGTACGTACCCACATGCAGGACCTGAAGGATGTGACACGGG
AGACACATTATGAGAACTACCGGGCACAGTGCATCCAGAGCATGACCCGCCTGGTGGTGAAGGAACGGAATCGCAAGTATGACCAGAAGCCAGGACAAAGCTGGCAGGGGGA
GATCCCAAGCCTAGCCTTGGGTGAGACCAAGCCCTACTTTTGTTCTTCTATAGGCCCTGGGCTCAATCTAAGCGGGTGCTGGGGTCCTCCTCGCCTTATCAACCCTTTTCTC
CCTTTAGCAAACTGACTCGGGAAAGTGGTACCGACT CCCCATCCCTGCTGTCCCACCAGGGACAGATCCAGAAACTGAGAAGCTTATCCGAGAGAAAGATGAGGAGCTGCG
GCGGATGCAGGAGATGCTACACAAAATACAAAAACAGATGAAGGAGAACTATTAACTGGCTTTCAGCCCTGGATATTTAAATCTCCTCCTCTTCTTCCTGTCCATGCCGGCC
CCTCCCAGCACCAGCTCTGCTCAGGCCCCTTCAGCTACTGCCACTTCGCCTTACATCCCTGCTGACTGCCCAGAGACTCAGAGGAAATAAAGTTTAATAAATCTGTAGGTGG
CTAAAAA
147
MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISL.IFSLKEEVGALAKVLRLFEENDVNLTHIESRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHE
148
CAGCTGGGGGTAAGGGGGGCGGATTATTCATATAATTGTTATACCAGACGGTCGCAGGCTTAGTCCAATTGCAGAGAACTCGCTTCCCAGGCTTCTGAGAGTCCCGGAAGTG CCT AACCTGTCTAATCGACGGGGCTTGGGTGGCCCGTCGCTCCCTGGCTTCTTCCCTTTACCCAGGGCGGGCAGCGAAGTGGTGCCTCCTGCGTCCCCCACACCCTCCCTC AGCCCCTCCCCTCCGGCCCGTCCTGGGCAGGTGACCTGGAGCATCCGGCAGGCTGCCCTGGCCTCCTGCGTCAGGACAAGCCCACGAGGGGCGTTACTGTGCGGAGATGCAC CACGCAAGAGACACCCTTTGTAACTCTCTTCTCCTCCCTAGTGCGAGGTTAAAACCTTCAGCCCCACGTGCTGTT'IGCAAACCTGCCTGTACCTGAGGCCCTAAAAAGCCAG AGACCTCACTCCCGGGGAGCCAGCATGTCCACTGCGGTCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGGACAGGAAACAAGCTATATTGAAGACAACTGCA ATCAAAATGGTGCCATATCACTGATCTTCTCACTCAAAGAAGAAGTTGGTGCATTGGCCAAAGTATTGCGCTTATT'IGAGGAGAATGATGTAAACCTGACCCACATTGAATC TAGACCTTCTCGTTTAAAGAAAGATGAGTATGAATTTTTCACCCATTTGGATAAACGTAGCCTGCCTGCTCTGACAAACATCATCAAGATCTTGAGGCATGACATTGGTGCC ACTGTCCATGAGCTTTCACGAGATAAGAAGAAAGACACAGTGCCCTGGTTCCCAAGAACCATTCAAGAGCTGGACAGATTTGCCAATCAGATTCTCAGCTATGGAGCGGAAC TGGATGCTGACCACCCTGGTTTTAAAGATCCTGTGTACCGTGCAAGACGGAAGCAGTTTGCTGACATTGCCTACAACTACCGCCATGGGCAGCCCATCCCTCGAGTGGAATA CATGGAGGAAGAAAAGAAAACATGGGGCACAGTGTTCAAGACTCTGAAGTCCTTGTATAAAACCCATGCTTGCTATGAGTACAATCACATTTTTCCACTTCTTGAAAAGTAC TGTGGCTTCCATGAAGATAACATTCCCCAGCTGGAAGACGTTTCTCAATTCCTGCAGACTTGCACTGGTTTCCGCCTCCGACCTGTGGCTGGCCTGCT'ITCCTCTCGGGATT TCTTGGGTGGCCTGGCCTTCCGAGTCTTCCACTGCACACAGTACATCAGACATGGATCCAAGCCCATGTATACCCCCGAΔCCTGACATCTGCCATGAGCTGTTGGGACATGT GCCCTTGTTTTCAGATCGCAGCTTTGCCCAGTTTTCCCAGGAAATTGGCCTTGCCTCTCTGGGTGCACCTGATGAA1ACATTGAAAAGCTCGCCACAATTTACTGGTTTACT GTGGAGTTTGGGCTCTGCAAACAAGGAGACTCCATAAAGGCATATGGTGCTGGGCTCCTGTCATCCTTTGGTGAATTACAGTACTGCTTATCAGAGAAGCCAAAGCTTCTCC CCCTGGAGCTGGAGAAGACAGCCATCCAAAATTACACTGTCACGGAGTTCCAGCCCCTGTATTACGTGGCAGAGAGTTTTAATGATGCCAAGGAGAAAGTAAGGAACTTTGC TGCCACAATACCTCGGCCCTTCTCAGTTCGCTACGACCCATACACCCAAAGGATTGAGGTCTTGGACAATACCCAGCAGCTTAAGATTTTGGCTGATTCCATTAACAGTGAA ATTGGAATCCTTTGCAGTGCCCTCCAGAAAATAAAGTAAAGCCATGGACAGAATGTGGTCTGTCAGCTGTGAATCTGTTGATGGAGATCCAACTATTTCTTTCATCAGAAAA AGTCCGAAAAGCAAACCTTAATTTGAAATAACAGCCTTAAATCCTTTACAAGATGGAGAAACAACAAATAAGTCAAAATAATCTGAAATGACAGGATATGAGTACATACTCA AGAGCATAATGGTAAATCTTTTGGGGTCATCTTTGATTTAGAGATGATAATCCCATACTCTCAATTGAGTTAAATCAGTAATCTGTCGCATTTCATCAAGATTAATTAAAAT TTGGGACCTGCTTCATTCAAGCTTCATATATGCTTTGCAGAGAACTCATAAAGGAGCATATAAGGCTAAA'ΓGTAAAACACAAGACTGTCATTAGAATTGAATTATTGGGCTT AATAΓAAATCGTAACCTATGAAGTTTATTTTCTATTTTAGTTAACTATGATTCCAATTACTACTTTGTTATTGTACCTAAGTAAATTTTCTTTAGGTCAGAAGCCCATTAAA ATAGTTACAAGCATTGAACTTCTTTAGTATTATATTAATATAAAAACATTTTTGTATGTTTTATTGTAATCATAAATACTGCTGTATAAGGTAATAAAACTCTGCACCTAAT CCCCATAACTTCCAGTATCATTTTCCAATTAATTATCAAGTCTGT TTGGGAAACACTTTGAGGACATTTATGATGCAGCAGATGTTGACTAAAGGCTTGGTTGGTAGATAT CAGGAAATGTTCACTGAATAAATAAGTAAATACAT ATTGAAAAGCAAATCTGTATAAATGTGAAATTTTTATTTGTATTAGTAATAAAACATTAGTAGTTTA
149
MALFGA FLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQE ETITIPDLRGKEGHFYYNISEVKVTELQLTSSELDFQPQQE MLQITNASLGLRFRRQLLYWFFYD GGYINASAEGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRFLLNQQICPVLYHAGTVLLNS DTVPVRSSVDELVGIDYS MKDPV ASTSN D^ROFRΣAFF LTERNWS PNRAVEPQ QEEERM YVAFSEFFFDSAMESYFRAGA QL LVGDKVPHDLDMLLRATYFGSIVL SPA IDSPLK ELRVLAPPRCT IKPSGTTISVTASVTIALVPPDQPEVQLSSTCTMDAPXSAKMALRGKALRTQLDLRRFTLIYSNHSALESTJΛIPLQAPLKTMLQIGVMPMLNERTWRGVQIPLPEGINFVHEV VTNHAGFLTIGADLHFAKGLREVIEKNRPADVRASTAPTPSTAAV
ISO
GTGGCCGCCGTCGCCCGGATCCCCTGAGCTGCCCGCCATCCCACGTGACCGCGCCGCCCCCCAGCTCCACCGCTGAGCCCGCTCGCCATGGCCCTCTTCGGGGCCCTCTTCC TAGCGCTGCTGGCAGGCGCACATGCAGAGTTCCCAGGCTGCAAGATCCGCGTCACCTCCAAGGCGCTGGAGCTGGTGAAGCAGGAGGGGCTGCGCTTTCTGGAGCAAGAGCT GGAGACTATCACCATTCCGGACCTGCGGGGCAAAGAAGGCCACTTCTACTACAACATCTCTGAGGTGAAGGTCACAGAGCTGCAACTGACATCTTCCGAGCTCGATTTCCAG CCACAGCAGGAGCTGATGCTTCAAATCACCAATGCCTCCTTGGGGCTGCGCTTCCGGAGACAGCTGCTCTACTGGTTCTTCTATGATGGGGGCTACATCAACGCCTCAGCTG AGGGΓGTGTCCATCCGCACTGGTCTGGAGCTCTCCCGGGATCCCGCTGGACGGATGAAAGTGTCCAATGTCTCCTGCCAGGCCTCTGTCTCCAGAATGCACGCGGCCTTCGG GGGAACCTTCAAGAAGGTGTATGATTTTCTCTCCACGTTCATCACCTCAGGGATGCGCTTCCTCCTCAACCAGCAGATCTGCCCTGTCCTCTACCACGCAGGGACGGTCCTG CTCAACTCCCTCCTGGACAC 3TGCCTGTGCGCAGTTCTGTGGACGAGCTTGTTGGCATTGACTATTCCCTCATGAAGGATCCTGTGGCTTCCACCAGCAACCTGGACATGG ACΓTCCGGGGGGCCTTCTTCCCCCTGACTGAGAGGAACTGGAGCCTCCCCAACCGGGCAGTGGAGCCCCAGCTGCAGGAGGAAGAGCGGATGGTGTATGTGGCCTTCTCTGA GTΓCTTCTTCGACTCTGCCATGGAGAGCTACTTCCGGGCGGGGGCCCTGCAGCTGTTGCTGGTGGGGGACAAGGTGCCCCACGACCTGGACATGCTGCTGAGGGCCACCTAC TTRGGGAGCATTGTCCTGCTGAGCCCAGCAGTGATTGACTCCCCATTGAAGCTGGAGCTGCGGGTCCTGGCCCCACCGCGCTGCACCATCAAGCCC-RCTGGCACCACCATCT CTGTCACTGCTAGCGTCACCATTGCCCTGGTCCCACCAGACCAGCCTGAGGTCCAGCTGTCCAGCATGACTATGGACGCCCGTCTCAGCGCCAAGATGGCTCTCCGGGGGAA GGCCCTGCGCACGCAGCTGGACCTGCGCAGGTTCCGAATCTATTCCAACCATTCTGCACTGGAGTCGCTGGCTCTGATCCCATTACAGGCCCCTCTGAAGACCATGCTGCAG ATTGGGGTGATGCCCAΓGCTCAATGAGCGGACCTGGCGTGGGGTGCAGATCCCACTACCTGAGGGCATCAACTTTGTGCATGAGGTGGTGACGAACCATGCGGGATTCCTCA CCATCGGGGCTGATCTCCACTTTGCCAAAGGGCTGCGAGAGGTGATTGAGAAGAACCGGCCTGCTGATGTCAGGGCGTCCACTGCCCCCACACCGTCCACAGCAGCTGTCTG AGCCCTCAATCCCCAAGCTGGCAGCTGTCATTCAGGACCCCAACCCCTCTCAGCCCC CTTTTCCCACATTCATAGCCTGTAGTGCCCCCTCTAACCCCCAGTGCCACAGAG AAGACGGGATTTGAAGCTGTACCCAATTTAATTCCATAATCAATCTATCAATTACAGTCCGTCCACCACC
151
MDAFKGGMSLERLPEGFRPPPPPPHDMGPAFHLARPADPREP EMSASESSDTELPEKERGGEPKGPEDSGAGGTGCGGADDPA KKQRRQRTHFTSQQLQELEATFQRNR YPDMSMREEIAVWTNLΓEPRVRV FKNRRAK RKRER QQLD CKGGYVPQFSGLVQPYEDVYAAGYSYNMWAAKSLAPAPLSTKSFTFFNSMSPLSSQSMFSAPSSISSMT MPSSMGPGAVPGMPNSGLNNINNLTGSS NSAMSPGACPYGRPASPYSVYRDTCNSSLASLRLKSKQHSSFGYGGLOGPASGLNACQYNS
152
GGGAGGGCGGCAGTGAGGGCGCGGCGGCGGGCGGCTTGAGGCTGGATTCCGGCTCCCTCGCTCGCRCGCTCCCTCCCGAGCCCCCTCCCACCCAGGCCCACCCCACCCAGCA CCCCTGGCGCAGGGACΓGCTGGAACCTGGCTGTGCCCGTGΓCGCTTTAAGACAGACTCTGCCGGCGCCGTCCGGAGCCTTAGAAACGGCCCCGGATCGCGAGCCGGAGCCGG AGCCGGAGCCGGAGCCGGAGCCGGGGCCGGCCGGGCTGCTGAGGCCCGAGCGGCAGGAGCGACGCGGAGCGCTGAGCCAGGCGCCCAGTCGCGAGAAGCTGCCGCCGCCTCT GGCCGCCGCCGCAGCCCCGGGGCGGTCCATGGGGCGGGCACCGGCGTCGCTGCAGGCTGTCGGCAGCCTGGAGGGCAGCCGCTTAGCGTGCGCTCTTGTCCCCGCAGGTCGC AGCCAGGGCGGCGGGCGCGCCCAGCCCCGGCCCCTGGAGCGCCCGCCGCGGTCCCCACCTCCARGGACGCCTTCAAGGGGGGCATGAGCCTGGAGCGGCTGCCGGAGGGGCT CCGGCCGCCGCCGCCGCCACCCCATGACATGGGGCCCGCCTRCCACCTGGCCCGGCCCGCCGACCCCCGCGAGCCGCTCGAGAACTCCGCCAGCGAGTCGTCTGACACGGAG CTGCCAGAGAAGGAGCGCGGCGGGGAACCCAAGGGGCCCGAGGACAGTGGTGCGGGAGGCACGGGCTGCGGCGGCGCAGACGACCCAGCCAAGAAGAAGAAGCAGCGGCGGC AACGTACGCACTTCACAAGCCAGCAGTTGCAAGΔGCTAGAGGCCACGTTCCAGAGGAACCGCΓACCCCGACATGAGCATGAGGGAGGAGATCGCCGTGTGGACCAACCTCAC CGAGCCGCGCGTGCGGGTCTGGTTCAAGAACCGGCGAGCCAAGTGGCGTAAGCGCGAGCGTAACCAGCAGCTGGACCTGTGCAAGGGTGGCTACGTGCCGCAGTTCAGCGGC CTAGTGCAGCCCTACGAGGACGTGTACGCCGCCGGCTACΓCCTACAACAACTGGGCCGCCAAGAGCCTGGCGCCAGCGCCGCTCTCCACCAAGAGCTTCACCTTCTTCAACT CCATGAGCCCGCTGTCGTCGCAGTCCATGTTCTCAGCACCCAGCTCCATCTCCTCCATGACCAΓGCCGTCCAGCATGGGCCCAGGCGCCGTGCCTGGCATGCCCAACTCGGG CCTCAACAACATCAACAACCTCACCGGCTCCTCGCTCAACTCGGCCATGTCGCCGGGCGCTTGCCCGTACGGCACTCCCGCCTCGCCCTACAGCGTCTACCGGGACACGTGC AACTCGAGCCTAGCCAGCCTGCGGCTCAAGTCCAAACAGCACTCGTCGTTTGGCTACGGCGGCCTGCAGGGCCCGGCCTCGGGCCTCAACGCGTGCCAGTACAACAGCTGAC
153
MATLIYVDKENGEPGTRVVAKDGL lGSGPSIKALDGRSQVSTPRFGKTFDAPPALiPKATR ALGTVNRATEKSVKTKGPLKQKQPSFSAKKMTEKTVKAKSSVPASDDAYP EIEKFFPFNPLDFESFDLPEEHQIAHLPLSGVPLMILDEERELEK FQLGPPSPVKMPSPP ESNLLQSPSSILSTLDVELPPVCCDIDI
154
GCGGCCTCAGATGAATGCGGCRGTTAAGACCTGCAATAARCCAGAATGGCTACTCTGATCTARGTTGATAAGGAAAATGGAGAACCAGGCACCCGTGTGGTTGCTAAGGATG GGCTGAAGCTGGGGTCTGGACCTTCAATCAAAGCCTTAGATGGGAGATCTCAAGTTTCAACACCACGTTTTGGCAAAACGTTCGATGCCCCACCAGCCTTACCTAAAGCTAC TAGAAAGGCTTTGGGAACTGTCAACAGAGCTACAGAAAAGTCTGTAAAGACCAAGGGACCCCTCAAACAAAAACAGCCAAGCTTTTCTGCCAAAAAGATGACTGAGAAGACT GTTAAAGCAAAAAGCTCTGTTCCTGCCTCAGATGATGCCTATCCAGAAATAGAAAAATTCTTΓCCCTTCAATCCTCTAGACTTTGAGAGTTTTGACCTGCCTGAAGAGCACC AGATTGCGCACCTCCCCTTGAGTGGAGTGCCTCTCATGATCCTTGACGAGGAGAGAGAGCTTGAAAAGCTGTTTCAGCTGGGCCCCCCTTCACCTGTGAAGATGCCCTCTCC ACCATGGGAATCCAATCTGTTGCAGTCTCCTTCAAGCATTCTGTCGACCCTGGATGTTGAATTGCCACCTGTTTGCTGTGACATAGATATTTAAATTTCTTAGTGCTTCAGA GTTTGTGTGTATTTGTAΓTAATAAAGCATTCTTCAACAGAAAAAAAAAAAAAAAAA
155
MASR TLLTLLLLLLAGDRASSNPNATSSSSQDPESLQDRGEGKVATTVISKMLFVEPILEVSSLPTTNSTTNSATKITANTTDEPTTQPTTEPTTQPTIQPTQPTTQ PTD
SPTQPTTGSFCPGPVTLCSDLESHSTEAVLGDALλmFSL LYHAFSAMKKVETN AFSPFSIASLLTQVLLGAGENTKTNLESILSYPKDFTCVHQALKGFTTKGVTSVSQI
FHSPDLAIRDTFVNASRrLYSSSPRVLSNNSDANLELINTVfVAKNTNNKISRL DSLPSDTRLVLLNAIYLSAK KTTFDPKKTRMEPFHFKNSVIKVPMMNSKKYPVAHFI
DQT KAKVGQLQLSHNLSLVI VPQNLKHRLEDMEQALSPεVFKAIMEK EMSKFςPTLLTLPRIKVTTSQDMLSIMEKLEFFDFSYDLNLCGLTEDPDLQVSAMQHQTVLE
LTETGVEAAAASAISVARTLLVFEVQQPFLFVLWDQQHKFPVFMGRVYDPRA
156
AGTCTGCACTGGAGCTGCCTGGTGACCAGAAGTTTGGAGTCCGCTGACGTCGCCGCCCAGATGGCCTCCAGGCTGACCCTGCTGACCCTCCTGCTGCTGCTGCTGGCTGGGG ATAGAGCCTCCTCAAATCCAAATGCTACCAGCTCCAGCTCCCAGGATCCAGAGAGTTTGCAAGACAGAGGCGAAGGGAAGGTCGCAACAACAGTTATCTCCAAGATGCTATT CGTTGAACCCATCCTGGAGGTTTCCAGCTTGCCGACAACCAACTCAACAACCAATTCAGCCACCAAAATAACAGCTAATACCACTGATGAACCCACCACACAACCCACCACA GAGCCCACCACCCAACCCACCATCCAACCCACCCAACCAACTACCCAGCTCCCAACAGATTCΓCCTACCCAGCCCACTACTGGGTCCTTCTGCCCAGGACCTGTTACTCTCT GCTCTGACTTGGAGAGTCATTCAACAGAGGCCGTGTTGGGGGATGCTTTGGTAGATTTCTCCCTGAAGCTCTACCACGCCTTCTCAGCAATGAAGAAGGTGGAGACCAACAT GGCCTTTTCCCCATTCAGCAΓCGCCAGCCTCCTTACCCAGGTCCTGCTCGGGGCTGGGCAGAACACCAAAACAAACCTGGAGAGCATCCTCTCTTACCCCAAGGACTTCACC TGTGTCCACCAGGCCCTGAAGGGCTTCACGACCAAAGGΓGΓCACCTCAGTCTCTCAGATCTTCCACAGCCCAGACCTGGCCATAAGGGACACCTTTGTGAATGCCTCTCGGA CCCTGTACAGCAGCAGCCCCAGAGTCCTAAGCAACAACAGRGACGCCAACTTGGAGCTCATCAACACCTGGGTGGCCAAGAACACCAACAACAAGATCAGCCGGCTGCTAGA CAGTCTGCCCTCCGARACCCGCCTTGTCCTCCTCAATGCTATCTACCTGAGTGCCAAGTGGAAGACAACATTTGATCCCAAGAAAACCAGAATGGAACCCTTTCACTTCAAA AACTCAGTTATAAAAGTGCCCATGATGAATAGCAAGAAGTACCCTGTGGCCCATTTCATTGACCAAACTTTGAAAGCCAAGGTGGGGCAGCTGCAGCTCTCCCACAATCTGA GTTTGGTAATCCTGGTACCCCAGAACCTGAAACATCGTCTRGAAGACATGGAACAGGCTCTCAGCCCTTCTGTTTTCAAGGCCATCATGGAGAAACTGGAGATGTCCAAGTT CCAGCCCACTCTCCTAACACΓACCCCGCATCAAAGTGACGACCAGCCAGGATATGCTCTCAAΓCATGGAGAAATTGGAATTCTTCGATTTTTCTTATGACCTTAACCTGTGT GGGCTGACAGAGGACCCAGARCTTCAGGTTTCTGCGATGCAGCACCAGACAGTGCTGGAACRGACAGAGACTGGGGTGGAGGCGGCTGCAGCCTCCGCCATCTCTGTGGCCC GCACCCTGCTGGTCTTTGAAGTGCAGCAGCCCTTCCTCTTCGΓGCTCTGGGACCAGCAGCACAAGTTCCCTGTCTTCATGGGGCGAGTATATGACCCCAGGGCCTGAGACCT GCAGGATCAGGTTAGGGCGAGCGCTACCTCTCCAGCCTCAGCΓCTCAGTTGCAGCCCTGCTGCTGCCTGCCTGGACTTGCCCCTGCCACCTCCTGCCTCAGGTGTCCGCTAT CCACCAAAAGGGCTCCTGAGGGTCTGGGCAAGGGACCTGCΓTCTATTAGCCCTTCTCCATGGCCCTGCCATGCTCTCCAAACCACTTTTTGCAGCTTTCTCTAGTTCAAGTT CACCAGACTCTATAAATAAAACCTGACAGACCAT
157
MEDLCVANT FAL π-FKH AKAS■PTQNLFLSP SISS^MA^WYMGSRGSTEDQM KVLQFNEVGA AVTPM PE FTSCGFMQQIQKGSYPDAI QAQAADKIHSSFRSLSS
AINASTGNYLLESVNK FGEKSASFREEYIRLCQ YYSSEPQAVDFLECAEEARKKINSWVKTQTKGKIPNLLPEGSVDGDTRMVLVNAVYFKGKWKTPFEKK NGLYPFRV
NSAQRTPVQMMYL,REKL,NIGYIEDLKAQILELPYAGDVSMF LPDEIADVSTGLELLESEITYDKLNKWTSKDKMAEDEVEVYIPQFKLEEHYELRSILRSMGMEDAFNKG
RANFSGMSER D F SEVFHQAMVDVNEEGTEAAAGTGGVMTGRTGHGGPQFVADHPF F IMHKITNCILFFGRFSSP
158
ACAACTCTCAGAGGAGCARRGCCCGTCAGACAGCAACRCAGAGAATAACCAGAGAACAACCAGATTGAAACAATGGAGGATCTTTGTGTGGCAAACACACTCTTTGCCCTCA ATTTATTCAAGCATCTGGCAAAAGCAAGCCCCACCCAGAACCTCTTCCTCTCCCCATGGAGCATCTCGTCCACCATGGCCATGGTCTACATGGGCTCSRAGGGGCAGCACCGA AGACCAGATGGCCAAGGRGCTTCAGTTTAATGAAGTGGGAGCCAATGCAGTTACCCCCARGACTCCAGAGAACTTTACCAGCTGTGGGTTCATGCAGCAGATCCAGAAGGGT AGTTATCCTGATGCGATΓΓΓGCAGGCACAAGCTGCAGAΓAAAATCCATTCATCCTTCCGCΓCTCTCAGCTCTGCAATCAATGCATCCACAGGGAATTATTTACTGGAAAGTG TCAATAAGCTGTTTGGTGAGAAGTCTGCGAGCTTCCGGGAAGAATATATTCGACTCTGRCAGAAATATTACTCCTCAGAACCCCAGGCAGTAGACTTCCTAGAATGTGCAGA AGAAGCTAGAAAAAAGARRAARTCCTGGGTCAAGACTCAAACCAAAGGCAAAATCCCAAACTTGTTACCTGAAGGTTCTGTAGATGGGGATACCAGGATGGTCCTGGTGAAT GCTGTCTACTTCAAAGGAAAGRGGAAAACTCCATTTGAGAAGAAACTAAATGGGCTTRARCCTTTCCGTGTAAACTCGGCTCAGCGCACACCTGTACAGATGATGTACTTGC GTGAAAAGCTAAACAΓTGGATACATAGAAGACCTAAAGGCTCAGATTCTAGAACTCCCAΓATGCTGGAGATGTTAGCATGTTCTTGTTGCTTCCAGATGAAATTGCCGATGT GTCCACTGGCTTGGAGCRGCTΒGAAAGTGAAATAACCTATGACAAACTCAACAAGTGGACCAGCAAAGACAAAATGGCTGAAGATGAAGTTGAGGTATACATACCCCAGTTC AAATTAGAAGAGCATRATGAACTCAGATCCATTCTGAGAAGCARGGGCATGGAGGACGCCRTCAACAAGGGACGGGCCAATTTCTCAGGGATGTCGGAGAGGAATGACCTGT TTCTTTCTGAAGTGTRCCACCAAGCCATGGTGGATGTGAATGAGGAGGGCACTGAAGCAGCCGCTGGCACAGGAGGTGTTATGACAGGGAGAACTGGACATGGAGGCCCACA GTTTGTGGCAGATCAΓCCΓTTTCΓTTTTCTTΆTTATGCATAAGATAACCAACTGCATΓΓΓATTTTTOJGCAGATTTTCCTCACCCTAAAACTAAGCGTGCTGCTTCTGCAAA AGATTTTTGTAGATGAGCRGTGTGCCTCAGAATTGCTARTTCAAATTGCCAAAAATTRAGAGATGTTTTCTACATATTTCTGCTCTTCTGAACAACTTCTGCTACCCACTAA ATAAAAACACAGAAATAATTAGACAATTGTCTATTATAACATGACAACCCTATTAATCATTTGGTCTTCTAAAATGGGATCATGCCCATTTAGATTTTCCTTACTATCAGTT TATTTTTATAACATTAACTTTTACTTTGTTATTTATTAΓTTTATATAATGGTGAGTTTTTAAATTATTGCTCACTGCCTATTTAATGTAGCTAATAAAGTTATAGAAGCAGA TGATCTGTTAATTTCCTATCTAATAAATGCCTTTAATTGΓTCΓCATAATGAAGAATAAGTAGGTACCCTCCATGCCCTTCTGTAATAAATATCTGGAAAAAACATTAAACAA TAGGCAAATATATGTTATGTGCATTTCTAGAAATACATAACACATATATATGTCTGTATCTTATATTCAATTGCAAGTATATAATAAATAAACCTGCTTCCAAACAAC
159
MRRAPAAERLLELGFPPRCGRQEPPFP GVTRGWGRWPIQ RREGARPVPFSERSQEDGRGPAARSSGTLWRIRTRLSLCRDPEPPPPLCLLRVSLLCA RAGGRGSR GED GAR L PPARAAGNGEAEPSGGPSYAGRMLESSGCKA KEGV EKRSDG QLWKKKCCI TEEGLLLIPPKQLQHQQQQQQQQQQQQQQPGQGPAEPSQPSGPAVAS EP PVKIKE HFS^ΠY|KTVDCVERKGKYMYFTVV^WEGKEIDF CPQDQG RAAEITLQ^RVQYKN QAI AVKSTRQKQQHLVQQQPPSQPQPQPQ QPQPQPQPQPQPQPQSQPQP QPQPKPQPQQ HPYPHPHPHPHSHPHSHPHPHPHPHPHQIPHPHPQPHSQPHGHRLLRSTSNSA
160
CCCGTATCCGCATCCACATCCACATCCACACTCTCATCCTCACTCGCACCCACACCCTCACCCGCACCCGCATCCGCACCAAATACCGCACCCACACCCACAGCCGCACTCG CAGCCGCACGGGCACCGGCTTCTCCGCAGCACCTCCAACTCTGCCTGAAAGGGGCAGCTCCCGGGCAAGACAAGGTTTTGAGGACTTGAGGAAGTGGGACGAGCACATTTCT ATRGTCTTCACTTGGATCAAAAGCAAAACAGTCTCTCCGCCCCGCACCAGATCAAGTAGTTTGGACATCACCCTACTGAACAACTTGGCGATTCTTCTTAGTTTTCTGCATA CTTTTCATCACCGATGCAGGAAACGATTTCGAGTCAAGAAGACTTTTATTTATGAACCTTTGAAAGGATCGTCTTGTATGGTGAATTTTCTAGGAGCGATGATGTACTGTAA TTTTATTTTAATGTATTTTGATTTATGATTATTTATTAGTTTTTTTTAAATGCTTGTTCTAAGACATTTCTGAATGTAGACCATTTTCCAAAAAGGAAACTTTATTTTCAAA AACCTAATCCGTAGTAATTCCTAATCTTGGAGAATAAAAAAGGGCGGTGGAGGGGAAAACATTAAGAATTTATTCATTATTTCTCGAGTACTTTCAGAAAGTCTGACACTTT CATTGTTGTGCCAGCTGGTTGAAATTAAAACTCTGATAΓTACTTTTTTTGAGGATTTTTATTTTTGTTTTTGCTTAAACACTATAGTTTGTCTAGAAGTTTAAAAAGCTAAA AGTTAAAAATGGTGTA&TTATGAAAATCTAACACTCAAGATAGTTTCTAAAAGGAAATCAGTAGTTAAGGATACCTGATTTCAAAATATTTAAAGCATAACCTAACTGATGG ΓAGGATGATTGTATCTTGAATATGTGGTAGGGCCACAΓCTAΓTGTAGGAAAACCTTGCTTTTATCATCTGTGTGTAAAGGGCTTAATAAGGAGAAGAGGCCTTTTGACTGAT RTGTGAGTATAAATGCATTTGCTGTTTCATTTCAAAAARGTRGTGGAGGAAAAGAGTACATTTAACTTGTATAAGAGAATATTTGTACTCCTGTCCAGGCTGCAGGACCTTT CTTCGAGAGCTTTGCACACTTGACTTGAACCACATTΓΓCTGATCCCTTTACTTTGTTTTAGAAGCACACTGAAAAATCTCGTTGTTTAAAGTACAATTTGTAAATATTTCAA AGGΓCTAGGAGTCATAACTTTTGTTTTCATACTGAAAAΓGAΓGTTGATCAGAGAAACCAACTGTTTTGCTTTTCATTGCTCTGTGAGAAATTGAGGATTCTGTTTTGCTGTT AGGTAAGCTAACTCAGAAATTGAAAGGAAAGACTGGAΓAAACACCGGATTTTCAGTAAGAAAACAACCCCAGTCTTG CTTAGAAGCCACTTGTTGAGGAGTCTGTTGGGGG AAAAAAGAGGATATGCTTTTAAAGGTAGAACAAACCTRCTRCTGTGTTAAATCAAAAGGATGTTCAAAATCCACCAGGACAGATGCTACTTGGGTTTAAATGGAGCCATAGA RGARACAAAGTCCRCTTGGGGCTGAAAATCACTTCCRATTTGCATGGCTTTACTAACTGGTTTCTGTTTTCCATTATCTTTTTCACAGAAAGTCTTGGTCAGTATTTTTCCA GCATTTAAATTGAAACGGTCAGTATTAGACCACTGCRAGGRRATGTAGTCAAGAAATAAAAATAGAATTACATGCTACAGATGTCTTTATTCTCCTTCCATCTAGAAAGGAG ΓTCCAAGGTCAAATTACTTTTTAGTGCAATAGTTAAAΓGACATTTTGAGATCATAACTCATATCCAAAAAGTTGCAGGGAAAATTAAAATAGCTTTCCCCTATTAAGCTAAT GGCAAACAAAACTTAAGTGGACCCCCACTTCCAGTGGΓΓGΓΓTAGGTTGCAGTTGTGAAAATATGCTGCCAACATTTAAAAACTTGTTTCATATGTATATATGTATACACAT AΓATGAATATGTATGTATATATACATATATGAGAACAΓGTGΓGTACACATATATGAATATGTATATATGTGTATGTATGTATAIATGTATATGAAATGAGAGCCACATCTAA AGATTTCTTAAATCAAGTTTGGTTCAGCTTCCTTAGAACTGΓGGCTGTACTTTTTGAGGAGTACCTCATAGTACTATATTTTTAATGCATGCAAATCATAATAGCTCCAAAT GAACCACAGTTTTTTCCCAATGGAGGATTTTTTTTTAATTCΓTGTACTAAAAAAAAAAAATCCATACCAAATATTTTTACAAATTAAGATTGATGTAGGTTTTAAAAAAGGC ATTTGTATGTTGTRAGCTTACATATEGGGCTAGGTAARTTCATTGCTTAAAAAGATGCGCCTAGGCTCCCTCTTGGTGGCTGGATTTCTTTTTCTTCGCCCGTGGTGGCCAT GGTTTTTAATAGGGCCACCGGAATCATGGTTTCTTTΓTTTΓΓTTTTTTTTTGGAGATGGAGTCTCGCCCTGTGACCCAGGCTGGAGTGCAGTGGCACGATCTCGGCTCACTG CAACCTCTGCCTCTTGGGTTCACGCCATTCTCCTGTGTCAGCCTCCTGAGTAGCTGGGACTACAGGTGAATGCCACCACGCCCGGCTGATTTTTGTATTTTTAGTAGAGATG GGGTTTCACCATAGTGGTCAGGCTGTTCTCGAACTCCΓGACCTCAGGTGATCCACCTGCCTTGGCCTCCCAAAGTGCTAGGATTACAGGTGTGAGCCACCACACCCGGCCCC AGAGTAATGGTTTCTTGACTTTCTGTAGCCCTTGTTCCTTAGTCTGCTGTGATATTTATGTTGACCTTTATCATTTTCTATTCTGAACCCCTCTTAGCATTTAATGTGAAAT CTAAGAAATTAGAAGTAGAATGGCTTTTATTGTTTTGACACCTTTGAAATTATTATTAATAATTTTTCCAGAGCAAAAAAGCAAACACGCTCAATAAGACTAAACAAAACAA AATATAAATGTACATCATTTAATGTCCCAGTGGCTCΓATΓCΓACCTGTAAGAAAATGATACAAAACCACCTAAGATATTTTGAAGCCTGACAAATCAGCTTCATGGAAAAAG GTAAAAAATGCATTTTTCAACCGAAAGGGCAGATCCAATAGAAGACCCGCTCCTTAAATAAACATAAAATGTAAAAAGTTGGAAAAAAAAA
161
MQSCESSGDSADDPLSRGLRRRGQPRVVVIGAGIAGI.AAAKALLEQGFTDVTVLEASSHIGGRVQSVKIjGHATFELGATWIHGSHGNPIYH AEANGLLEETTDGERSVGRI SLYSKNGVACYLTNHGRRIPKDVVEEFSD YNEVYN TQEFFRHDKPVNAESQNSVGVFTREEVRNRIRNDPDDPEATKRLKLAMIQQYLKVESCESSSHSMDEVSLSAFGE WTEIPGAHHIIPSGFMRVVELLAEGIPAHVIQLGKPVRCIHHDQASARPRGPEIEPRGEGDHNHDTGEGGQGGEEPRGGRWDEDEQWSVVVECEDRELIPADHVIVTVSLGV LKRQYTSFFRPGLPTE VAAIHRLGIGTTDKIFLEFEEPF GPECNSLQFVWEDEAESHTLTYPPEL YRKICGFDVLYPPERYGHV SG ICGEEALVMEKCDDEAVAEIC TEMLRQFTGNPNIPKPRRILRSAWGSNPYFRGSYSYrQVGSSGADVEKLAKPLPYTESSKTAPMQVLFSGEATHRKYYSTTHGALLSGQREAARLIEMYRDLFQQGT
162
CGCCGCTCGCCGCAGACTTACTTCCCCGGCTCAGCAGGGAAAΒGTTCCTAGAAGGTGAΣCΣCGGACGGTATGCAAAGTTGTGAATCCAGTGGTGACAGTGCGGATGACCCTC TCAΒTCGCGGCCTAC-FFIAGAAGGGGACAGCCTCGTGRGGRGGTGATCGGCGCCGGCTTGGCTGGCCTGGCTGCAGCCAAAGCACTTCTTGAGCAGGGTTTCACGGATGTCAC TGTGCTTGAGGCTTCCAGCCACATCGGAGGCCGTGTGCAGAGTGTGAAACTTGGACACGCCACCTTTGΔGCTGGGAGCCACCTGGATCCATGGCTCCCATGGGAACCCTATC TATCATCTAGCAGAAGCCAACGGCCTCCTGGAAGAGACAACCGATGGGGAACGCAGCGTGGGCCGCATCAGCCTCTATTCCAAGAATGGCGTGGCCTGCTACCTTACCAACC ACGGCCGCAGGATCCCCAAGGACGTGGTTGAGGAATΓCAGCGAΓTTATACAACGAGGTCTATAACTTGACCCAGGAGTTCTTCCGGCACGATAAACCAGTCAATGCTGAAAG TCAAAATAGCGTGGGGGTGRTCACCCGAGAGGAGGTGCGRAACCGCATCAGGAATGACCCTGACGACCCAGAGGCTACCAAGCGCCTGAAGCTCGCCATGATCCAGCAGTAC CTGAAGGTGGAGAGCTGRGAGAGCAGCTCACACAGCATGGACΒAGGTGTCCCTGAGCGCCTTCGGGGAGTGGACCGAGATCCCCGGCGCTCACCACATCATCCCCTCGGGCT TCATGCGGGTTGTGGAGCRGCRGGCGGAGGGCATCCCTGCCCACGTCATCCAGCTAGGGAAACCTGTCCGCTGCATTCACTGGGACCAGGCCTCAGCCCGCCCCAGAGGCCC TGAGATTGAGCCCCGGGGΓGAGGGCGACCACAATCACGACACΓGGGGAGGGTGGCCAGGGTGGAGAGGAGCCCCGGGGGGGCAGGTGGGATGAGGATGAGCAGTGGTCGGTG GTGGTGGAGTGCGAGGACCGTGAGCTGATCCCGGCGGACCATGTGATTGTGACCGTGTCGCTAGGTGTGCTAAAGAGGCAGTACACCAGTTTCTTCCGGCCAGGCCTGCCCA CAGAGAAGGTGGCTGCCARCCACCGCCTGGGCATTGGCACCACCGACAAGATCTTTCTGGAATTCGAGGAGCCCTTCTGGGGCCCTGAGTGCAACAGCCTACAGTTTGTGTG GGAGGACGAAGCGGAGAGCCACACCCTCACCTACCCACCTGAGCTCTGGTACCGCAAGATCTGCGGCTTTGATGTCCTCTACCCGCCTGAGCGCTACGGCCATGTGCTGAGC GGCTGGATCTGCGGGGAGGAGGCCCTCGTCATGGAGAAGΓGTGATGACGAGGCAGTGGCCGAGATCTGCACGGAGATGCTGCGTCAGTTCACAGGGAACCCCAACATTCCAA AACCTCGGCGAATCTTGJCGCΓCGGCCTGGGGCAGCAACCCTTACTTCCGTGGCTCCTATTCATACACGCAGGTGGGCTCCAGCGGGGCGGATGTGGAGAAGCTGGCCAAGCC CCTGCCGTACACGGAGAGCTCAAAGACAGCGCCCATGCAGGTGCTGTTTTCCGGTGAGGCCACCCACCGCAAGTACTATTCCACCACCCACGGTGCTCTGCTGTCCGGCCAG CGTGAGGCTGCCCGCCTCATRGAGATGTACCGAGACCRCTTCCAGCAGGGGACCTGAGGGCTGTCCTCGCTGCTGAGAAGAGCCACTAACICGTGACCTCCAGCCTGCCCCT TGCTGCCGTGTGCTCCTGCCΓΓCCTGATCCTCTGTAGAAAGGATTTTTATCTTCTGTAGAGCTAGCCGCCCTGACTGCCTTCAGACCTGGCCCTGTAGCTTT
163 RFA TVLLLGPLQLCALVHCAPPAAGQQQPPREPPAAPGAWRQQIQWENNGQVFSL SLGSQYQPQRRRDPGAAVPGAANASAQQPRTPILLIRDNRTAAARTRTAGSSGV TAGRPRPTARHWFQAGYSTSRAREAGASRAENQTAPGEVPALSNLRPPSRVDGMVGDDPYNPYKYSDDNPYYNYYDTYERPRPGGRYRPGYGTGYFQYG PDLVADPYYIQA STYVQKMSMYNLRCAAEENCLASTAYRADVRDYDHRV LRFPQRVKNQGTSDFLPSRPRYS EWHSCHQHYHSMDEFSHYDLLDANTQRRVAEGHKASFCLEDTSCDYGYHR RFACTAHTQGLSPGCYDTYGADIDCQWIDITDVKPGNYILKVSVNPSYLVPESDYTNNWRCDIRYTGHHAYASGCTISPY
164
GGGCCAGGACTGAGAAAGGGGAAAGGGAAGGGTGCCACGTCCGAGCAGCCGCCTTGACTGGGGAAGGGTCTGAATCCCACCCTTGGCATTGCTTGGTGGAGACTGAGATACC CGTGCTCCGCTCGCCTCCΓTGGTTGAAGATTTCTCCΓΓCCCTCACGTGATTTGAGCCCCGTTTTTATTTTCTGTGAGCCACGTCCTCCTCGAGCGGGGTCAATCTGGCAAAA GGAGTGATGCGCTTCGCCΓGGACCGΓGCTCCTGCTCGGGCCTTTGCAGCTCTGCGCGCΓAGTGCACTGCGCCCCTCCCGCCGCCGGCCAACAGCAGCCCCCGCGCGAGCCGC CGGCGGCTCCGGGCGCCΓGGCGCCAGCAGATCCAATGGGAGAACAACGGGCAGGTGTTCAGCTTGCTGAGCCTGGGCTCACAGTACCAGCCTCAGCGCCGCCGGGACCCGGG CGCCGCCGTCCCTGGTGCAGCCAACGCCTCCGCCCAGCAGCCCCGCACTCCGATCCTGCTGATCCGCGACAACCGCACCGCCGCGGGGCGAACGCGGACGGCCGGCTCATCT GGAGTCACCGCTGGCCGCCCCAGGCCCACCGCCCGTCACTGGTTCCAAGCTGGCTACTCGACATCTAGAGCCCGCGAAGCTGGGCCCTCGCGCGCGGAGAACCAGACAGCGC CGGGAGAAGTTCCTGCTCTCAGTAACCTGCGGCCGCCCAGCCGCGTGGACGGCATGGTGGGCGACGACCCTTACAACCCCTACAAGTACTCTGACGACAACCCTTATTACAA CTACTACGATACTTAΓGAAAGGCCCAGACCTGGGGGCAGGΓACCGGCCCGGATACGGCACTGGCTACTTCCAGTACGGTCTCCCAGACCTGGTGGCCGACCCCTACTACATC CAGGCGTCCACGTACGRGCAGAAGATGTCCATGTACAACCRGAGATGCGCGGCGGAGGAAAACTGTCTGGCCAGTACAGCATACAGGGCAGATGTCAGAGATTATGATCACA GGGTGCTGCTCAGATRTCCCCAAAAAGTGAAAAACCAAGGGACATCAGATTTGTTACCCAGCCGACCAAGATATTCCTGGGAATGGCACAGTTGTCATCAACATTACCACAG TATGGATGAGTTTAGCCACTTGTACCTGCTTGATGCCAACACCCAGAGGAGATGGGCTGAAGGCCACAAAGCAAGΓTΓCTGTCTTGAAGACACATCCTGTGACTATGGCTAC CACAGGCGATTTGCATGTACTGCACACACACAGGGATTGAGTCCTGGCTGTTATGATACCTATGGTGCAGACATAGACTGCCAGTGGATTGATATTACAGAΓGTAAAACCTG GAAACTATATCCTAAAGGTCAGTGTAAACCCCAGCTACCTGGTTCCTGAATCTGACTATACCAACAATGTTGTGCGCΓGTGACATTCGCTACACAGGACATCATGCGTATGC CTCAGGCTGCACAATTRCACCGTATTAGAAGGCAAAGCAAAACTCCCAATGGATAAATCAGTGCCTGGTGTTCTGAAGRGGGAAAAAATAGACTAACRRCAGTAGGATTTAT GTATTTTGAAAAAGAGAACAGAAAACAACAAAAGAATTTTTGTTTGGACTGTTΓTCAATAACAAAGCACATAACTGGAΓΓTTGAACGCTTAAGTCATCATTACTTGGGAAAT TTTTAATGTTTATTATTTACATCACTTTGTGAATTAACACAGTGTTTCAATTCRGTAATTACATATTTGACTCTTRCAAAAAAAAAAAAAAAAAAAAAAA
165
MGGCTVKPQLLLLALV HPVMPCLGADSEKPSSIPTDK LVITVATKESDGFHRFMQSAKYFNYTVKVLGQGEEWRGGDGINSIGGGQKVR MKEVMEHYADQDDLVVMFTE
CFDVIFAGGPEEVLK FQKANHKVVFAAIXSILHPDKXLADKYPVVHIGKRYI^SGGFIGYAPYVNRIVQQWNIΛDNDDDQ FYTKVΎIDPLKREAINIΓ
AVDEWLKFENG ARAKNTFYETLPVAINGNGPTKI LNYFGNYVPNSWTQDNGCT CEFDTVDLSAVDVHPNVSIGVFIEQPTPFLPRFLDILLTLDYPKEA KLFIHNKE
VYHEKDIKVFFDI AKHERKTIKIVGPEEN SQAEARNMGMDFCRQDEKCDYYFSVDADVVL,TNPRTLKILIEQNRKIIAP VTRHGKL SNFWGALSPDGYYARSEDYVDIV
QG RVGV NVPY^ ANVY IKGKT SEMNE NYFVRDK DPDMALCRNAREMGVFMYISNRHEFGR STANYNTSHY INDL QIFE PVDWKEK I IRDYSKIFTENIVEQ
PCPDVF FPIFSEKACDE VEEMΞHYGKWSGG HHDSRISGGYENVPTDDIH KQVD EHVWLDFIREFIAPV LKVFAGYYTKGFALLNFWKYSPERQRSLRPHHDASTF
TINIALNNVGEDFQGGGCKFLRYNCSIESPRKG SFMHPGR TH HEGLPVKNGTRYIAVSFIDP
166
ATGGGGGGATGCACGGTGAAGCCTCAGCTGCTGCΓCCTGGCGCTCGTCCTCCACCCCTGGAATCCCTGTCTGGGTGCGGACTCGGAGAAGCCCTCGAGCATCCCCACAGATA AATTATTAGTCAΓAACTGTAGCAACAAAAGAAAGTGAΓGGAΓTCCATCGATTTATGCAGTCAGCCAAATATTTCAATTATACTGTGAAGGTCCTTGGTCAAGGAGAAGAATG GAGAGGTGGTGAΓGGAATTAATAGTATTGGAGGGGGCCAGAAAGTGAGATTAATGAAAGAAGTCATGGAACACTATGCTGATCAAGATGATCTGGTTGTCATGTTTACTGAA TGCTTTGATGTCATAΓΓΓGCTGGTGGTCCAGAAGAAGΓTCΓAAAAAAATTCCAAAACSGCAAACCACAAAGTGGTCTTTGCAGCAGATGGAATTTTGTGGCCAGATAAAAGAC TAGCAGACAAGTATCCTGΓTGTGCACATTGGGAAACGCTATCTGAATTCAGGAGGATTΓAΓTGGCTATGCTCCATATGTCAACCGTATAGTTCAACAATGGAATCTCCAGGA TAATGATGATGATCAGCRCTRTTACACTAAAGTTRACATRGATCCACTGAAAAGGGAAGCTATTAACATCACATTGGATCACAAATGCAAAATTTTCCAGACCTTAAATGGA GCTGTAGATGAAGTTGTTTTAAAATTTGAAAATGGCAAAGCCAGAGCTAAGAATACATTΓTATGAAACATTACCAGTGGCAATTAATGGAAATGGACCCACCAAGATTCTCC TGAATTATTTTGGAAACTAΓGTACCCAATTCATGGACACAGGATAATGGCTGCACTCTTTGΓGAATTCGATACAGTCGACTTGTCTGCAGTAGATGTCCATCCAAACGTATC AATAGGTGTTTTTATRGAGCAACCAACCCCTTTTCTACCTCGGTTTCTGGACATATTGTTGACACTGGATTACCCAAAAGAAGCACTTAAACTTTTTATTCATAACAAAGAA GTTTATCATGAAAAGGACAΓCAAGGTATTTTTTGAΓAAAGCΓAAGCATGAAATCAAAACTAΓAAAAATAGTAGGACCAGAAGAAAATCTAAGTCAAGCGGAAGCCAGAAACA TGGGAATGGACTTTTGCCGTCAGGATGAAAAGTGΓGATTAΓTACTTTAGTGTGGATGCAGATGTTGTTTTGACAAATCCAAGGACTTTAAAAATTTTGATTGAACAAAACAG AAAGATCATTGCTCCTCTTGRAACTCGTCATGGAAAGCRGTGGTCCAATTTCTGGGGAGCATTGAGTCCTGATGGATACTATGCACGATCTGAAGATTATGTGGATATTGTT CAAGGGAATAGAGTAGGAGΓAΓGGAATGTCCCATATAΓGGCΓAATGTGTACTTAATTAAAGGAAAGACACTCCGATCAGAGATGAΔTGAAAGGAACTATTTTGTTCGTGATA AACTGGATCCTGATATGGCΓCTTTGCCGAAATGCTAGAGAAAΓGGGTGTATTTATGTACATΓTCTAATAGACATGAATTTGGAAGGCTATTATCCACTGCTAATTACAATAC TTCCCATTATAACAATGACCTCTGGCAGATTTTTGAAAATCCRGTGGACTGGAAGGAAAAGRATATAAACCGTGATTATTCAAAGATTTTCACTGAAAATATAGTTGAACAG CCCTGTCCAGATGTCTTΓTGGTTCCCCATATTTTCΓGAAAAAGCCTGTGATGAATTGGΓAGAAGAAATGGAACATTACGGCAAATGGTCTGGGGGAAAACATCATGATAGCC GTATATCTGGTGGTTATGAAAATGTCCCAACIGATGATARCCACARGAAGCAAGTTGARCTGGAGAATGTATGGCTTGATTTTATCCGGGAGTTCATTGCACCAGTTACACT GAAGGTCTTTGCAGGCTATTATACGAAGGGATTTGCACΓACTGAATTTTGTAGTAAAATACTCCCCTGAACGACAGCGTTCTCTTCGTCCTCATCATGATGCTTCTACATTT ACCATAAACATTGCACTTAATAACGTGGGAGAAGACTΓΓCAGGGAGGTGGTTGCAAATTTCTAAGGTACAATTGCTCTATTGAGTCACCACGAAAAGGCTGGAGCTTCATGC ATCCTGGGAGACTCACACAΓTTGCATGAAGGACTTCCΓGTTAAAAATGGAACAAGATACATTGCAGTGTCATTTATAGATCCCTAAGTTATTTACTTTTCATTGAATTGAAA TTTATTTTGGGTGAATGACTGGCATGAACACGTCTTΓGAAGTTGTGGCTGAGAAGATGAGAGGAATATTTAAATAACATCAACAGAACAACTTCACTTTGGGCCAAACATTT GAAAAACTTTTTATAAAAAATTGTTTGATATTTCTTAATGTCTGCTCTGAGCCTTAAAACACAGATTGAAGAAGAAAAGAAAGAAAAAACTTAAATATTTATTTCTATGCTT TGTTGCCTCTGAGAATAATGACAATTTATGAATTTGTGTTTCAAATTGATAAAATATTTAGGTACAAATAACAAGACTAATAATATTTTCTTATTTAAAAAAAGCATGGGAA GATTTTTATTTATCAAAATATAGAGGAAATGTAGACAAAATGGATATAAATGAAAATTACCATGTTGTAAAACCTTGAAAATCAGATTCTAACTGATTGTATGCAACTAAGT ATTTCTGAACACCTATGCAGGTCTTATTTACAGTGTTACTAAGGGAACACACAAAGAATTACACAACGTTTTCCTCAAGAAAATGGTACAAAACACAACCGAGGAGCGTATA CAGTTGAAAACATTTTTGTTTTGATTGGAAGGCAGATTATTTTATATTAGTATTAAAAATCAAACCCTATGTTTCTTTCAGATGAATCTTCCAAAGTGGATTATATTAAGCA GGTATTAGATTTAGAAAACCTTTCCATTTCTTAAAGTATTATCAAGTGTCAAGATCAGCAAGTGTCCTTAAGTCAAATAGGTTTTTTTTTGTTGGTGGTTGTGCTTGCTTTC CTTTTTTAGAAAGTTCTAGAAAATAGGAAAACGAAAAATTTCATTGAGATGAGTAG GCATTTAATTATTTTTTAAAAAACTTTTTAAGTACTTGAATTTTATATCAGGAAA ACAAAGTTGTTGAGCCTTGCTTCTTCCGTTTTGCCCTTTGTCTCGCTCCTTATTCTTTTTTGGGGGGAGGGTTATTTGCTTTTTTATCTTCCTGGCATAATTTCCATTTTAT TCTΓCTGAGTGTCTATGTTAACTTCCCTCTATCCCGCTTATAAAAAAATTCICCAACAAAAATACTTGTTGACTTGATGTTTTATCACTTCTCTAAGTAAGGTTGAAATATC CTRATTGTAGCTACTGTTTTTAATGTAAAGGTTAAACTTGAAAAGAAATTCTTAATCACGGTGCCAAAATTCATTT'ICTAACACCATGTGTTAGAAAATTATAAAAAATAAA ATAATTTTAAAAAAAAAAAAAAAAAAAAAAA
167
MGGCTVKPQLLLLALV HPtMPC GADSEKPSSIPTDKLLVITVATKESDGFHRFMQSAKYFNYTVKΛ^GQGEEWRGGDGINSIGGGQKVR MKEVMEHYADQDDLVVMFTE
CFDVIFAGGPEEVLKKFQKA MKWFAAIXSILWPDKRI ffiKYPWHIGKRYLNSGGFIGYAPYWRIVQQVraM
AVDEW KFENGKARAKNTFYET PVAINGNGPTKILLNYFGNYVPNS TQDNGCTLCEFDTVDLSAVDVHPNVSIGVFIEQPTPFLPRFLDI TLDYPKEA KLFIHNKE
VYHEKDIKVFFDKAKHEIKTIKIVGPEENLSQAEARNMGMDFCRQDEKCDYYFSVDADVVLTNPRTLKILIEQNRKI IAPLVTRHGKLW8NFWGAL8PDGYYAR8EDYVDIV
QGNRVGVWNVPYMANVYLIKGKTLRSElWERirYFVRDKLDPDl^ CRNAREMGVFMYISNRHEFGR LSTANYNTSHYNNDLWQIFENPVD KEKYINRDYSKIFTENIVEQ
PCPDVF FPIFSEKACDELVEEMEHYGKW8GGKHHDSRISGGYENVPTDDIH KQVDLENVWLDFIREFIAPVTLKVFAGYYTKGFALLNFVVKYSPERQRSLRPHHDASTF
TINIALNNVGEDFQGGGCKFLRYNC8IESPRKGWSFMHPGR TH HEGLPVKNGTRYIAVSFIDP
168
ATGGGGGGATGCACGGTGAAGCCTCAGCTGCTGCTCCTGGCGCTCGTCCTCCACCCCTGGAATCCCTGTCTGGGTGCGGACTCGGAGAAGCCCTCGAGCA'ICCCCACAGATA AATTATTAGTCATAACTGTAGCAACAAAAGAAAGTGATGGATTCCATCGATTTATGCAGTCAGCCAAATATTTCAATTATACTGTGAAGGTCCTTGGTCAAGGAGAAGAATG GAGAGGTGGTGATGGAATTAATAGTATTGGAGGGGGCCAGAAAGTGAGATTAATGAAAGAAGTCATGGAACACTATGCTGATCAAGATGATCTGGTTGTCATGTTTACTGAA TGCTTTGATGTCATATTTGCTGGTGGTCCAGAAGAAGTTCTAAAAAAATTCCAAAAGGCAΔACCACAAAGTGGTCTTTGCAGCAGATGGAATTTTGTGGCCAGATAAAAGAC TAGCAGACAAGTATCCTGTTGTGCACATTGGGAAACGCTATCTGAATTCAGGAGGAITTATTGGCTATGCTCCATATGTCAACCGTATAGTTCAACAATGGAATCTCCAGGA TAATGATGATGATCAGCTCTTTTACACTAAAGT'ITACATTGATCCACTGAAAAGGGAAGCTATTAACATCACATTGGATCACAAATGCAAAATTTTCCAGACCTTAAATGGA GCTGTAGATGAAGTTGTTTTAAAATTTGAAAATGGCAAAGCCAGAGCTAAGAATACATTTTATGAAACATTACCAGTGGCAATTAATGGAAATGGACCCACCAAGATTCTCC TGAATTATTTTGGAAACTATGTACCCAATTCATGGACACAGGATAATGGCTGCACTCTTTGTGAATTCGATACAGTCGACTTGTCTGCAGTAGATGTCCATCCAAACGTATC AATAGGTGTTTTTATTGAGCAACCAACCCCTTTTCTACCTCGGTTTCTGGACATATTGTTGACACTGGATTACCCAAAAGAAGCACTTAAACTTTTTATTCATAACAAAGAA GTTTATCATGAAAAGGACATCAAGGTATTTTTTGATAAAGCTAAGCATGAAATCAAAACTATAAAAATAGTAGGACCAGAAGAAAATCTAAGTCAAGCGGAAGCCAGAAACA TGGGAATGGACTTTTGCCGTCAGGATGAAAAGTGTGATTATTACTTTAGTGTGGATGCAGATGTTGTTTTGACAAATCCAAGGACTTTAAAAATTTTGATTGAACAAAACAG AAAGATCATTGCTCCTCTTGTAACTCGTCATGGAAAGCTGTGGTCCAATTTCTGGGGAGCATTGAGTCCTGATGGATACTATGCACGATCTGAAGATTATGTGGATATTGTT CAAGGGAATAGAGTAGGAGTATGGAATGTCCCATATATGGCTAATGTGTACTTAATTAAAGGAAAGACACTCCGATCAGAGATGAATGAAAGGAACTATTTTGTTCGTGATA AACTGGATCCTGATATGGCTCTTTGCCGAAATGCTAGAGAAATGGGTGTATTTATGTACATTTCTAATAGACATGAATTTGGAAGGCTATTATCCACTGCTAATTACAATAC TTCCCATTATAACAATGACCTCTGGCAGATTTTTGAAAATCCTGTGGACTGGAAGGAAAAGTATATAAACCGTGATTATTCAAAGATTTTCACTGAAAATATAGTTGAACAG CCCTGTCCAGATGTCTTTTGGTTCCCCATATTTTCTGAAAAAGCCTGTGATGAATTGGTAGAAGAAATGGAACATTACGGCAAATGGTCTGGGGGAAAACATCATGATAGCC GTATATCTGGTGGTTATGAAAATGTCCCAACTGATGATATCCACATGAAGCAAGTTGATCTGGAGAATGTATGGCTTGATTTTATCCGGGAGTTCATTGCACCAGTTACACT GAAGGTCTTTGCAGGCTATTATACGAAGGGATTTGCACTACTGAATTTTGTAGTAAAATACTCCCCTGAACGACAGCGTTCTCTTCGTCCTCATCATGATGCTTCTACATTT ACCATAAACATTGCACTTAATAACGTGGGAGAAGACTTTCAGGGAGGTGGTTGCAAATTTCTAAGGTACAATTGCTCTATTGAGTCACCACXSAAAAGGCTGGAGCTTCAT'GC ATCCTGGGAGACTCACACATTTGCATGAAGGACTTCCTGTTAAAAATGQAACAAGATACATTGCAGTGTCATTTATAGATCCCTAAGTTATTTACTTTTCATTGAATTGAAA TTTATTTTGGGTGAATGACTGGCATGAACACGTCTTTGAAGTTGTGGCTGAGAAGATGAGAGGAATATTTAAATAACATCAACAGAACAACTTCACTTTGGGCCAAACATTT GAAAAACTTTTTATAAAAAATTGTTTGATATTTCTTAATGTCTGCTCTGAGCCTTAAAACACAGATTGAAGAAGAAAAGAAAGAAAAAACTTAAATATTTATTTCTATGCTT TGTTGCCTCTGAGAATAATGACAATTTATGAATTTGTGTTTCAAATTGATAAAATATTTAGGTACAAATAACAAGACTAATAATATTTTCTTATTTAAAAAAAGCATGGGAA GATTTTTATTTATCAAAATATAGAGGAAATGTAGACAAAATGGATATAAATGAAAATTACCATGTTGTAAAACCTTGAAAATCAGATTCTAACTGATTGTATGCAACTAAGT ATΓTCTGAACACCTAΓGCAGGTCTTATTTACAGTGTTACTAAGGGAACACACAAAGAATTACACAACGTTTTCCTCAAGAAAATGGTACAAAACACAACCGAGGAGCGTATA CAGTTGAAAACATTTΓTGTTTTGATTGGAAGGCAGATΓATΓTTATATTAGTATTAAAAATCAAACCCTATGTTTCTTTCAGATGAATCTTCCAAAGTGGATTATATTAAGCA GGTATTAGATTTAGAAAACCTTTCCATTTCTTAAAGTATTATCAAGTGTCAAGATCAGCAAGTGTCCTTAAGTCAAATAGGTTTTTTTTTGTTGGTGGTTGTGCTTGCTTTC CTTTTTTAGAAAGTΓCTAGAAAATAGGAAAACGAAAAATTΓCATTGAGATGAGTAGTGCATTTAATTATTTTTTAAAAAACTTTTTAAGTACTTGAATTTTATATCAGGAAA ACAAAGTTGTTGAGCCTTGCTTCTTCCGTTTTGCCCΓTTGΓCTCGCTCCTTATTCTTTTTTGGGGGGAGGGT'IATTTGCTTTTTTATCTTCCTGGCATAAT'TTCCATTTTAT TCTTCTGAGTGTCTATGTRAACTTCCCTCTATCCCGCTRATAAAAAAATTCTCCAACAAAAATACTTGTTGACTTGATGTTTTATCACTTCTCTAAGTAAGGTTGAAATATC CTTATTGTAGCTACΓGTTTTTAATGTAAAGGTTAAACΓΓGAAAAGAAATTCTTAATCACGGTGCCAAAATTCATTTTCTAACACCATGTGTTAGAAAATTATAAAAAATAAA ATAATTTTAAAAAAAAAAAAAAAAAAAAAAA
169
M PSLQESMDGDEKE ESSEEGGSAEERR EPPSSSHYCLYSYRGSRIiAQQRGDSEDGSPSGTNAETPSGDDFSLSIiADTNLPSEVEPELRSPIAKRLSRGAVFEGLGNVAS VELKIPGYRVGCYYCLFQNEKLLPETVTIDSEF^PSEYVVCFLGGSEKGLELFRLEIJDKYIQG ranmNCEARGLESHIKSY 8SWFEDVVCPIQRVVLLFQEKLTFLLHAA LSYTPVEVKESDEKTKRDINRFLεVASLQG IHEGTMrS CMAMTEEQHKSWIDCSSSQPQFCNAGENRFCEDWMQAFLNGAKGGNPFFFRQVLENFKLKAIQDTNNLKRF I RQAEMNHYA FKCYMF K CGSGDTFEDC
170
CACAGGGCCGCTCAGAGGCCGCCGCAATGCTCCCCTCTTTGCAGGAGTCGATGGATGGAGATGAAAAGGAACTAGAGAGCAGCGAAGAGGGAGGCTCAGCCGAGGAGCGGAG ACTCGAGCCGCCGTCCAGCAGCCACTACTGTCTTTACAGCTARCGCGGAAGCAGATTGGCACAGCAACGAGGGGACAGTGAGGACGGAAGCCCAAGTGGCACAAATGCAGAA ACTCCCTCTGGTGATGAΓΓTCAGCCTCTCCTTGGCAGATACTAATCTACCATCCGAAGTGGAGCCAGAGCTGCGCAGTTTCATTGCTAAGCGTCTTTCAAGAGGTGCAGTCT TTGAAGGGCTGGGTAATGTTGCATCTGTGGAGCTAAAAATTCCAGGTTACCGAGTTGGTTGTTATTACTGCCTTTTCCAAAATGAAAAACTGCTTCCTGAAACAGTAACGAT AGACTCTGAACGTAACCCΓΓCAGAATATGTGGTCTGTΓTTTTAGGAGGGTCTGAAAAAGGACTTGAGCTTTTCAGGCITGAATTGGACAAGTACATTCAAGGGCTGAAAAAT AACATGAATTGTGAGGCAAGGGGCCTGGAGAGTCACAXAAAATCCTATCTGAGCAGCTGGTTTGAGGATGTTGTATGCCCAATCCAAAGGGTTGTTCTTCTCTTTCAGGAAA AGCTTACCTTTCTGCTACARGCRGCTTTGAGTTACACTCCTGTTGAAGTTAAAGAATCAGATGAAAAAACAAAGAGAGACATTAACAGGTTTCTGAGTGTGGCCAGTCTTCA AGGACTTATTCATGAAGGCACCATGACTTCTTTGTGCATGGCCATGACAGAGGAGCAGCATAAGTCTGTGGTCATCGATTGCAGCAGCTCCCAGCCTCAGTTCTGCAATGCA
AAGACACAAACAATTTGAAGAGATTTATCCGACAGGCAGAAATGAATCATTATGCTTTGTTTAAATGTTACATGTTCCTAAAGAACTGTGGTAGTGGAGATACTTTTGAAGA TTGTTAAAGTGGAACATGAAGAAATGCCTGAAGCCAAAAATGTGAΓAGCTGTCCTTGAAGAATTCATGAAAGAAGCTCTTGACCAAAGTTTTTGATCATATGTTTTGAGATA ATTGTATGATCAAGTTGΓATATTTAAGTCTTAGTGTTTGAAATTGCAGTTATAATTGTTCATAGGATTGCTATTTAAGATGATTTGAAACTCAATCCAGATTTTCTTTTTGT ATTTTACCAATTTAACTΓAAATAAAAATCTGAAGAACAAAAAAAAAAAAAA
171
MVPLVPALVMLGLVAGAHGDSKPVFIKVPEDQTGLSGGVASFVCQATGEPKPRITWMKKGK VSSQRFEVIEFDDGAGSVLRIQPLRVQRDEAIYECTATNS GEINTSAKL
SV EEEQLPPGFPSIDMGPQLKWEKARTATMLCAAGGNPDPΞISWFKDFLPVDPATSNGRIKQLRSGA QIESSEESDQGKYECVATNSAGTRYSAPANLYVRVRRVAPRF
SIPPSSQEVMPGGSΛ«R TCVAVGAPMPYVKWI^GAEELTKEDEMPVGF-^VLELS ^VV SA YTCVAISSLGMIEATAQV^VKA PKPPID VV ET ATSVTLT DSGNS
VTYYGIQYRAAGTEGPFQEVDGVATTRYSIGG SPFSEYAFRVLAVNSIGRGPPSEAVRARTGEQAPSSPPRRVQARNLSASTM VQ EPPEEPNGLVRGYRVYYTPDSRRP
PNAWHKHNTDAGL TTVGS LPGITYSLRV AFTAVGDGPPSPTIQVKTQQGVPAQPADFQAEVESDTRIQLSWLLPPQERIIMYELVYWAAEDEDQQHKVTFDPTSSYTLE
D KPDT YRFQLAARSDMGVGVFTPTIEARTAQSTPSAPPQKVMCVSMGSTTVRVS VPPPADSRNGVITQYSVAHEAVDGEDRGRHVVDGISREHSS DLVGLEKWTEYRV VRAHTDVGPGPESSPVLVRTDEDVPSGPPRKVEVEP NΞTAVHVYWKLPVPSKQHGQIRGYQVTYVR ENGEPRG PIIQDVM AEAQWRPEESEDYETTISGLTPETTYS
VTVAAYTTKGDGARSKPKIVTTTGAVPGRPTMMISTTAMNTAL QWHPPKELPGE IXJYRLQYCRADEARPNTIDFGKDDQHFTVTGLHKGTTYIFRLAAKNRAGLGEEFEK EIRTPEDLPSGFPQNLHVTGLTTSTTELAWDPPVLAERNGRII8YTVVFRDIN8QQELQNITTDTRFTLTGLKPDTTYDIKVRAWTSKG8GPL8PSIQSRTMPVEQVFAKNF RVAAAMKTSVLLS EVPDSYKSAVPFKILYNGQgVEVDGHSMRK IADLQPNTEYSFV MNRGSSAGGLQHLVSIRTAPDLLPHKPLPASAYIEDGRFDLSMPHVQDPS VR FYIVWPIDRVGGSMLTPR STPEE ELDELLEAIEQGGEEQRRRRRQAERLKPYVAAQLDVLPETFTLGDKKNYRGFYNRP SPDLSYQCFV ASLKEPMDQKRYASSPY SDEIVVQVTPAQQQEEPEML VTGPVLAVILIILIVIAILLFKRKRTHSPSSKDEQSIGLKDS AHSSDPVEMRRLNYQTPGMRDHPPIPITDLADNIERLKANDG KFSQ EYEΞIDPGQQFTWENSN EVNKPKNRYANVIAYDHSRVILTSIDGVPGSDYINANYIDGYRKQNAYIATQGPLPETMGDF RNV EQRTATVWMTRLEEKSRVKCDQYWPA RGTETCGLIQVTL LTIVELATYTVRTFALHKΞGSSEKRELRQFQFMAWPDHGVPEYPTPITΛF RRVKACNP DAGP^WVHC8AσVG TGCFIVIDAM ERMK^EKTVDIYG HVTCMRSQRNY^WQ EDQYVFIHEA LEAATCGHTE PAR YAHIQKLGQ PPGES TAMELEFK LA88KAH ^RFISAN PC KFKN LVNIMPYELTRVCLQPIRGVE GSDYINASFLDGYRQQKAYIATQGP AESTEDFWRMLWEHNSTIIVMLTKLREMGREKCHQYWPAERSARYQYFVVDPMAEYNMPQYILREFKVTDARDGQSRTIRQFQFTD WPEQGVPKTGEGFIDFIGQVHKTKEQFGQDGPITVHCSAGVGRTGVFITLSIVLERMRYEGWDMFQTVKTLRTQRPAMVQTEDQYQ CYRAALEYLGSFDHYAT
172
CGGGAGCGGCGGGAGCGGTGGCGGCGGCAGAGGCGGCGGCTCCAGCTTCGGCTCCGGCTCGGGCTCGGGCTCCGGCTCCGGCTCCGGCTCCGGCTCCAGCTCGGGTGGCGGT
GGCGGGAGCGGGACCAGGTGGAGGCGGCGGCGGCAGAGGAGTGGGAGCAGCGGCCCTAGCGGCTTGCGGGGGGACATGCGGACCGACGGCCCCTGGATAGGCGGAAGGAGTG
GAGGCCCTGGTGCCCGGCCCTTGGTGCTGAGTATCCAGCAAGAGTGACCGGGGTGAAGAAGCAAAGACTCGGTTGATTGTCCTGGGCTGTGGCTGGCTGTGGAGCTAGAGCC
CTGGATGGCCCCTGAGCCAGCCCCAGGGAGGACGATGGTGCCCCTTGTGCCTGCACTGGTGATGCTTGGTTTGGTGGCAGGCGCCCATGGTGACAGCAAACCTGTCTTCATT
AAAGTCCCTGAGGACCAGACTGGGCTGTCAGGAGGGGTAGCCTCCTTCGTGTGCCAAGCTACAGGAGAACCCAAGCCGCGCATCACATGGATGAAGAAGGGGAAGAAAGTCA
GCTCCCAGCGCTTCGAGGTCATTGAGTTTGATGATGGGGCAGGGTCAGTGCTTCGGATCCAGCCATTGCGGGTGCAGCGAGATGAAGCCATCTATGAGTGTACAGCTACTAA
CAGCCTGGGTGAGATCAACACTAGTGCCAAGCTCTCAGTGCTCGAAGAGGAACAGCTGCCCCCTGGGTTCCCTTCCATCGACATGGGGCCTCAGCTGAAGGTGGTGGAGAAG
GCACGCACAGCCACCATGCTATGTGCCGCAGGCGGAAATCCAGACCCTGAGATTTCTTGGTTCAAGGACTTCCTTCCTGTAGACCCTGCCACGAGCAACGGCCGCATCAAGC
AGCTGCGTTCAGGTGCCTTGCAGATAGAGAGCAGTGAGGAATCCGACCAAGGCAAGTACGAGTGTGTGGCGACCAACTCGGCAGGCACACGTTACTCAGCCCCTGCGAACCT
GTATGTGCGAGTGCGCCGCGTGGCTCCTCGTTTCTCCATCCCTCCCAGCAGCCAGGAGGTGATGCCAGGCGGCAGCGTGAACCTGACATGCGTGGCAGTGGGTGCACCCATG
CCCTACGTGAAGTGGATGATGGGGGCCGAGGAGCTCACCAAGGAGGATGAGATGCCAGTTGGCCGCAACGTCCTGGAGCTCAGCAATGTCGTACGCTCTGCCAACTACACCT
GTGTGGCCATCTCCTCGCTGGGCATGATCGAGGCCACAGCCCAGGTCACAGTGAAAGC'rCTTCCAAAGCCTCCGATTGATCTTGTGGTGACAGAGACAACTGCCACCAGTGT
CACCCTCACCTGGGACTCTGGGAACTCGGAGCCTGTAACCTACTATGGCATCCAGTACCGCGCAGCGGGCACGGAGGGCCCCTTTCAGGAGGTGGATGGTGTGGCCACCACC
CGCTACAGCATTGGCGGCCTCAGCCCTTTCTCGGAATATGCCTTCCGCGTGCTGGCGGTGAACAGCATCGGGCGAGGGCCGCCCAGCGAGGCAGTGCGGGCACGCACGGGAG
AACAGGCGCCCTCCAGCCCACCGCGCCGCGTGCAGGCACGCATGCTGAGCGCCAGCACCATGCTGGTGCAGTGGGAGCCTCCCGAGGAGCCCAACGGCCTGGTGCGGGGATA
CCGCGTCTACTATACTCCGGACTCCCGCCGCCCCCCGAACGCCTGGCACAAGCACAACACCGACGCGGGGCTCCTCACGACCGTGGGCAGCCTGCTGCCTGGCATCACCTAC
AGCCTGCGCGTGCTTGCCTTCACCGCCGTGGGCGATGGCCCTCCCAGCCCCACCATCCAGGTCAAGACGCAGCAGGGAGTGCCTGCCCAGCCCGCGGACTTCCAGGCCGAGβ
TGGAGTCGGACACCAGGATCCAGCTCTCGTGGCTGCTGCCCCCTCAGGAGCGGATCATCATGTATGAACTGGTGTACTGGGCGGCAGAGGACGAAGACCAACAGCACAAGGT
CACCTTCGACCCAACCTCCTCCTACACACTAGAGGACCTGAAGCCTGACACACTCTACCGCTTCCAGCTGGCTGCACGCTCGGATATGGGGGTGGGCGTCTTCACCCCCACC
ATTGAGGCCCGCACAGCCCAGTCCACCCCCTCCGCCCCTCCCCAGAAGGTGATGTGTGTGAGCATGGGCTCCACCACGGTCCGGGTAAGTTGGGTCCCGCCGCCTGCCGACA
GCCGCAACGGCGTTATCACCCAGTACTCCGTGGCCCACGAGGCGGTGGACGGCGAGGACCGCGGGCGGCATGTGGTGGATGGCATCAGCCGTGAGCACTCCAGCTGGGACCT
GGTGGGCCTGGAGAAGTGGACGGAGTACCGGGTGTGGGTGCGGGCACACACAGACGTGGGCCCCGGCCCCGAGAGCAGCCCGGTGCTGGTGCGCACCGATGAGGACGTGCCC
AGCGGGCCTCCGCGGAAGGTGGAGGTGGAGCCACTGAACTCCACTGCTGTGCATGTCTACTGGAAGCTGCCTGTCCCCAGCAAGCAGCATGGCCAGATCCGCGGCTACCAGG
TCACCTACGTGCGGCTGGAGAATGGCGAGCCCCGTGGACTCCCCATCATCCAAGACGTCATGCTAGCCGAGGCCCAGTGGCGGCCAGAGGAGTCCGAGGACTATGAAACCAC
TATCAGCGGCCTGACCCCGGAGACCACCTACTCCGTTACTGTTGCTGCCTATACCACCAAGGGGGATGGTGCCCGCAGCAAGCCCAAAATTGTCACTACAACAGGTGCAGTC
CCAGGCCGGCCCACCATGATGATCAGCACCACGGCCATGAACACTGCGCTGCTCCAGTGGCACCCACCCAAGGAACTGCCTGGCGAGCTGCTGGGCTACCGGCTGCAGTACT
GCCGGGCCGACGAGGCGCGGCCCAACACCATAGATTTCGGCAAGGATGACCAGCACTTCACAGTCACCGGCCTGCACAAGGGGACCACCTACATCTTCCGGCTTGCTGCCAA
GAACCGGGCTGGCTTGGGTGAGGAGTTCGAGAAGGAGATCAGGACCCCCGAGGACCTGCCCAGCGGCTTCCCCCAAAACCTGCATGTGACAGGACTGACCACGTCTACCACA
GAACTGGCCTGGGACCCGCCAGTGCTGGCGGAGAGGAACGGGCGCATCATCAGCTACACCGTGGTGTTCCGAGACATCAACAGCCAACAGGAGCTGCAGAACATCACGACAG
ACACCCGCTTTACCCTTACTGGCCTCAAGCCAGACACCACTTACGACATCAAGGTCCGCGCATGGACCAGCAAAGGCTCTGGCCCACTCAGCCCCAGCATCCAGTCCCGGAC
CATGCCGGTGGAGCAAGTGTTTGCCAAGAACTTCCGGGTGGCGGCTGCAATGAAGACGTCTGTGCTGCTCAGCTGGGAGGTTCCCGACTCCTATAAGTCAGCTGTGCCCTTT
AAGATTCTGTACAATGGGCAGAGTGTGGAGGTGGACGGGCACTCGATGCGGAAGCTGATCGCAGACCTGCAGCCCAACACAGAGTACTCGTTTGTGCTGATGAACCGTGGCA
GCAGCGCAGGGGGCCTGCAGCACCTGGTGTCCATCCGCACAGCCCCCGACCTCCTGCCTCACAAGCCGCTGCCTGCCTCTGCCTACATAGAGGACGGCCGCTTCGATCTCTC
CATGCCCCATGTGCAAGAGCCCTCGCTTGTCAGGTGGTTCTACATTGTTGTGGTACCCATTGACCGTGTGGGCGGGAGCATGCTGACGCCAAGGTGGAGCACACCCGAGGAA CTGGAGCTGGACGAGCTTCTAGAAGCCATCGAGCAAGGCGGAGAGGAGCAGCGGCGGCGGCGGCGGCAGGCAGAACGTCTGAAGCCATATGTGGCTGCTCAACTGGATGTGC TCCCGGAGACCTTTACCTTGGGGGACAAGAAGAACTACCGGGGCTTCTACAACCGGCCCCTGTCTCCGGACTTGAGCTACCAGTGCTTTGTGCTTGCCTCCTTGAAGGAACC CATGGACCAGAAGCGCTATGCCTCCAGCCCCTACTCGGATGAGATCGTGGTCCAGGTGACACCAGCCCAGCAGCAGGAGGAGCCGGAGATGCTGTGGGTGACGGGTCCCGTG CTGGCAGTCATCCTCATCATCCTCATTGTCATCGCCATCCTCTTGTTCAAAAGGAAAAGGACCCACTCTCCGTCCTCTAAGGATGAGCAGTCGATCGGACTGAAGGACTCCT TGCTGGCCCACTCCICTGACCCTGTGGAGATGCGGAGGCTCAACTACCAGACCCCAGGTATGCGAGACCACCCACCCATCCCCATCACCGACCTGGCGGACAACATCGAGCG CCTCAAAGCCAACGATGGCCTCAAGTTCTCCCAGGAGTATGAGTCCATCGACCCTGGACAGCAGTTCACGTGGGAGAATTCAAACCTGGAGGTGAACAAGCCCAAGAACCGC TATGCGAATGTCATCGCCTACGACCACTCTCGAGTCATCCTTACCTCTATCGATGGCGTCCCCGGGAGTGACTACATCAATGCCAACTACATCGATGGCTACCGCAAGCAGA ATGCCTACATCGCCACGCAGGGCCCCCTGCCCGAGACCATGGGCGATTTCTGGAGAATGGTGTGGGAACAGCGCACGGCCACTGTGGTCATGATGACACGGCTGGAGGAGAA GTCCCGGGTAAAATGTGATCAGTACTGGCCAGCCCGTGGCACCGAGACCTGTGGCCTTATTCAGGTGACCCTGTTGGACACAGTGGAGCTGGCCACATACACTGTGCGCACC TTCGCACTCCACAAGAGTGGCTCCAGTGAGAAGCGTGAGCTGCGTCAGTTTCAGTTCATGGCCTGGCCAGACCATGGAGTTCCTGAGTACCCAACTCCCATCCTGGCCTTCC TACGACGGGTCAAGGCCTGCAACCCCCTAGACGCAGGGCCCATGGTGGTGCACTGCAGCGCGGGCGTGGGCCGCACCGGCTGCTTCATCGTGATTGATGCCATGTTGGAGCG GATGAAGCACGAGAAGACGGTGGACATCTATGGCCACGTGACCTGCATGCGATCACAGAGGAACTACATGGTGCAGACGGAGGACCAGTACGTGTTCATCCATGAGGCGCTG CTGGAGGCTGCCACGTGCGGCCACACAGAGGTGCCTGCCCGCAACCTGTATGCCCACATCCAGAAGCTGGGCCAAGTGCCTCCAGGGGAGAGTGTGACCGCCATGGAGCTCG AGTTCAAGTTGCTGGCCAGCTCCAAGGCCCACACGTCCCGCTTCATCAGCGCCAACCTGCCCTGCAACAAGTTCAAGAACCGGCTGGTGAACATCATGCCCTACGAATTGAC CCGTGTGTGTCTGCAGCCCATCCGTGGTGTGGAGGGCTCTGACTACATCAATGCCAGCTTCCTGGATGGTTATAGACAGCAGAAGGCCTACATAGCTACACAGGGGCCTCTG GCAGAGAGCACCGAGGACTTCTGGCGCATGCTATGGGAGCACAATTCCACCATCATCGTCATGCTGACCAAGCTTCGGGAGATGGGCAGGGAGAAATGCCACCAGTACTGGC CAGCAGAGCGCTCTGCTCGCTACCAGTACTTTGTTGTTGACCCGATGGCTGAGTACAACATGCCCCAGTATATCCTGCGTGAGTTCAAGGTCACGGATGCCCGGGATGGGCA GTCAAGGACAATCCGGCAGTTCCAGTTCACAGACTGGCCAGAGCAGGGCGTGCCCAAGACAGGCGAGGGATTCATTGACTTCATCGGGCAGGTGCATAAGACCAAGGAGCAG TTTGGACAGGATGGGCCTATCACGGTGCACTGCAGTGCTGGCGTGGGCCGCACCGGGGTGTTCATCACTCTGAGCATCGTCCTGGAGCGCATGCGCTATGAGGGCGTGGTCG ACATGTTTCAGACCGTGAAGACCCTGCGTACACAGCGTCCTGCCATGGTGCAGACAGAGGACCAGTATCAGCTGTGCTACCGTGCGGCCCTGGAGTACCTCGGCAGCTTTGA CCACTATGCAACGTAACTACCGCTCCCCTCTCCTCCGCCACCCCCGCCGTGGGGCTCCGGAGGGGACCCAGCTCCTCTGAGCCATACCGACCATCGTCCAGCCCTCCTACGC AGATGCTGTCACTGGCAGAGCACAGCCCACGGGGATCACAGCGTTTCAGGAACGTTGCCACACCAATCAGAGAGCCTAGAACATCCCTGGGCAAGTGGATGGCCCAGCAGGC AGGCACTGTGGCCCTTCTGTCCACCAGACCCACCTGGAGCCCGCTTCAAGCTCTCTGTTGCGCTCCCGCATTTCTCATGCTTCTTCTCATGGGGTGGGGTTGGGGCAAAGCC TCCTTTTTAATACATTAAGTGGGGTAGACTGAGGGATTTTAGCCTCTTCCCTCTGATTTTTCCTTTCGCGAATCCGTATCTGCAGAATGGGCCACTGTAGGGGTTGGGGTTT ATTTTGTTTTGTTTTTTTTTTTTTTTTGTATGACTTCTGCTGAAGGACAGAACATTGCCTTCCTCGTGCAGAGCTGGGGCTGCCAGCCTGAGCGGAGGCTCGGCCGTGGGCC GGGAGGCAGTGCTGATCCGGCTGCTCCTCCAGCCCTTCAGACGAGATCCTGTTTCAGCTAAATGCAGGGAAACTCAATGTTTTTTTAAGTTTTGTTTTCCCTTTAAAGCCTT TTTTTAGGCCACATTGACAGTGGTGGGCGGGGAGAAGATAGGGAACACTCATCCCTGGTCGTCTATCCCAGTGTGTGTTTAACATTCACAGCCCAGAACCACAGATGTGTCT GGGAGAGCCTGGCAAGGCATTCCTCATCACCATCGTGTTTGCAAAGGTTAAAACAAAAACAAAAAACCACAAAAATAAAAAACAAAAAAAACAAAAAACCCAAAAAAAAAAA AAAAAAGAGTCAGCCCTTGGCTTCTGCTTCAAACCCTCAAGAGGGGAAGCAACTCCGTGTGCCTGGGGTTCCCGAGGGAGCTGCTGGCTGACCTGGGCCCACAGAGCCTGGC TTTGGTCCCCAGCATTGCAGTATGGTGTGGTGTTTGTAGGCTGTGGGGTCTGGCTGTGTGGCCAAGGTGAATAGCACAGGTTAGGGTGTGTGCCACACCCCATGCACCTCAG GGCCAAGCGGGGGCGTGGCTGGCCTTTCAGGTCCAGGCCAGTGGGCCTGGTAGCACATGTCTGTCCTCAGAGCAGGGGCCAGATGATTTTCCTCCCTGGTTTGCAGCTGTTT TCAAAGCCCCCGATAATCGCTCTTTTCCACTCCAAGATGCCCTCATAAACCAATGTGGCAAGACTACTGGACTTCTATCAATGGTACTCTAATCAGTCCTTATTATCCCAGC TTGCTGAGGGGCAGGGAGAGCGCCTCTTCCTCTGGGCAGCGCTATCTAGATAGGTAAGTGGGGGCGGGGAAGGGTGCATAGCTGTTTTAGCTGAGGGACGTGGTGCCGACGT CCCCAAACCTAGCTAGGCTAAGTCAAGATCAACATTCCAGGGTTGGTAATGTTGGATGATGAAACATTCATTTTTACCTTGTGGATGCTAGTGCTGTAGAGTTCACTGTTGT ACACAGTCTGTTTTCTATTTGTTAAGAAAAACTACAGCATCATTGCATAATTCTTGATGGTAATAAATTTGAATAATCAGATTTCT
173
MAPTWGPG1WSVVGPMGLLVV LVGGCAAEEPPRFIKEPKD<3IGV8GGVASFVCQATGDPKPRVTWNKKGKKVNSQRFETIEFDESAGAVLRIQPLRTPRDENVYECVAQNS VGEITVHAK TVLREDQLPSGFPNIDMGPQLKWERTRTATMLCAASGNPDPEIT FKDFLPVDPSASNGRIKQ RSETFESTPIRGALQIESSEETDQGKYECVATNSAGV RYSSPANLYVRELREVRRVAPRFS ILPMSHEIMPGGNVNITCVAVGSPMPYVK NQGAEDLTPEDDMPVGRNVLELTDVKDSANYTCVAMSS GVIEAVAQITVKSLPKAPG TPMVTENTATSITITHDSGNPDPVSYYVIEYKSKSQDGPYQIKEDITTTRYSIGGLSPNSEYEI VSAVNSIGQGPPSESWTRTαEQAPASAPRNVQARMLSATTMIVQWE EPVEPNGLIRGYRVYYTMEPEHPVGNWQKHNVDDS LTTVG8LLEDETYTVRVLAFTEVGDGPLSDPIQVKTQQGVPGQPMNLRAEARSET8 ITLSWSPPRQESI IKYELLF REGDHGREVGRTFDPTTSYWEDLKPNTEYAFRLAARSPQGLGAFTPWRQRTLQSKPSAPPQDVKCVSVRSTAILVSWRPPPPETHNGA VGYSVRYRPLGSEDPEPKEVN GIPPTTTQILLEALEKWTQYRITTVAHTEVGPGPESSPVWRTDEDVPSAPPRKVEAEALNATAIRVLWLGPVPGRQHGQIRGYQVHYVRMEGAEGRGPPRIKDVMLADAQ ETDDT EYE^WITNLQPETAYSITVAAYTMKGDGARSKPKVVVTKGAVLGRPTLS QQTPEGS LARWEPPAGTAEDQVLGYR QFGREDSTPLATLEFPPSEDRYTASGVH KGATYVFRLAARSRGGLGEEAAEVLS I PEDTPRGHPQILEAAGNASAGTVLLRWLPFVPAERNGAIVKYTVAVREAGALGPARETELPAAAEPGAENAVTLQGLKPDTAYDL QVRAHTRRGPGPFεPPVRYRTFLRDQVSPKKFK rKMIMKTSVLLSWEFPDNYNSPTPYKIQYNGLTLDVDGRTTKKLITHLKPHTFYWFVLTNRGSSLGGLQQTVTAWTAFN LLNGKPSVAPKPDADGFIMVYLPDGQSPVPVQSYFIλΛWPLRKSRGGQFLTPLGSPEDMDLEELIQDISRLςRRTVRHSRQLEVPRPYIAARFSVLPPTFHPGDQKQYGGFD NRG EPGHRYVLF /IΛVLQKSEPTFAASPFSDPFQLDNPDPQPIVDGEEGLIVTVIGEVIΛVVFI ICIVIAILLYKNKPDSKRKDSEPRTKCLLNNADI-APHHPKDPVEMRRI NFQTPDSGLRSPLREPGFHFESMLSHPPI PIADMAEHTERLKANDSLKLSQEYESIDEGQQFTWEHSNLEVNKPKNRYANVIAYDHFRVII,QPIEGIMGSDYINANYVDGYR RQNAYIATQGPL,PETFGDFWPJW EQRSATIVMMTRLEEKSRIKCDQY PNRGTETYGFIQVTLLDTIELATFCVRTFSLHKNGSSEKREVRQFQFTAWPDHGVPEYPTPFL AFLRRVKTCNP DAGPIV HCSAG G TGCFIVIDA lLERIKPEKTVDV^GHVTLMRSQ ^r ^WQTEDQYSFIHEALLEAVGCGNTEVPARS YAYIςKLAQVEPGEHVTGM ELEFKRLANSKAHTSRFISANLPCNKFKNRLVNIMPYESTRVCLQPIRGVEGSDYINASFIDGYRQQKAYIATQGPLAETTEDFWRMLWENNSTIWMLTKLREMGREKCHQ Y PAERSARYQYFWDPMAEYN PQYI REFKVTDARDGQSRTVRQFQFTD PEQGVPKSGEGFIDFIGQλWKTKEQFGQDGPISVHCSAGVGRTGVFIT SIVLERMRYEG WDIFQTVKMLRTQRPAMVQTEDEYQFCYQAALEYLGSFDHYAT
174
CGGCCAGCCTCCAGACGTTGCCCCATCTGACGCTCGGCTCGAGGCCTCTCTGTGAGGGACCGGGGGGCCATCCCCCTCCAGGGCGGAGATCGGAGGTCGCTGCCAAGCATGG CGCCCACCTGGGGCCCTGGCATGGTGTCTGTGGTTGGTCCCATGGGCCTCCTTGTGGTCCTGCTCGTTGGAGGCTGTGCAGCAGAAGAGCCCCCCAGGTTTATCAAAGAACC CAAGGACCAGATCGGCGTGTCGGGGGGTGTGGCCTCTTTCGTGTGTCAGGCCACGGGTGACCCCAAGCCACGAGTGACCTGGAACAAGAAGGGCAAGAAGGTCAACTCTCAG CGCTTTGAGACGATTGAGTTTGATGAGAGTGCCGGGGCAGTGCTGAGGATCCAGCCGCTGAGGACACCGCGGGATGAAAACGTGTACGAGTGTGTGGCCCAGAACTCGGTTG GGGAGATCACAGTCCATGCCAAGCTTACTGTCCTCCGAGAGGACCAGCTGCCCTCTGGCTTCCCCAACATCGACATGGGCCCACAGTTGAAGGTGGTGGAGCGGACACGGAC AGCCACCATGCTCTGTGCAGCCAGCGGCAACCCTGACCCTGAGATCACCTGGTTCAAGGACTTCCTGCCTGTGGATCCTAGTGCCAGCAATGGACGCATCAAACAGCTGCGA TCAGAAACCTTTGAAAGCACTCCGATTCGAGGAGCCCTGCAGATTGAAAGCAGTGAGGAAACCGACCAGGGCAAATATGAGTGTGTGGCCACCAACAGCGCCGGCGTGCGCT ACTCCTCACCTGCCAACCTCTACGTGCGAGAGCTTCGAGAAGTCCGCCGCGTGGCCCCGCGCTTCTCCATCCTGCCCATGAGCCACGAGATCATGCCAGGGGGCAACGTGAA CATCACCTGCGTGGCCGTGGGCTCGCCCATGCCATACGTGAAGTGGATGCAGGGGGCCGAGGACCTGACCCCCGAGGATGACATGCCCGTGGGTCGGAACGTGCTGGAACTC ACAGATGTCAAGGACTCGGCCAACTACACCTGCGTGGCCATGTCCAGCCTGGGCGTCATTGAGGCGGTTGCTCAGATCACGGTGAAATCTCTCCCCAAAGCTCCCGGGACTC CCATGGTGACTGAGAACACAGCCACCAGCATCACCATCACGTGGGACTCGGGCAACCCAGATCCTGTGTCCTATTACGTCATCGAATATAAATCCAAGAGCCAAGACGGGCC GTATCAGATTAAAGAGGACATCACCACCACACGTTACAGCATCGGCGGCCTGAGCCCCAACTCGGAGTACGAGATCTGGGTGTCGGCCGTCAACTCCATCGGCCAGGGGCCC CCCAGCGAGTCCGTGGTCACCCGCACAGGCGAGCAGGCCCCGGCCAGCGCGCCGCGGAACGTGCAAGCCCGGATGCTCAGCGCGACCACCATGATTGTGCAGTGGGAGGAGC CGGTGGAGCCCAACGGCCTGATCCGCGGCTACCGCGTCTACTACACCATGGAACCGGAGCACCCCGTGGGCAACTGGCAGAAGCACAACGTGGACGACAGCCTGCTGACCAC CGTGGGCAGCCTGCTGGAGGACGAGACCTACACCGTGCGGGTGCTCGCCTTCACCTCCGTCGGCGACGGGCCCCTCTCGGACCCCATCCAGGTCAAGACGCAGCAGGGAGTG CCGGGCCAGCCCATGAACCTGCGGGCCGAGGCCAGGTCGGAGACCAGCATCACGCTGTCCTGGAGCCCCCCGCGGCAGGAGAGTATCATCAAGTACGAGCTCCTCTTCCGGG AAGGCGACCATGGCCGGGAGGTGGGAAGGACCTTCGACCCGACGACTTCCTACGTGGTGGAGGACCTGAAGCCCAACACGGAGTACGCCTTCCGCCTGGCCGCCCGCTCGCC GCAGGGCCTGGGCGCCTTCACCCCCGTGGTGCGGCAGCGCACGCTGCAGTCCAAACCGTCAGCCCCCCCTCAAGACGTTAAATGTGTCAGCGTGCGCTCCACGGCCATTTTG GTAAGTTGGCGCCCGCCGCCGCCGGAAACGCACAACGGGGCCCTGGTGGGCTACAGCGTCCGCTACCGACCGCTGGGCTCAGAGGACCCGGAACCCAAGGAGGTGAACGGCA TCCCCCCGACCACCACTCAGATCCTGCTGGAGGCCTTGGAGAAGTGGACCCAGTACCGCATCACGACTGTCGCTCACACAGAGGTGGGACCAGGGCCCGAGAGCTCACCCGT GGΓCGTCCGCACCGACGAGGATGTGCCCAGCGCGCCGCCGCGGAAGGTGGAGGCGGAGGCGCTCAACGCCACGGCCATCCGCGTGCTGTGGCTCGGCCCTGTGCCCGGCCGG CAGCACGGCCAGATCCGCGGCTACCAGGTCCACTACGTGCGCATGGAGGGCGCCGAGGGCCGCGGGCCGCCGCGCATCAAGGACGTCATGCTGGCCGATGCCCAGTGGGAGA CGGATGACACGGCCGAATATGAGATGGTCATCACAAACTTGCAGCCTGAGACCGCGTACTCCATCACGGTAGCCGCCTACACCATGAAGGGCGATGGCGCTCGCAGCAAACC CAAGGTGGTTGTGACCAAGGGAGCAGTGTTGGGCCGCCCAACCCTGTCGGTGCAGCAGACCCCCGAGGGCAGCCTGCTGGCACGCTGGGAGCCCCCGGCTGGCACCGCGGAG GACCAGGTGCTGGGCTACCGCCTGCAGTTTGGCCGTGAGGACTCGACGCCCCTGGCCACCCTGGAGTTCCCGCCCTCCGAGGACCGCTACACGGCATCAGGCGTGCACAAGG GΒGCCACGTATGTGTTCCGGCTTGCGGCCCGGAGCCGGGGCGGCCTGGGCGAGGAGGCAGCCGAGGTCCTGAGCATCCCGGAGGACACGCCCCGTGGCCACCCGCAGATTTT GGAAGCCGCCGGCAACGCCTCGGCCGGGACCGTCCTTCTCCGCTGGCTGCCACCCGTGCCCGCCGAGCGCAACGGGGCCATCGTCAAATACACGGTGGCCGTGCGTGAGGCC GGTGCCCTGGGCCCTGCCCGAGAGACTGAGCTGCCGGCAGCGGCTGAGCCGGGCGCGGAGAACGCCGTCACGCTGCAGGGCCTGAAGCCCGACACGGCCTATGACCTCCAAG TGCGAGCCCACACGCGCCGGGGCCCTGGCCCCTTCAGCCCCCCCGTCCGCTACCGGACGTTCCTGCGGGACCAAGTCTCGCCCAAGAACTTCAAGGTGAAAATGATCATGAA GACATCAGTTCTGCTCAGCTGGGAGTTCCCTGACAACTACAACTCACCCACACCCTACAAGATCCAGTACAATGGGCTCACACTGGATGTGGATGGCCGTACCACCAAGAAG CTCATCACGCACCTCAAGCCCCACACCTTCTACAACTTTGTGCTGACCAATCGCGGCAGCAGCCTGGGCGGCCTCCAGCAGACGGTCACCGCCTGGACTGCCTTCAACCTGC TCAACGGCAAGCCCAGCGTCGCCCCCAAGCCTGATGCTGACGGCTTCATCATGGTGTATCTTCCTGACGGCCAGAGCCCCGTGCCTGTCCAGAGCTATTTCATTGTGATGGT GCCACTGCGCAAGTCTCGTGGAGGCCAATTCCTGACCCCGCTGGGTAGCCCAGAGGACATGGATCTGGAAGAGCTCATCCAGGACATCTCACGGCTACAGAGGCGCACCGTG CGGCACTCGCGTCAGCTGGAGGTGCCCCGGCCCTATATTGCAGCTCGCTTCTCTGTGCTGCCACCCACGTTCCATCCCGGCGACCAGAAGCAG'IATGGCGGCTTCGATAACC GGGGCCTGGAGCCCGGCCACCGCTATGTCCTCTTCGTGCTTGCCGTGCTTCAGAAGAGCGAGCCTACCTTTGCAGCCAGTCCCTTCTCAGACCCCTTCCAGCTGGATAACCC GGACCCCCAGCCCATCGTGGATGGCGAGGAGGGGCTTATCTGGGTGATCGGGCCTGTGCTGGCCGTGGTCTTCATAATCTGCATTGTCATTGCTATCCTGCTCTACAAGAAC AACCCGACAGTAAACGCAAGGACTCAGAACCCCGCACCAAATGCCTCCTGAACAATGCCGACCTCGCCCCTCACCACCCCAAGGACCCTGTGGAAATGAGACGCATTAACT TCCAGACTCCAGATTCAGGCCTCAGGAGCCCCCTCAGGGAGCCGGGGTTTCACTTTGAAAGCATGCTTAGCCACCCGCCAATTCCCATCGCAGACATGGCGGAGCACACGGA GCGGCTCAAGGCCAACGACAGCCTCAAGCTCTCCCAGGAGTATGAGTCCATCGACCCTGGACAGCAGTTCACATGGGAACATTCCAACCTGGAAGTGAACAAGCCGAAGAAC CGCTATGCCAACGTCATCGCCTATGACCACTTCCGTGTCATCCTCCAGCCCATTGAAGGCATCATGGGCAGTGATTACATCAATGCCAACTATGTGGACGGCTACCGGCGTC GAACGCGTACATTGCCACGCAGGGGCCGCTGCCTGAGACCTTTGGGGACTTCTGGCGTATGGTGTGGGAGCAGCGGTCGGCGACCATCGTCATGATGACGCGGCTGGAGGA GAAGTCACGGATCAAGTGTGATCAGTATTGGCCCAACAGAGGCACGGAGACCTACGGCTTCATCCAGGTCACGTTGCTAGATACCATCGAGCTGGCCACATTCTGCGTCAGG ACATTCTCΤCTGCACAAGAATGGCTCCAGTGAGAAACGCGAGGTCCGCCAGTTCCAGTTTACGGCGTGGCCGGACCA'IGGCGTGCCCGAATACCCAACGCCCTTCCTGGCTT TCCTGCGGAGAGTCAAGACCTGCAACCCGCCAGATGCCGGCCCCATCGTGGTTCACTGCAGTGCCGGTGTGGGCCGCACAGGCTGCTTTATCGTCATCGACGCCATGCTTGA GCGGATCAAGCCAGAGAAGACAGTCGATGTCTATGGCCACGTGACGCTCATGAGGTCCCAGCGCAACTACATGGTGCAGACGGAGGACCAGTACAGCTTCATCCACGAGGCC CTGCTGGAGGCCGTGGGCTGTGGCAACACAGAAGTGCCCGCACGCAGCCTCIATGCCTACATCCAGAAGCTGGCCCAGGTGGAGCCTGGCGAACACGTCACTGGCATGGAAC TCGAGTTCAAGCGGCTGGCTAACTCCAAGGCCCACACGTCACGCTTCATCAGTGCCAATCTGCCTTGTAACAAGTTCAAGAACCGCCTGGTGAACATCATGCCCTATGAGAG CACACGGGTCTGTCTGCAACCCATCCGGGGTGTGGAGGGCTCTGACTACATCAACGCCAGCTTCATTGATGGCTATAGGCAGCAGAAGGCCTACATCGCGACACAGGGGCCG CTGGCGGAGACCACGGAAGACTTCTGGCGCATGCTGTGGGAGAACAATTCGACGATCGTGGTGATGCTGACCAAGCTGCGGGAGATGGGCCGGGAGAAGTGTCACCAGTACT GGCCGGCCGAGCGCTCTGCCCGCTACCAGTACTTTGTGGTAGATCCGATGGCAGAATACAACATGCCTCAGTATATCCTGCGAGAGTTCAAGGTCACAGA'IGCCCGGGATGG CCAGTCCCGGACTGTCCGGCAGTTCCAGTTCACAGACTGGCCGGAACAGGGTGTGCCAAAGTCGGGGGAGGGCTTCATCGACTTCATTGGCCAAGTGCATAAGACTAAGGAG CAGTTTGGC'CAGGACGGCCCCATCTCTGTCCACTGCAGTGCCGGCGTGGGCAGGACGGGCGTCTTCATCACGCTTAGCATCGTGCTGGAGCGGATGCGGTATGAAGGCGTGG TGGACATCTTTCAGACGGTGAAGATGCTACGAACCCAGCGGCCGGCCATGGTGCAGACAGAGGATGAGTACCAGTTCTGTTACCAGGCGGCACTGGAGTACCTCGGAAGCTT TGACCACTATGCAACCTAAAGCCATGGTCCCCCCCAGGCCCGACACCACTGGCCCCGGATGCCTCTGCCCCTCCCGGGCGGACCTCCTGAGGCCTGGACCCCCAGTGGGCAG GGCAGGAGGTGGCAGCGGCAGCAGCTGTGTTTTTCIGCACCATTTCCGAGGACGACGCATCCCCTCGAGCCCCCCCACCGGCCCCGGCCGCCCCAGCGACCTCCCTGGCACC GGCCGCCGCCTTCAAATACTTGGCACATTCCTCCTTTCCTTCCAATTCCAAAACCAGATTCCGGGGTGGGGGGTGGGGGGATGGTGAGCAAATAGGAGTGCTCCCCAGAACC AGAGGAGGGTGGGGCACAGACCATAGACGGACCCCTCGTCCTCCCCCAGCGGTGGTAGGGGGACCCGGGGGGCTCCTCCCCGCTCTGCACC
175
MEMEKEFEQIDKSGS AAIYQDIRHEASDFPCRVAK PKNKNRNRYRDVSPFDHSRIK HQEDNDYINASLIKMEEAQRSYILTQGP PNTCGHF EIWWEQKSRGVVMLNR
VMEKGSLKCAQY PQKEEKEMIFEDTNLKLTLISEDIKSYYTVRQ ELENLTTQETREILHFHYTTWPDFGVPESPASFLNFLFKVRESGSLSPEHGPλAAfflCSAGIGRSGT
FCL_^TC L ^TOKRKDPSSVDIKKV EMRKFRMGLIQTADQ RFSYLAVIEGAKFIMGDSSVQDQ KELSHEDLEPPPEHIPPPPRPPKRILEPHNGKCREFFP HQWVKE
ETQEDKDCPIKEEKGSPLNAAPYGIESMSQDTEVRSRWGGSLRGAQAASPAKGEPSLPEKDEDHALSYWKPFLVNMCVATVLTAGAYLCYRF FNSN'I
176
GCGCGACGCGGCCTAGAGCGGCAGACGGCGCAGTGGGCCGAGAAGGAGGCGCAGCAGCCGCCCTGGCCCGTCATGGAGATGGAAAAGGAGTTCGAGCAGATCGACAAGTCCG GGAGCTGGGCGGCCATTTACCAGGATATCCGACATGAAGCCAGTGACTTCCCATGTAGAGTGGCCAAGCTTCCTAAGAACAAAAACCGAAATAGGTACAGAGACGTCAGTCC CTTTGACCATAGTCGGATTAAACTACATCAAGAAGATAATGACTATATCAACGCTAGTTTGATAAAAATGGAAGAAGCCCAAAGGAGTTACATTCTTACCCAGGGCCCTTTG CCTAACACATGCGGTCACTTTTGGGAGATGGTGTGGGAGCAGAAAAGCAGGGGTGTCGTCATGCTCAACAGAGTGATGGAGAAAGGTTCGTTAAAATGCGCACAATACTGGC CACAAAAAGAAGAAAAAGAGATGATCTTTGAAGACACAAATTTGAAATTAACATTGATCTCTGAAGATATCAAGTCATATTATACAGTGCGACAGCTAGAATTGGAAAACCT TACAACCCAAGAAACTCGAGAGATCTTACATTTCCACTATACCACATGGCCTGACTTTGGAGTCCCTGAATCACCAGCCTCATTCTTGAACTTTCTTTTCAAAGTCCGAGAG TCAGGGTCACTCAGCCCGGAGCACGGGCCCGTTG1GGTGCACTGCAGTGCAGGCATCGGCAGGTCTGGAACCTTCTGTCTGGCTGATACCTGCCTCTTGCTGATGGACAAGA GGAAAGACCCTTCTTCCGTTGATATCAAGAAAGTGCTGTTAGAAATGAGGAAGTTTCGGATGGGGCTGATCCAGACAGCCGACCAGCTGCGCTTCTCCTACCTGGCTGTGAT CGAAGGTGCCAAATTCATCATGGGGGACTCTTCCG GCAGGATCAGTGGAAGGAGCTTTCCCACGAGGACCTGGAGCCCCCACCCGAGCATATCCCCCCACCTCCCCGGCCA CCCAAACGAATCCTGGAGCCACACAATGGGAAA'IGCAGGGAGTTCTTCCCAAATCACCAGTGGGTGAAGGAAGAGACCCAGGAGGATAAAGACTGCCCCATCAAGGAAGAAA AAGGAAGCCCCTTAAARGCCGCACCCTACΣΣCATCGAAAGCATGAGTCAAGACACTGAAGTTAGAAGTCGGGTCGTGGGGGGAAGTCTTCGAGGTGCCCAGGCTGCCTCCCC AGCCAAAGGGGAGCCGRCACTGCCCGAGAAGGACGAGGACCATGCACTGAGTTACTGGAAGCCCTTCCTGGTCAACATGTGCGTGGCTACGGTCCTCACGGCCGGCGCTTAC CTCTGCTACAGGTTCCRGRTCAACAGCAACACATAGCCTGACCCTCCTCCACTCCACCTCCACCCACTGTCCGCCTCTGCCCGCAGAGCCCACGCCCGACTAGCAGGCATGC CGCGGTAGGTAAGGGCCGCCGGACCGCGTAGAGAGCCGGGCCCCGGACGGACGTTGGTTCTGCACTAAAACCCATCTTCCCCGGATGTGTGTCTCACCCCTCATCCTTTTAC TTTTTGCCCCTTCCACΓΓΓGAGTACCAAATCCACAAGCCATTTTTTGAGGAGAGTGAAAGAGAGTACCATGCTGGCGGCGCAGAGGGAAGGGGCCTACACCCGTCTTGGGGC TCGCCCCACCCAGGGCΓCCCTCCTGGAGCATCCCAGGCGGGCGGCACGCCAGACAGCCCCCCCCTTGAATCTGCAGGGAGCAACTCTCCACTCCATATTTATTTAAACAATT TTTTCCCCAAAGGCATCCAΓAGTGCACTAGCATTTTCTTGAACCAATAATGTATTAAAATTTTTTGATGTCAGCCT'IGCATCAAGGGCTTTATCAAAAAGTACAATAATAAA TCCTCAGGTAGTACTGGGAATGGAAGGCTTTGCCATGGGCCTGCTGCGTCAGACCAGTACTGGGAAGGAGGACGGTTGTAAGCAGTTGTTATTTAGTGATATTGTGGGTAAC GTGAGAAGATAGAACAARGCTATAATATATAATGAACACGTGGGTATTTAATAAGAAACATGATGTGAGATTACTTTGTCCCGCTTATTCTGCTCCCTGTTATCTGCTAGAT CTAGTTCTCAATCACTGCΓCCCCCGTGTGTATTAGAATGCATGTAAGGTCTTCTTGTGTCCTGATGAAAAATATGTGCTTGAAATGAGAAACTTTGATCTCTGCTTACTAAT GTGCCCCATGTCCAAGRCCAACCTGCCTGTGCATGACCTGATCATTACATGGCTGTGGTTCCTAAGCCTGTTGCTGAAGTCATTGTCGCTCAGCAATAGGGTGCAGTTTTCC AGGAATAGGCATTTGCCRAATTCCTGGCATGACACTCTAGTGACTTCCTGGTGAGGCCCAGCCTGTCCTGGTACAGCAGGGTCTTGCTGTAACTCAGACATTCCAAGGGTAT GGGAAGCCATATTCACACCΓCACGCTCTGGACATGATTTAGGGAAGCAGGGACACCCCCCGCCCCCCACCTTTGGGATCAGCCTCCGCCATTCCAAGTCGACACTCTTCTTG AGCAGACCGTGATTTGGAAGAGAGGCACCTGCTGGAAACCACACTTCTTGAAACAGCCTGGGTGACGGTCCTTTAGGCAGCCTGCCGCCGTCTCTGTCCCGGTTCACCTTGC CGAGAGAGGCGCGTCTGCCCCACCCTCAAACCCTGTGGGGCCTGATGGTGCTCACGACTCTTCCTGCAAAGGGAACTGAAGACCTCCACATTAAGTGGCTTTTTAACATGAA AAACACGGCAGCTGTAGCRCCCGAGCTACTCTCTTGCCAGCATTTTCACATTTTGCCT TCTCGTGGTAGAAGCCAGTACAGAGAAATTCTGTGGTGGGAACATTCGAGGTG TCACCCTGCAGAGCTAΓGGΓGAGGTGTGGATAAGGCT AGGTGCCAGGCTGTAAGCATTCTGAGCTGGCTTGTTGTTTTTAAGTCCTGTATATGTATGTAGTAGTTTGGGTG TGTATATATAGTAGCAΓΓΓCAAAATGGACGTACTGGTTTAACCTCCTATCCTTGGAGAGCAGCTGGCTCTCCACCTTGTTACACATTATGTTAGAGAGGTAGCGAGCTGCTC TGCTATGTCCTTAAGCCAAΓATTTACTCATCAGGTCATTATTTTTTACAATGGCCATGGAATAAACCATTTTTACAAAA
177
MSSNSDTGDLQESLKHG rPIGAG PDPΛGSPIPARGRLVMLPKVETEA GLARSHGEOGQMPEN QVSQFraWNYEYDEDLEELCPVCGDKVSGYHYGLLTCESCKGFFKR TVQNNKRYTCIENQNCQIDKTQRKRCPYCRFQKCLSVGMKLEAVPJffiRMRGGRNKFGPMYKRDRA KQQKKALIRANGLKLEAMSQVIQAMPSD TISSAIQNIHSASKG P LNHAA PPTDYDRSPFVTSPISMTMPPHGSLOGYQTYGHFPSRAIKSEYPDPYTSSPESIMGYSYMDSYQTSSPASIPH ILELLKCEPDEPQVQAKIMAYLQQEQANRSKH EKLSTFGLMCKMADQT FSIVEWARSSIFFRELKVDDCMKLLQNCWSELLILDHIYRQVVHGKEGSIFLVTGQQVDYSIIASQAGAT NHLMSHAQELVAKLRSLQFDQREF VCLKFLV FSLDVKNLENFQLVEGVQEQVNAALLDYTMCNYPQQTEKFGQLLLRLPEIRAISMQAEEY YYKHLNGDVPYNNLLIEM HAKRA
178
TCCTTCCCAAGGCCACGAAATTTGACAAGCTGCACTTTTCTTTTGCTCAATGATTTCTGCTTTAAGCCAAAGAACTGCCTATAATTTCACTAAGAATGTCTTCTAATTCAGA TAC GGGGATTTACAAGAGΓCTTTAAAGCACGGACTTACACCTATTGTGTCTCAATTTAAAATGGTGAATTACTCCTATGATGAAGATCTGGAAGAGCTTTGTCCCGTGTGT GGAGATAAAGTGTCTGGGRACCATTA GGGCTCCTCACCTGTGAAAGCTGCAAGGGATTTTTTAAGCGAACAGTCCAAAATAATAAAAGGTACACATGTATAGAAAACCAGA ACTGCCAAATTGACAAAACACAGAGAAAGCGTTGTCCTTACTGTCGTTTTCAAAAATGTCTAAGTGTTGGAATGAAGCTAGAAGCTGTAAGGGCCGACCGAATGCGTGGAGG AAGGAATAAGTTTGGGCCAAΓGTACAAGAGAGACAGGGCCCTGAAGCAACAGAAAAAAGCCCTCATCCGAGCCAA'IGGACTTAAGCTAGAAGCCATGTCTCAGGTGATCCAA GCTATGCCCTCTGACCTGACCATTTCCTCTGCAATTCAAAACATCCACTCTGCCTCCAAAGGCCTACCTCTGAACCATGCTGCCTTGCCTCCTACAGACTATGACAGAAGTC CCTTTGTAACATCCCCCAΓΓAGCATGACAATGCCCCCTCACGGCAGCCTGCAAGGTTACCAAACATATGGCCACTTTCCTAGCCGGGCCATCAAGTCTGAGTACCCAGACCC CTATACCAGCTCACCCGAGTCCATAATGGGCTATTCA'IATATGGATAGTTACCAGACGAGOTCTCCAGCAAGCATCCCACATCTGATACTGGAACTTTTGAAGTGTGAGCCA
GATGAGCCTCAAGTCCAGGCTAAAATCATGGCCTATTIGCAGCAAGAGCAGGCTAACCGAAGCAAGCACGAAAAGCTGAGCACCTTTGGGCTTATG'IGCAAAATGGCAGATC
AAACTCTCTTCTCCATTGTCGAGTGGGCCAGGAG'IAG'IATCTTCTTCAGAGAACTTAAGGTTGATGACCAAATGAAGCTGCTTCAGAACTGCTGGAG'IGAGCTCTTAATCCT CGACCACATTTACCGACAAGTGGTACATGGAAAGGAAGGATCCATCTTCCTGGTTACTGGGCAACAAGTGGACTATTCCATAATAGCATCACAAGCCGGAGCCACCCTCAAC AACCTCATGAGTCATGCACAGGAGTTAGTGGCAAAACTTCGTTCTCTCCAGTTTGATCAACGAGAGTTCGTATGTCTGAAATTCTTGGTGCTCT'ITAGTTTAGATGTCAAAA ACCTTGAAAACTTCCAGCTGGTAGAAGGTGTCCAGGAACAAGTCAATGCCGCCCTGCTGGACTACACAATGTGTAACTACCCGCAGCAGACAGAGAAATTTGGACAGCTACT TCTTCGACTACCCGAAATCCGGGCCATCAGTATGCAGGCTGAAGAATACCTCIACTACAAGCACCTGAACGGGGATGTGCCCTATAATAACCTTCTCATTGAAATGTTGCAT GCCAAAAGAGCATAAGTTACAACCCCTAGGAGCTCTGCTTTCAAAACAAAAAGAGATTGGGGGAGTGGGGAGGGGGAAGAAGAACAGGAAGAAAAAAAGTACTCTGAACTGC TCCAAGCAACGCTAATTAAAAACTTGCTTTAAAGATATTGAATTTAAAAAGGCATAATAATCAAATACTTAATAGCAAATAAATGATGTATCAGGGTATTTGTATTGCAAAC
TGRGAATCAAAGGCTTCACAGCCCCAGAGGATTCCATATAAAAGACATTGTAATGGAGTGGATTGAACTCACAGATGGATACCAACACGGTCAGAAGAAAAACGGACAGAAC GGΓTCTTGTATATTTAAACTGATCTCCACTA'IGAAGAAATTTAGGAACTAATCTTATTAATTAGGCTTATACAGCGGGGGATTTGAGCTTACAGGATTCCTCCATGGTAAAG CTGAACTGAAACAATTCTCAAGAATGCATCAGCTGTACCTACAATAGCCCCTCCCTCTTCCTTTGAAGGCCCGAGCACCTCTGCCCTGTGGTCACCGAATCTGTACTAAGGA CCΓGTGTTCAGCCACACCCAGTGGTAGCTCCACCAAATCATGAACAGCCTAATTTTGAGTGTCTGTGTCTTAGACCTGCAAACAGCTAATAGGAAATTCTATTAATATGTTA GCΓTGCCATTTTAAATATGTTCTGAGGGTTGTTTTGTCTCGTGTTCATGATGTTAAGAAAATGCAGGCAGTATCCCTCATCTTATGTAAGTGTGAATTAATATTAAGGGAAA TGACTACAAACTTTCAAAGCAAATGCTCCATAGCTAAAGCAACTTAGACCTTATTTCTGCTACTGTTGCTGAAATGTGGCTTTGGCATTGTTGGATTTCATAAAAAATTTCT GGCAGGAAGTCTTGTTAGTATACATCAGTCTTTTTCATCATCCAAGTTTGTAGTTCATTTAAAAATACAACATTAAACACATTTTGCTAGGATGTCAAATAGTCACAGTTCT AAGTAGTTGGAAACAAAATTGACGCATGTTAATCTATGCAAAGAGAAAGGAAAGGATGAGGTGATGTATTGACTCAAGGTTCATTCTTGCTGCAATTGAACATCCTCAAGAG TTGGGATGGAAATGGTGATTTTTACATGTGTCCTGGAAAGATATTAAAGTAATTCAAATCTTCCCCAAAGGGGAAAGGAAGAGAGTGATACTGACCTTTTTAAGTCATAGAC CAAAGTCTGCTGTAGAACAAATATGGGAGGACAAAGAATCGCAAATTCTTCAAATGACTATTATCAGTATTATTAACATGCGATGCCACAGGTATGAAAGTCTTGCCTTATT TCACAATTTTAAAAGGTAGCTGTGCAGATGTGGATCAACATTTGTTTAAAATAAAGTATTAATACTTTAAAGTCAAAAAAAAAAAAAAA
179
MLSQVYRCGFQPFNQHLLPVWKCTTVFRSHCIQPSVIR«VRSWSNIPFITVPLSRTHGKSFAHR8ELKJ1AKRIVVKLGSAVVTRGDECGLALGRIJVSIVEQVSVLQNQGREM MLV SGAVAFGKQRLPJIEI LSQSVRQALHSGQNQLKEMAIPVLEARACAAAGQEGLMALYEAMFTQYSICAAQILV NLDFHDEQKRRNLNGTLHELLRMNIVPIVNTNDA VVPPAEPNSDLQGVISVKDLSΠ3SL-^RLAVEMKTDLLIVLSDVEGLFDSPPGSDDAKLIDIFYPGDQQSVTFGTKSRVGMGGMEAKVKAAL ALQGGTSVVIANGTHPKVSGH VIΓDIVEGKKVGTFFSEVKPAGPTVEQQGENIARSGGPΛIΛTLEPEQRAEIIHHLADLLTDQRDEILLANKKDLEEAEGRLAAPL KRLSLSTSK NSLAIGLRQIAASSQDS VGRV RRTRIAKNLELEQVTVPIGV LVIFESRPDCLPQVAA AIASGNGLLLKGGKEAAHSNRILHLLTQEALSIHGVKEAVQ VNTREEVEDLCRLDKMIDLIIPRGSSQ LVRDIQKAAKGIPVMGHSEGICHMYVDSEASVDKVTRLVRDSKCEYPAACNALETLLIHRDLLRTP FDQIIDMLRVEQVKIHAGPKFASYLTFSPSEVKSLRTEYGDLELC IEWDNVQDAIDHIHKYGSSHTDVIVTEDENTAEFFLQHVDSACVFWNASTRFSDGYRFGLGAEVGISTSRIHARGPVG EG LTTKWLLRGKDHWSDFSEHGSLKY HEN LPIPQRNTN
180
AGGGGGCGAAGGCGGCGGTGGTGAGGAAGATACTTTGGTTAGTGACCACATCGCAGCATGTTGAGTCAAGTTTACCGCTGTGGGTTCCAGCCCTTCAACCAACATCTTCTGC CCΓGGGTCAAGTGTACAACCGTCTTCAGATCTCATTGTATCCAGCCTTCAGTCATCAGACATGTTCGTTCTTGGAGCAACATCCCGTTTATCACTGTACCCCTCAGTCGTAC ACATGGCAAGTCCTTCGCCCACCGCAGTGAGCTGAAGCATGCCAAGAGAATCGTGGTGAAGCTCGGCAGTGCCGTGGTGACCCGAGGGGATGAATGTGGCCTGGCCCTGGGG CGCTTGGCATCTATTGTΓGAGCAGGTATCAGTGCTGCAGAATCAGGGCAGAGAGATGATGCTGGTGACCAGTGGAGCCGTAGCCTTTGGCAAACAACGCTTGCGCCATGAGA TCCTTCTGTCTCAGAGCGTGCGGCAGGCCCTCCACTCGGGGCAGAACCAGCTGAAAGAAATGGCAATTCCAGTCTTAGAGGCACGAGCCTGTGCAGCTGCCGGACAGAGTGG GCTGATGGCCTTGTATGAGGCTATGTTTACCCAGTACAGCATCTGTGCTGCCCAGATTTTGGTGACCAATTTGGATTTCCATGATGAGCAGAAGCGCCGGAACCTCAATGGA ACACTTCATGAACTCCTΓAGAATGAACATTGTCCCCATTGTCAACACAAATGATGCTGTTGTCCCCCCAGCTGAGCCCAACAGTGACCTGCAGGGGGTTATTAGTGTTAAAG AΓAATGATAGCCTGGCTGCCCGACTGGCTGTGGAAATGAAAACTGATCTCTTGAT'IGTTCTTTCAGATGTAGAAGGCCTTTTTGACAGCCCCCCAGGTTCAGATGATGCAAA GCTTATTGATATATTTTATCCCGGAGATCAGCAGTCTGTGACATTTGGAACCAAGTCTAGAGTGGGAATGGGTGGCATGGAAGCCAAGGTGAAAGCAGCCCTCTGGGCTTTG CAAGGTGGCACTTCTGTRGTTATTGCCAATGGAACCCACCCAAAGGTGTCTGGGCACGTCATCACAGACATTGTGGAGGGGAAGAAAGTTGGTACCTTCTTTTCAGAAGTAA AGCCTGCAGGCCCTACTGTTGAGCAGCAGGGAGAAATGGCGCGATCTGGAGGAAGGATGTTGGCCACCTTGGAACCTGAGCAGAGAGCAGAAATTATCCATCATCTGGCTGA TCTGTTGACGGACCAGCGTGATGAGATCCTGTTAGCCAACAAAAAAGACTTGGAGGAGGCAGAGGGGAGACTTGCAGCTCCTCTGCTGAAACGTTTAAGCCTCTCCACATCC AATTGAACAGCCTGGCCATCGGTCTGCGACAGAICGCAGCCTCCTCCCAGGACAGCGTGGGACGTGTTTTGCGCCGCACCCGAATCGCCAAAAACTTGGAACTGGAACAAG TGACTGTCCCAATTGGAGTTCTGCTGGTGATCTTTGAATCTCGTCCTGACTGTCTACCCCAGGTGGCAGCTTTGGCTATCGCAAGTGGCAATGGCTTGTTACTCAAAGGAGG GAAGGAGGCTGCACACAGCAACCGGATTCTCCACCTCCTGACCCAGGAGGCTCTCTCAATCCATGGAGTCAAGGAGGCCGTGCAACTGGTGAATACCAGAGAAGAAGTTGAA GATCTTTGCCGCCTAGACAAAATGATAGATCTGATCATTCCACGTGGCTCTTCCCAGCTGGTCAGAGACATCCAGAAAGCTGCTAAGGGGATTCCAGTGATGGGGCACAGCG
AAGGGATCTGTCACATGTATGTGGATTCCGAGGCCAGTGTTGATAAGGTCACCAGGCTAGTCAGAGACTCTAAATG'IGAATATCCAGCTGCCTGTAATGCTTTGGAGACTTT
GΓTAATCCACCGGGATCΓGCTCAGGACACCATTATTTGACCAGATCATTGATATGCTGAGAGTGGAACAGGTAAAAATTCATGCAGGCCCCAAATTTGCCTCCTATCTGACC RRCAGCCCCTCCGAAGTGAAGTCACTCCGAACTGAGTATGGGGACCTGGAATTATGCATTGAAGTAGTGGACAACGTTCAGGATGCCATTGACCACATCCACAAGTATGGCA GCTCCCACACGGATGTCATCGTCACAGAGGACGAAAACACAGCGGAGTTCTTCCTGCAGCACGTAGACAGTGCCTGTGTGTTCTGGAATGCCAGCACTCGCTTTTCTGATGG RTACCGCTTTGGACTGGAAGCTGAAGTGGGAATCAGTACATCGAGAATCCACGCCCGGGGACCAGTAGGACTTGAGGGACTGCTTACTACTAAGTGGCTGCTGCGAGGGAAG GACCACGTGGTCTCAGAΓTTCTCAGAGCATGGAAGTTTAAAATATCTTCATGAGAACCTCCCTATTCCTCAGAGAAACACCAACTGAAAAGAGCCAGGAAAACCCGGGAATT RRCCAAAAGGTCTTCACGTTAAACTTGTCTTATCRCAGGAGAGAGCCCGCTCTTGTCTCCCAGTTCCTGGTAGGGTCTGCCTGTTGGAAAGTGTACCTGGATGCTTCTGGGC
RATCTTCTAGGATTGAAAGGTGCATTTTCCCCATAAAAAAGGCGAGGAAAACCCATGGCTGCTTTGTGTCACCICAGTGACTTACAGTCCCCCTTGGCATTTAGTTGGTACT AGAGCCAGTCATCCTTAACAAATCTTTTCACATTTTATTTCTTTCACATGTAGTCATCTTCAAAAAGGAAAGATTTGGAATTTTAGAAAAGGGGCAACTCTTCTTTTTAGCA RTCTCATCAGAAAGTCACAAAAATCGATGGAATCATTTCCACTGGGAAGA'N'GACCTTTTGTATTTATTTGTGGGGTAAATTAATAAGCATTCCAGATGCTTGCAGCTTCCT GCATCCAGGAGATGCTGTGTTCCCCGTGATGCAGCTGGAACCCAAGCTGCAGCAGGAGATGCAAGTTTCAGGATGTTCCCCACTGAGCTGGAGGAATATCTACAGCAGTGAT GCTTGAAATTTTTGTATGAATTATTTTGTCGTCCTACCCTTTTCCTCCAAAACAAAAATTAGAGGATTATTTTAATACTTTGGATTCTTCCCCCTTTTTTGAGAAATAAAGT ΓTTTTATG
181
MGTRDDEYDY FKWLIGDSGVGKSNLLSRFTRNEFNLESKSTIGVEFATRSIQVDGKTIKAQIWDTAGQERYRRITSAYYRGAVGALLVYDIAKHLTYENVERW KELRDH ADSNIVIMLVGNKSDI-RHLRAVPTDEARAFAEKNNLSFIETΞALDSTNVEEAFKNILTEIYRIVSQKQIADRAAHDESPGNNVVDISVPPTTDGQKPNKLQCCQNL
182
CGGACAATGGGGACCCGGGACGACGAGTACGACTACCTATTCAAAGTGGTGCTCATCGGGGACTCAGGCGTGGGCAAGAGCAACCTGCTGTCGCGCTTCACCCGCAACGAGT ΓCAACCTGGAGAGCAAGAGCACCATCGGCGTGGAGTTCGCCACCCGCAGCATCCAGGTGGACGGCAAGACCATCAAGGCGCAGATCTGGGACACCGCTGGCCAGGAGCGCTA CCGCCGCATCACCTCCGCGTACTACCGTGGTGCAGTGGGCGCCCTGCTGGTGTACGACATCGCCAAGCACCTGACCTATGAGAACGTGGAGCGCTGGCTGAAGGAGCTGCGG GACCACGCAGACAGCAACATCGTCATCATGCTGGTGGGCAACAAGAGTGACC GCGCCACCTGCGGGCTGTGCCAACTGACGAGGCCCGCGCCTTCGCAGAAAAGAACAACT TGTCCTTCATCGAGACCTCAGCCTTGGATTCCACTAACGTAGAGGAAGCATTCAAGAACATCCTCACAGAGATCTACCGCATCGTGTCACAGAAACAGΔTCGCAGACCGCGC TGCCCACGACGAGTCCCCGGGGAACAACGTGGTGGACATCAGCGTGCCGCCCACCACGGACGGACAGAAGCCCAACAAGCTGCAGTGCTGCCAGAACCTGTGACCCCTGCGT CCTCCACCCAGCGTGCGTGCACGTCCTCC
183
MRSAAAAPRSPAVATESRRFAAAR PGWRSLQRPARRSGRGGGGAAPGPYPSAAPPPPGPGPPPSRQSSPPSASDCFGSNGNGGGAFRPGSRRLLGLGGPPRPFWVLLPLA
SPGAPPAAPTRASP GARASPPRSGVSLARPAPGCPRPACEPVYGPLTMSLKPQQQQQQQQQQQQQQQQQQQQQQEPPAAANVRKPGGSGXIIASPAAAPSPSSSSVSSSSAT APSSVVAATSGGGRPGLGRGRNSNKGLPQSTISFDGIYAN R VHILTSVVGSKCEVQVKNGGIYEGVFKTY8PKCDLVLDAAHEKSTESSSGPKREEI ESILFKCSDFVV VQFKDrøJSSYAKRDAFTDSAISAKVNGEHKEKDLEPVClAGELTA EE EALENDVSNσ DPNDMFRYNEENYGVVSTYDSSLSSYTVPLERDNSEEFLKREARANQLAEEIE SSAQYKARVALENDDRSEEEKYTAVQRNSSEREGHSI TRENKYIPPGQRNREVIS GSGRQNSPRMGQPGSGSMPSRSTSHTSDFNPNSGSDQRWNGGVFWPSPCPSPSS RPPSRYQSGPNSLPPRAATPTRPPSRPPSRPSRPPSHPSAHGSPAPVSTMPKRMSSEGPPRMSPKAQRHPRNHRVSAGRGSISSG EFVSHNPPSEAATPPVARTSPSGGT SSVVSGVPR SPKTHRPRSPRQNSIGNTPSGPVLASPQAGIIPTEAVAMPIPAASPTPASPASNRAV PSSEAKDSRLQDQRQNSPAGNKENIKPNETSPSFSKAENKGI8P VVSEH KQIDD KKFK DF QPSSTSES^mQLLNKN EGEKSRDLIKEKIEPSAKDSFIENSSSNC SGSSKP ε SIS SI S TEHKRG E TSOG QTSSPACKQEKD DKEEKKDAAEQVRK8TLNPNAKEFNPRSFSQPKPSTTPTSPRPQAQPSPSMVGHQQPTPVYTQPVCFAPNMMYPVPVSPGVQPLYPIPMTPMPVNQAKTYRAVPNMPQQRQD QHHQSAMMHPASAAGPPIAATPPAYεTQYVAY8PQQFPNQPLVQHVPHYQSQHPHΛrYSPVIQGNARMMAPPTHAQPGLVSεSATQYGAHEQTHAMYACPKLPYNKETSPSFY FAISTGSLAQQYAHPNATLHPHTPHPQPSATPTGQQQSQHGGSHPAPSPVQHHQHQAAQALHLASPQQQSAIYHAGLAPTPPSMTPASNTQSPQNSFPAAQQTVFTIHPSHV QPAYTNPPHMAHVPQAHVQSGMVPSHPTAHAPMMLNTTQPPGGPQAA AQSA QPIPVSTTAHFPYMTHPSVQAHHQQQL
184
ACCCCCGAGAAAGCAACCCAGCGCGCCGCCCGCTCCTCACGTGTCCCTCCCGGCCCCGGGGCCACCTCACGTTCTGCTTCCGTCTGACCCCTCCGACTTCCGGTAAAGAGTC CCTATCCGCACCTCCGCTCCCACCCGGCGCCTCGGCGCGCCCGCCCTCCGATGCGCTCAGCGGCCGCAGCTCCTCGGAGTCCCGCGGTGGCCACCGAGTCTCGCCGCTTCGC CGCAGCCAGGTGGCCCGGGTGGCGCTCGCTCCAGCGGCCGGCGCGGCGGAGCGGGCGGGGCGGCGGTGGCGCGGCCCCGGGACCGTATCCCTCCGCCGCCCCTCCCCCGCCC GGCCCCGGCCCCCCTCCCTCCCGGCAGAGCTCGCCTCCCTCCGCCTCAGACTGTTTTGGTAGCAACGGCAACGGCGGCGGCGCGTTTCGGCCCGGCTCCCGGCGGCTCCTTG GTCTCGGCGGGCCTCCCCGCCCCTTCGTCGTCGTCCTTCTCCCCCTCGCCAGCCCGGGCGCCCCTCCGGCCGCGCCAACCCGCGCCTCCCCGCTCGGCGCCCGTGCGTCCCC GCCGCGTTCCGGCGTCTCCITGGCGCGCCCGGCTCCCGGCTGTCCCCGCCCGGCGTGCGAGCCGGTGTATGGGCCCCTCACCATGTCGCTGAAGCCCCAGCAGCAGCAGCAG CAGCAGCAGCAACAGCAGCAGCAGCAACAGCAGCAGCAGCAGCAGCAGCAGCCGCCGCCCGCGGCTGCCAATGTCCGCAAGCCCGGCGGCAGCGGCCTTCTAGCGTCGCCCG CCGCCGCGCCTTCGCCGTCCTCGTCCTCGGTCTCCTCGTCCTCGGCCACGGCTCCCTCCTCGGTGGTCGCGGCGACCTCCGGCGGCGGGAGGCCCGGCCTGGGCAGAGGTCσ AAACAGTAACAAAGGACTGCCTCAGTCTACGATTTCTT1TGATGGAATCTATGCAAATATGAGGATGGTTCATATACTTACATCAGTTGTTGGCTCCAAATGTGAAGTACAA GTGAAAAATGGAGGTATATATGAAGGAGTTTTTAAAACTTACAGTCCGAAGTGTGATTTGGTACTTGATGCCGCACATGAGAAAAGTACAGAATCCAGTTCGGGGCCGAAAC GTGAAGAAATAATGGAGAGTATTTTGTTCAAATGTTCAGACTTTGTTGTGGTACAGTTTAAAGATATGGACTCCAGTTATGCAAAAAGAGATGCTTTTACTGACTCTGCTAT CAGTGCTAAAGTGAATGGCGAACACAAAGAGAAGGACCTGGAGCCCTGGGATGCAGGTGAACTCACAGCCAATGAGGAACTTGAGGCTTTGGAAAATGACGTATCTAATGGA TGGGATCCCAATGATATGTTTCGATATAATGAAGAAAATTATGGTGTAGTGTCTACGTATGATAGCAGTTTATCTTCGTATACAGTGCCCTTAGAAAGAGATAACTCAGAAG AATTTTTAAAACGGGAAGCAAGGGCAAACCAGT'IAGCAGAAGAAATTGAGTCAAGTGCCCAGTACAAAGCTCGAGTGGCCCTGGAAAATGATGATAGGAGTGAGGAAGAAAA ATACACAGCAGTTCAGAGAAATTCCAGTGAACGTGAGGGGCACAGCATAAACACTAGGGAAAATAAATATATTCCTCCTGGACAAAGAAATAGAGAAGTCATATCCTGGGGA AGTGGGAGACAGAATTCACCGCGTATGGGCCAGCCTGGATCGGGCTCCATGCCATCAAGATCCACTTCTCACACTTCAGATTTCAACCCGAATTCTGGTTCAGACCAAAGAG TAGTTAATGGAGGTGTTCCCTGGCCATCGCCTTGCCCATCTCCTTCCTCTCGCCCACCTTCTCGCTACCAGTCAGGTCCCAACTCTCTTCCACCTCGGGCAGCCACCCCTAC ACGGCCGCCCTCCAGGCCCCCCTCGCGGCCATCCAGACCCCCGTCTCACCCCTCTGCTCATGGTTCTCCAGCTCCTGTCTCTACTATGCCTAAACGCATGTCTTCAGAAGGG CCTCCAAGGATGTCCCCAAAGGCCCAGCGACATCCTCGAAATCACAGAGTTTCTGCTGGGAGGGGTTCCATATCCAGTGGCCTAGAATTTGTATCCCACAACCCACCCAGTG AAGCAGCTACTCCTCCAGTAGCAAGGACCAGTCCCTCGGGGGGAACGTGGTCATCAGTGGTCAGTGGGGTTCCAAGATTATCCCCTAAAACTCATAGACCCAGGTCTCCCAG ACAGAACAGTATTGGAAATACCCCCAGTGGGCCAGTTCTTGCTTCTCCCCAAGCTGGTATTATTCCAACTGAAGCTGTTGCCATGCCTATTCCAGCTGCATCTCCTACGCCT GCTAGTCCTGCATCGAACAGAGCTGTTACCCCTTCTAGTGAGGCTAAAGATTCCAGGCTTCAAGATCAGAGGCAGAACTCTCCTGCAGGGAATAAAGAAAATATTAAACCCA ATGAAACATCACCTAGCTTCTCAAAAGCTGAAAACAAAGGTATATCACCAGTTGTTTCTGAACATAGAAAACAGATTGATGATTTAAAGAAATTTAAGAATGATTTTAGGTT ACAGCCAAGTTCTACTTCTGAATCTATGGATCAACTACTAAACAAAAATAGAGAGGGAGAAAAATCAAGAGATTTGATCAAAGACAAAATTGAACCAAGTGCTAAGGATTCT TTCATTGAAAATAGCAGCAGCAACTGTACCAGTGGCAGCAGCAAGCCGAATAGCCCCAGCATTTCCCCTTCAATACTTAGTAACACGGAGCACAAGAGGGGACCTGAGGTCA CTTCCCAAGGGGTTCAGACTTCCAGCCCAGCATGTAAACAAGAGAAAGACGATAAGGAAGAGAAGAAAGACGCAGCTGAGCAAGTTAGGAAATCAACATTGAATCCCAATGC AAAGGAGTTCAACCCACGTTCCTTCTCTCAGCCAAAGCCTTCTACTACCCCAACTTCACCTCGGCCTCAAGCACAACCTAGCCCATCTATGGTGGGTCATCAACAGCCAACT CCAGTTTATACTCAGCCTGTTTGTTTTGCACCAAATATGATGTATCCAGTCCCAGTGAGCCCAGGCGTGCAACCTTTATACCCAATACCTATGACGCCCATGCCAGTGAATC AAGCCAAGACATATAGAGCAGTACCAAATATGCCCCAACAGCGGCAAGACCAGCATCATCAGAGTGCCATGATGCACCCAGCGTCAGCAGCGGGCCCACCGATTGCAGCCAC CCCACCAGCTTACTCCACGCAATATGTTGCCTACAGTCCTCAGCAGTTCCCAAATCAGCCCCTTGTTCAGCATGTGCCACATTATCAGTCTCAGCATCCTCATGTCTATAGT CCTGTAATACAGGGTAATGCTAGAATGATGGCACCACCAACACACGCCCAGCCTGGTTTAGTATCTTCTTCAGCAACTCAGTACGGGGCTCATGAGCAGACGCATGCGATGT ATGCATGTCCCAAATTACCATACAACAAGGAGACAAGCCCTTCTTTCTACTTTGCCATTTCCACGGGCTCCCTTGCTCAGCAGTATGCGCACCCTAACGCTACCCTGCACCC ACATACTCCACACCCTCAGCCTTCAGCTACCCCCACTGGACAGCAGCAAAGCCAACATGGTGGAAGTCATCCTGCACCCAGTCCTGTTCAGCACCATCAGCACCAGGCCGCC CAGGCTCTCCATCTGGCCAGTCCACAGCAGCAGTCAGCCATTTACCACGCGGGGCTTGCGCCAACTCCACCCTCCATGACACCTGCCTCCAACACGCAGTCGCCACAGAATA GTTTCCCAGCAGCACAACAGACTGTCTTTACGATCCATCCTTCTCACGTTCAGCCGGCGTATACCAACCCACCCCACATGGCCCACGTACCTCAGGCTCATGTACAGTCAGG AATGGTTCCTTCTCATCCAACTGCCCATGCGCCAATGATGCTAATGACGACACAGCCACCCGGCGGTCCCCAGGCCGCCCTCGCTCAAAGTGCACTACAGCCCATTCCAGTC TCGACAACAGCGCATTTCCCCTATATGACGCACCCTTCAGTACAAGCCCACCACCAACAGCAGTTGTAAGGCTGCCCTGGAGGΔACCGAAAGGCCAAATTCCCTCCTCCCTT CTACTGCTTCTACCAACTGGAAGCACAGAAAACTAGAATTTCATTTATTTTGTTTTTAAAATATATATGTTGATTTCTTGTAACATCCAATAGGAATGCTAACAGTTCACTT GCAGTGGAAGATACTTGGACCGAGTAGAGGCATTTAGGAACTTGGGGGCTATTCCATAATTCCATATGCTGTTTCAGAGTCCCGCAGGTACCCCAGCTCTGCTTGCCGAAAC TGGAAGTTATTTATTTTTTAATAACCCTTGAAAGTCATGAACACATCAGCTAGCAAAAGAAGTAACAAGAGTGATTCTTGCTGCTATTACTGCTAAAAAAAAAAAAAAAAAA A
185
M GDYRFLDHPQPMEILNLYLGDSLEPHPGECPRETCSHEDPPEPFEEQT ATDPPEPTRQNVPPWGSGVELTHLGSWVHQDGLEPCQEQTRATDPPESTRQDAPP GSGVE LTH GSPSAQREHRQNTASPGSPVNSHLPGSPKQNRSTSTQWFWAGILQAQMCVLDLEEELEKTEGLKAGLKCCLPTPPVDLPGDTG HSSPPENEDSGEDSSEPEGEGQA WLREGTPDSSPQWGAEEESMFFSNPLFLASPCSENSASGECFSWGASDSHAGVRTGPESPATLEFFLPΞDTVLWELESEPDLGDGAAISGHCTPPFPVPIYKPHSICWASVA AAEGAPAAPFGHGESEGDRLGPAPSAAPCVDEALTWESGCVGSDLGPAAHPVQPWASLΞPEGWQRGGPFWPQVILNSQDRDEREGGHPQESFPCTLAPCPWRSPASSPEPSS PESESRGPGPRPSPAS8QEGSPQLQHHSSGILPKWTLDASQSSLLETDGEQP8SLKKKEAGEAPKPGEEVKSEGTARPAETGDVQPDIH TSAEHENLRTPMNSS LPGSPM PQAQEPEEGQRPPAGDKXJ^GVRNNKVAWNLASRLYRLEGFRKSEVAAYLQKNNDFSRAVAEEYLSFFQFGGQSLDRA RSFLQA V SGETQERERILYQFSRRFHHCNPG IFPSVDSVHTLTCAIMLLNTDLHGQNIGKSMSCQEFITNLNG RIXMNFPKELLKALYWSIRSEKLEWAVDEEDTARPEKAQPSLPAGKMSKPFLQLAQDPTVPTYKQGILA RKMHQDADGKKTPWGKRGWKMFHTLLRGrLYFLKQGEDHC EGES VGQ^1VDEP GVHHSTΛTPATHYTKKPHVFQLRTADWRLYLFQAPTAKEMSS IARINLAAATHSA PPFPAAVGSQRRFVRPI PVGPAQSSLEEQHRSHENCLDAAADD LDLQRNLPERRGRGRELEEHRLRKEYLEYEKTRYETYVQLLVARLHCPSDALDLWEEQLGREAGGTR EPKLSLKKSHSSPSLHQDEAPTTAKVKRNISERRTYRKIIPKRNRNQL
186
TCCACACAGTGAGACCGTGAAAGCAGATGTCCGGGGCACTCCTGGGCAGCTTTTGCTCAGTGGATGATGGGTGACTACAGATTCCTTGACCACCCCCAGCCCATGGAAATTC TCAACCTGTACTTGGGAGACAGCCTGGAGCCCCACCCAGGAGAGTGCCCAAGGGAAACGTGCAGCCATGAGGATCCACCGGAGCCTTTCGAGGAGCAAACCTGGGCCACTGA CCCTCCTGAACCTACCAGACAAAATGTTCCTCCCTGGGGCTCCGGTGTGGAGCTCACACACCTGGGGAGCTGGGTCCATCAGGACGGGCTGGAGCCTTGCCAGGAGCAAACC CGGGCCACTGACCCTCCTGAATCTACCAGACAAGATGCTCCTCCCTGGGGCTCCGGTGTGGAGCTCACACACCTGGGGAGCCCCTCTGCCCAGAGGGAGCACAGGCAGAACA CAGCATCACCAGGGTCACCAGTGAACAGCCATCTACCGGGGAGCCCAAAGCAGAACCGGAGCACGTCCACACAGGTAGTGTTCTGGGCAGGCATCCTGCAGGCCCAGATGTG TGTCCTAGACCTGGAGGAGGAGCTGGAGAAGACGGAAGGGCTCAAGGCTGGGCTGAAATGCTGTCTCCCCACGCCCCCTGTGGACCTCCCCGGGGACACGGGCCTGCACTCC AGCCCACCTGAGAATGAAGACTCAGGGGAAGACAGCAGTGAGCCTGAGGGAGAGGGCCAGGCATGGCTGAGAGAGGGAACCCCAGACTCTTCCCCACAGTGGGGAGCTGAGG AGGAGAGCATGTICTTCAGCAACCCCCTCTTCCTGGCGAGTCCTTGCTCAGAGAACAGTGCTTCTGGAGAGTGCTTTTCCTGGGGGGCTTCAGACTCCCATGCAGGTGTGAG GACTGGACCTGAGAGCCCAGCGACTCTGGAGCCTCCCCTCCCAGAAGACACAGTGCTGTGGGAGCTGGAAAGTGAGCCAGATTTGGGGGACGGCGCTGCTATCAGTGGGCAT TGTACCCCTCCATTCCCTGTGCCCATCTATAAACCACACTCCATCTGCTGGGCCTCAGTGGCTGCCGCTGAGGGGGCTCCTGCAGCACCTCCTGGTCACGGGGAGAGTGAGG GAGATAGGCTTGGTCCTGCTCCATCTGCAGCACCGTGTGTGGACGAAGCATTGACCTGGGAATCAGGATGTGTCGGATCTGATCTTGGCCCTGCTGCACATCCTGTGCAACC TTGGGCCTCTCTCAGCCCTGAGGGCTGGCAGAGAGGAGGTCCTTTTTGGCCCCAGGTGATTCTTAACTCCCAGGACAGAGATGAGAGGGAGGGTGGGCACCCCCAGGAATCT TTTCCCTGCACCTTGGCCCCCTGCCCCTGGAGGAGCCCAGCTTCTTCTCCAGAGCCTAGCAGCCCAGAATCTGAGAGCAGAGGCCCTGGTCCCAGGCCCAGCCCTGCATCGT CCCAGGAGGGCAGCCCGCAGCTTCAACACCACAGCTCAGGCATTTTGCCCAAGTGGACACTAGATGCTTCACAGTCTTCACTCTTGGAGACGGATOGGGAACAGCCAAGTTC CTTGAAGAAAAAGGAGGCAGGGGAGGCCCCAAAACCAGGCGAGGAAGTAAAGAGTGAAGGAACAGCCAGGCCTGCAGAGACTGGAGACGTCCAGCCTGACATTCACCTGACT TCTGCAGAACATGAGAATCTGAGGACACCGATGAACTCTTCTTGGCTTCCTGGGAGCCCTATGCCCCAAGCACAGTCCCCAGAGGAAGGCCAGAGACCACCAGCTGGAGACA AGCTAGCTAATGGCGTCAGGAACAACAAGGTAGCCTGGAACTTGGCCTCACGCCTCTATCGCCTGGAGGGCTTCCGGAAGTCTGAAGTGGCTGCCTACCTGCAGAAGAACAA TGACTTTAGCAGGGCTGTGGCTGAGGAGTACCTGTCCTTCTTCCAGTTTGGAGGCCAGAGTCTGGACCGAGCCCTCCGGAGCTTCCTCCAGGCCTTGGTGCTCAGTGGGGAG ACTCAGGAACGGGAGCGAATCCTCTACCAGTTCTCCAGACGCTTCCACCATTGCAATCCGGGGATCTTCCCCTCAGTAGATTCTGTACACACCTTGACATGTGCAATCATGC TGCTTAACACGGACCTGCATGGACAGAACATTGGGAAGAGCATGAGCTGCCAGGAATTCATAACCAACCTGAATGGGCTGAGGGATGGCGGGAACTTCCCCAAGGAGCTGCT GAAGGCCCTCTACTGGTCTATCCGCAGCGAGAAGCTCGAGTGGGCCGTGGATGAAGAAGACACAGCCAGACCTGAGAAGGCCCAGCCGTCCCTGCCAGCTGGCAAGATGAGC AAGCCCTTCCTTCAGCTGGCTCAGGATCCCACAGTGCCCACCTACAAGCAGGGCATCCTGGCTCGGAAAATGCATCAAGATGCAGACGGCAAGAAGACGCCATGGGGCAAGC GTGGCTGGAAGATGTTCCACACCTTACTGCGAGGGATGGTTCTCTACTTCCTGAAGCAGGGAGAAGACCAC GTCTGGAGGGGGAGAGCTTGGTGGGGCAGATGGTGGATGA GCCCGTGGGGGTGCACCACTCGCTGGCCACCCCCGCCACGCATTACACCAAGAAGCCGCACGTCTTCCAGCTGCGCACGGCTGACTGGCGCCTCTACCTCTTCCAGGCACCC AC GCCAAGGAGATGAGCTCCTGGATCGCGCGCATCAACTTGGCTGCGGCCACCCACTCCGCGCCGCCCTTCCCCGCCGCTGTGGGCTCCCAGCGCAGATTCGTGCGGCCCA TCCTGCCCGTGGGCCCCGCCCAGAGCTCCCTGGAGGAGCAGCATCGATCCCACGAGAACTGCCTGGACGCTGCCGCGGACGACCTGCTGGATCTACAGAGGAACCTGCCGGA GCGGCGGGGCCGTGGCCGCGAGCTGGAGGAGCACCGCCTGCGGAAGGAGTACCTGGAGTACGAGAAAACCCσCTACGAGACCTACGTGCAGC GCTGGTGGCCCGCCTGCAC TGCCCCTCTGATGCTCTGGACCTGTGGGAGGAGCAGCTGGGGAGGGAAGCTGGAGGCACTCGGGAGCCCAAGCTCAGCCTGAAGAAGTCCCACTCGAGCCCGTCCCTGCACC AGGATGAGGCTCCCACCACGGCCAAGGTGAAGCGCAACATCTCAGAGCGCAGAACCTACCGGAAGATCATCCCTAAGCGGAACCGCAATCAGCTGTGAAGCCAGCACCACCT CAGAGACACTGTTCCCTGCTCCCAGGGTTAGACCTGAGATGAANCTCCCTGGAGGAGACTTATTTCAATGAGTCCACCATGACGGATGAGGCACCTCCTTTCCCTGCTGAAG GACAAACCTTGTTTCCCTGTGGCCCTCATTCTTGTGCTCCCTGAAGCTTTCCTAATATTGCTGTGCTCCCCACCACCCCCATGGCAGTCCCTCCGCAGCCCCAGTCCCTGGC CACGCCCAAGGGAAGAGGGAGGTGAGGACTTGACTTICCTCCCAGAGCTCAGCCCATGTCACCCTCCAGGCCCCAGAATCCAGAGTGGCCTCATTTCCTAGACTTGCTGAGA ACTCAGCACTTGTTTGAGAACCAGTGCTTATGTTGGIGTTGCCCTTGGCTTCTGGGGGAGAGCTTGGGGCAGCAGAGGCCCCTGGGCAGCCCAGCCAGGGGAGCCACAGCCC CGAGGATGGTCTTGCTCTGGGAATTAGGTGACCTTCCTGGGGAGGCCCCAGGAGAGTGAATCAGGGACTCTTGAGAAATTCCTAACCAGCCTCCTGTGACCCAGGGAGCAGG GTCGCTAAGGTCCTGCCCACTGAGGGGACAGCCTTCTGGGCAGGGACCTCGGGGGGCTTCAAGGGCTCTGCACGGCTGTGGGGCCCTGTGCCTTTGTCTCCTTGTGTCTCCT TTCCCCCGAAGTAGATGAAACAGTCTCACATACCCAACTGCTCATCAACAGAGCAGAGCTGATGGCATGAGTGAGGGCTGGGCGGGGTGGGGCCTCCAGAGCTTTGCAGGGA ACCCTGGAACCCTAGGAACAAGGAGCCTTTGTTCCAACAGAGCAGAGAAGGAGGTTCTCTATGTTCAGACCACTGGAGAGGATAGAGAGGTAAAAGGTGGCGACAGTTTCCC TTAGGGGTCTGCCTGGCAGGAGCCACAGCTCAGGAGAGTTGTGAGGGATGGGACGGAGGCTGGCGACCAGGCGAGGCCTAGGCCAGGCTCGGGAGACTTTTCTGTGCTCCTT TCTACACATGCCTTAAACCTTCCTTCCTGTGGGGTGCCTGGACCCCTTCCCCATCTCTGGCAGCTCAGAGGGTCTCTGCTGCTCTCCCCTGGGAAATCCCCTCATCCTGCCC TCTGGCTGCCTCCCAGCTGGGCTTGTTCTCTGAGGGAGGTTCCGGAGACTCATGGACTTGGGGCTCTGCCTGTAGGAAGGAGGCTGGGCCGGAGGGACCAGCCACCATTGTC TCTGTTCAGCCAAGTGTGCAAGTAGGCTGCCCGCCAAGAGGGGGCCTCTGCTACCCGCTGCTGCCTGCCGGCTGACACACTGCCTCCCCAGCCTTCCTGCTAGGCCACCCTC CTCCCTTCCCATGCTTGTAACCAGCTCTGGGGCTTGCACCTCCACAAAGTAAGGTTGGCCCTTGGAGGCCATGTTTGGGTCTCCGGCCAGGGCCTAGGGCTAGGCCATGCAC CCAATGGGTTGCACAATAAATAACAGGTTCAACA
187
MAMTGSTPCSSMSNHTKERVTMTKVTLENFY8NLIAQHEEREMRQKKLEKVMEEEGLKDEEKRLRRSAHARKETEFLRLKRTRLGLEDFE8LKVIGRGAFGEVRLVQKKDTG HVYAMKI RKADM EKEQVGHIRAERDILVEADSLWWKMFYSFQDKLNLYLIMEFLPGGDMMTLLMKKDTLTEEETQFYIAETV AIDS IHQ GFIHRDIKPDN LLDSKG HVK SDFGLCTG KKAHRTEFYPΛLNHSLP8DFTFQN^ΦJSKRKAET KRN RQIΛFSTVGTPDYIAPEVFMQTGYNKLCD WS GVIMYEM IGYPPFCSETPQETYKKV N KETLTFPPEVPIEEKAKDLILRFCCEWEHRIGAPGVEEIKSNSFFEGVDWEHIRERPAAIEIEIKS IDDTSNFDEFPESDILKPTVATSNHPETDYKNKD VFINYTYKRF EG TARGAI PSYMKAAK
188
GGCAATGACGGCAGGGACTACAACAACCTTTCCTATGAGCAACCATACCCGGGAAAGAGTGACTGTAGCCAAGCTCACATTGGAGAATTTTTATAGCAACCTAATTTTACAG
CATGAAGAGAGAGAAACCAGGCAGAAGAAATTAGAAGTGGCCATGGAAGAAGAAGGATTAGCAGATGAAGAGAAAAAGTTACGTCGATCACAACACGCTCGCAAAGAAACAG
AGTTCTTACGGCTCAAAAGGACCAGACTTGGCTTGGATGACTTTGAGTCTCTGAAAGTTATAGGAAGAGGAGCTTTTGGAGAGGTGCGGTTGGTCCAGAAGAAAGATACAGG
CCATATCTATGCAATGAAGATATTGAGAAAGTCTGATATGCTTGAAAAAGAGCAGGTGGCCCATATCCGAGCAGAAAGAGATATTTTGGTAGAAGCAGATGGTGCCTGGGTG
GTGAAGATGTTTTACAGTTTTCAGGATAAGAGGAATCITTATCTAATCATGGAATTTCTCCCTGGAGGTGACATGA'IGACATTGCTAATGAAGAAAGACACCTTGACAGAAG
AGGAAACACAGTTCTACATTTCAGAGACTGTTCTGGCAATAGATGCGATCCACCAGTTGGGTTTCATCCATCGGGA'IATTAAGCCAGACAACCTTTTATTGGATGCCAAGGG
TCATGTAAAATTATCTGATTTTGGTTTATGTACGGGATTAAAGAAAGCTCACAGGACTGAATTTTATAGAAATCTCACACACAACCCACCAAGTGACTTCTCATTTCAGAAC
ATGAACTCAAAGAGGAAAGCAGAAACTTGGAAGAAGAACAGGAGACAACTGGCATATTCCACAGTTGGGACACCAGATTACATTGCTCCAGAAGTATTCATGCAGACTGGTT
ACAACAAATTGTGTGACTGGTGGTCTTTGGGAGTGATTATGTATGAAATGCTAATAGGATATCCACCTTTCTGCTCTGAAACACCTCAAGAAACATACAGAAAAGTGATGAA
CTGGAAAGAAACTCTGGTATTTCCTCCAGAGGTACCTATATCTGAGAAAGCCAAGGACTTAATTCTCAGATTTTGTATTGATTCTGAAAACAGAATTGGAAATAGTGGAGTA
GAΔGAAATAAAAGGTCATCCCTTTTTTGAAGGTGTCGACTGGGAGCACATAAGGGAAAGGCCAGCAGCAATCCCTA'IAGAAATCAAAAGCATTGATGATACTTCAAATTTTG
ATGACTTCCCTGAATCTGATATTTTACAACCAGTGCCAAATACCACAGAACCGGACTACAAATCCAAAGACTGGGTTTTTCTCAATTATACCTATAAAAGGTTTGAAGGGTT
GACTCAACGTGGCTCTATCCCCACCTACATGAAAGCTGGGAAGTTATGAATGAAGATAACATTCACCCATAACCAAGAGAACTCAGGTAGCTGCATCACCAGGCTTGCTrGG
CGTAGATAACAATACACTGAAATACTCCTGAAGATGGTGGTGCTTATTGACTACAAGAGGAAATTCTACAGGATTAGGATTTCTAAGACTACTATAGGAATTGGTTGGCAGT
GCCAGCTGGCTCTTTTTTTTAATATTTTATTATTTTTGTTAACTTTATTATATGAAGGTACTGGAATAAAAGGAACAGACATCCCTTTCTAACTGCACTGCCTACATGCGTA
TTAAGGTCCATTCTGCCTGTGTGTGCTGTGGCTTTGAACTGTAACACCTCTAATCAATTCAGGAGAAACACATATCATTTAAAGCAACATAGGCTAACCTGTAGGTAACACT
GCAGTATTGATGTTTTACTGCAAATCTTATGGGTCTAGATAATCAGTAAAAGCCATCTTCCATAGTTGGTGTTAGAACATTGCCCTATTGGTTTGGACATCTGTAGAATATA
TATGAAGACAATTTCTGTAATGGTTTTAAGAGATTTAAAAAGAAATTCACTGGTTCTTTACAAAATAGAATTTATCATCAAGTTATTACACAAACTTCACAGTAAGGAGTGA
CAAGTTTATAATAAGGAAGACAAAGTTTAACACCTTCACTCAAGCACTCCACTAATATATTTACGTTGCATTCAGAAATACTGATGACCTTCATATACGTAGTCTGTATACT
CATAGGGAGATGTACTGTATTATATAACATGTAAAGTTGATTTTCTTGTGACAAGAGAACTTCTTTTTTTAACAAGAGGACATGGCATTATTTTAATTTGATTATGGTGAGT
TGAATTTAAGACATGACCATGAAGGCTGCTTGTAGAATTAGTGTATTTTTAT'IAAACTATTTTTTTAAATGTCAAACTTCTATCATGTAAATGGACTTATAGAGAACAAAAA
GCTATTTACTTTGGTTTTCTAGAAAGTTGTTACATATCATGGCTGGTTAACTTTTATTTCTTTTGATGAAAATTTTTCCTTTGATAGTACTTGTATTATTGTGCCATTATTT
TCTTATGCTCCAAATGTACCAAAGATCTTGAACAGAGTGGATGTTCACAACTGAGTAGAATTTTCCTTTCCTGTGGGCATGCTGTATTCAGACCTGACAGATCTTTGATAGA
GGTCAGCTTATTAAAGGGCAATATTGTTCTTGTTTAGCTACATCACTGTGGTGAATATAGATGGAATTAAGGAAGTAAATGCAGGCCAGGGGGTTGTGATGAGAGGATAGGG
GAGATAATATCAGCATCAAATTCTTTGGGTATCTCTCTAAGAATTAAATAATCTTTTCTAGCTTAATATTTTAATTCTAATTCAAACAACTCTGAGGTTTTGGTTTCATTAG
TAATAGTTGAGGAATAATATACTAGCAAAGAATGGCCTAATGTTTGTCATAACTGTTAATGGATGAAATTTTTTAAAGATACAACCATGATAACCATTATAAATGATCTATG
ATCAAAATCTAAAGTGATGAATTATTTGTAGGAATGTCTTCCTAATGGGGAAGAATTGCATAGGAGCATTATGCAAATCTACACAAGCTTTTATAAATGTTGCTGCTGGGTA
GCTCCACAGTGTTTCATAAGGCCATCCTGTTICCCCCAACTCCCCCATTTTTGGTTTGTTTCTTTTTAAATATTTGTTGAGTACTTACGTGTTTATCTAACAGTTCACTTCC
ATTTTTCTAGTCTGGATTTTTTGAGTATTTAGGAAAGAGAGCTATTAAAAACTCTGGGGATTTCTCAATGTGACTAACTCTAATTTTTCTAATTATAACTGCCTTTAATTAA
CATAATATTAACTTTTGCTGAGGTTTATGAGATTTTCTCACCCCACATCGCTCCCCTTTTTTTAAAAAGGACTGTTTTGCTAGTGTGATAATGAATAGGTAAGATATGAGAT
AATTGCAACATTGTCTAGTTCTAGTATGGTAACTATTCTTGAAATGGTATTGAAAAATACCGTTAATTCAAATTGACAGAGATTGATAAAAAGAAACTGATTTACCTAAGTT
TACTTTTTAATTGCATAATAGAGCATTTTTTGTTTTGAGTTCCCTCATTCTTATTACCAGAAAGAGCTTGCAAATAGTTTTACTTTCTTGGCACTGGAAGGGTAGTTCTGGA
AAGCTACTTTGTTGAGAGTCTCATTCTTCCCTGGAGTTAATAGAGTGATTCACAATCTTTGGGGTTTTCTCCTCATCAAAAGCATTTCTTAAGTGCCTATCTAAAAGCAATT
AAAGACTGTGTCTGCCCTTTAGAAGCTAAGAATTTGATTCATGATGCAAATTAACTAGATAATTTGCAAAGTACCCTTGAGATTGAATTTTCTCTATTATATATTTCCCATA
TTTCAGGTGAATAATTTAATTTAAATGACAAAACCCTATCTAGTCAACTGGGCATAATGACATTTTCTTTAAATTAGACTCTATTTTGAATTAAAAGAGTTTTATTATAAAC
CGTGTGTTTTTGGTTTTTCTAAGTATATAGAAAGCTTGTATAATTCAGATTTATCAATTTCCTGATTTAATGTAGACTTTGACTTTTTTATTAAAAACCTTTGTATTAAAGC
AAGTTATGTTATTTTTCTTTTATGCATTTATTACTAACATAGCTTTAAATCTTTAAATGTATTGAAGCATTGTGCTGTCTGAAAATAAGGAATTGCTTATAAACCAGCCACT
TCTGAATACAATATGTAGCTGATTTAATAAGCTAGTTAGTGAATGGAAAATAAGTGTGGAGTATTAAAAATGTTCTTTGGTTGGTAAGGCCTAAGATAGGGTTTCATTTATT
TCTATACTTTTTCTGTTTTTTAAACACCTGCATATTTTTATGTAAATCTCTAAA'ITTAAAATATTTTAAGTACATTTATTTTTGGTGTTTTATTGTATAAAACCTTAGACAA
TCAATCAGTCAGTCTTTACTGACAGGAGCAGCAGCTATCTGTCTTTTGCTGATCTACAAATAAATGAATTGAGAATTTAGTCCATAGAGGTCCCTGGCIACCAAACACATTC
TCCTTTGAATTGTTAAAATTCAGAACATTCAAAATAACTGTTTTGCTACAACCCATGATTATTTTCCTGTTGTGTTTATTTAAATTTACTTTCTCTTTAGAAGTGCACTTAT
TTCTGAAAAATCTTAATGAAACAAACGCTTAGAACAAATATAAATATGAGACACTTGGGACTACTAGAGATATTTTAGATTTTTATGAAAAAAATGTGAGGGGATATTGCTG
CTTTAAAAAGGAATAAAGTAATAAAAATATATCTCAGCTATTTTTTTAAAGCAATATAATTCAGCAATTGTCTAGAAAAGTAATCATGAGGCTACTGAGTTTGGTGTTCAGT
TACTGAGTTTCAAAAATGTTTTGGTGGCATGAGGACAAAATTTCATTGAAGGTAAGATAAGAATAAAAACTATGTTTAC
189
MLLL LLPLL GRERVEGQKSNRKDYSLTNQSSVTVQEGMCVHVRCSFSYPVDSQTDSDPVHGY FRAGNDISWKAPVATNNPAWAVQEETRDRFHLLGDPQTKNCTLSIRD ARMSDAGRYFFR EKGNIK NYKYDQLSVNVTALTHRPNI IPGTLE8GCFQNLTCSVP ACEQGTPPMISWMGT8VSP HPSTTRSSVLTLIPQPQHHGTSLTCQVTLPGA GVrTNRTIQLNVSYPPQNLTVTVFQGEGTASTA GNSSSLSVLEGQSLRLVCAVDSNPPARLSWTWRSLTLYP8QPSNPLVLELQVHLGDEGEFTCRAQNSLGSQHVS NLS LQQEYTGKNRPVSGVLLGAVGGAGATALVFLSFCVIFIVVRSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQ DLSGQEATNNEYSEIKIPK
190
CCACGCGTCCGGAACCCTGAGGAACAGACGTTCCCTCGCGGCCCTGGCACCTCCAACCCCAGATATGCTGCTGCTGCTGCTGCTGCCCCTGCTCTGGGGGAGGGAGAGGGTG
GAAGGACAGAAGAGTAACCGGAAGGATTACTCGCTGACGATGCAGAGTTCCGTGACCGTGCAΔGAGGGCATGTGTGTCCATGTGCGCTGCTCCTTC CCTACCCAGTGGACA GCCAGACTGACTCTGACCCAGTTCATGGCTACTGGTTCCGGGCAGGGAATGATATAAGCTGGAAGGCTCCAGTGGCCACAAACAACCCAGCTTGGGCAGTGCAGGAGGAAAC TCGGGACCGATTCCACCTCCTTGGGGACCCACAGACCAAAAATTGCACCCTGAGCATCAGAGATGCCAGAATGAGTGATGCGGGGAGATACTTCTTTCGTATGGAGAAAGGA AATATAAAATGGAATTATAAATATGACCAGCTCTCTGTGAACGTGACAGCCTTGACCCACAGGCCCAACATCCTTATCCCCGGTACCCTGGAGTCTGGCTGCTTCCAGAATC TGACCTGCTCTGTGCCCTGGGCCTGTGAGCAGGGGACGCCCCCTATGATCTCCTGGATGGGGACCTCTGTGTCCCCCCTGCACCCCTCCACCACCCGCTCCTCAGTGCTCAC CCTCATCCCACAGCCCCAGCACCACGGCACCAGCCTCACCTGTCAGGTGACCTTGCCTGGGGCCGGCGTGACCACGAACAGGACCATCCAACTCAATGTGTCCTACCCTCCT CAGAACTTGACTGTGACTGTCTTCCAAGGAGAAGGCACAGCATCCACAGCTCTGGGGAACAGCTCATCTCTTTCAGTCCTAGAGGGCCAGTCTCTGCGCTTGGTCTGTGCTG TTGACAGCAATCCCCCTGCCAGGCTGAGCTGGACCTGGAGGAGTCTGACCCTGTACCCCTCACAGCCCTCAAACCCTCTGGTACTGGAGCTGCAAGTGCACCTGGGGGATGA AGGGGAATTCACCTGTCGAGCTCAGAACTC'ICTGGGTTCCCAGCACGTTTCCCTGAACCTCTCCCTGCAACAGGAGTACACAGGCAAAATGAGGCCTGTATCAGGAGTGTTG CTGGGGGCGGTCGGGGGAGCTGGAGCCACAGCCCTGGTCTTCCTCTCCTTCTGTGTCATCTTCATTGTAGTGAGGTCCTGCAGGAAGAAATCGGCAAGGCCAGCAGCGGACG TGGGAGACATAGGCATGAAGGATGCAAACACCATCAGGGGCTCAGCCTCTCAGGGTAACCTGACTGAGTCCTGGGCAGATGATAACCCCCGACACCATGGCCTGGCTGCCCA CTCCTCAGGGGAGGAAAGAGAGATCCAGTATGCACCCCTCAGCTTTCATAAGGGGGAGCCTCAGGACCTATCAGGACAAGAAGCCACCAACAATGAGTACTCAGAGΔTCAAG ATCCCCAAGTAAGAAAATGCAGAGGCTCGGGCTTGTTTGAGGGTTCACGACCCCTCCAGCAAAGGAGTCTGAGGCTGATTCCAGTAGAATTAGCAGCCCTCAATGCTGTGCA ACAAGACATCAGAACTTATTCCTCTTGTCTAACTGAAAATGCATGCCTGATGACCAAACTCTCCCTTTCCCCATCCAATCGGTCCACACTCCCCGCCCTGGCCTCTGGTACC CACCATTCTCCTCTGTACTTCTCTAAGGATGACTACTTTAGATTCCGAATATAGTGAGATTGTAACGTGAAAAAAAAAAAAAAAGG
191
MLE PLVIGTIPYNGFGSRNSSIASQFSMDMSWLTLT PEQPEAPPNYADVV8EEEFSRHIPPYPQPPNCEGEVCCPVFACIQEFRFQPPPLYSEVDPHPSDVEE8QPVSFI
L
192
CTATTCCTTAGCTGTATACATTCACATTCCTGGTGCTAAAAAATTGATGCTCGAACTGCCATTAGTGATCGGTACAATTCCATATAATGGTTTTGGCAGCAGAAACTCCAGC ATTGCCAGCCAGTTCAGTATGGATATGAGCTGGTTGACACTGACCCTGCCAGAGCAGCCTGAAGCACCACCAAATTATGCAGATGTGGTACCAGAGGAAGAATTCTCTAGAC ACATTCCTCCTTACCCTCAACCCCCTAACTGTGAGGGAGAAGTGTGCTGTCCTGTGTTTGCCTGTATACAAGAATTCCGGTTTCAACCCCCACCTCTTTATTCAGAGGTTGA CCCACATCCTAGCGACGTAGAAGAGAGCCAGCCTGTTTCCTTCATTCTCTGAACGTATTTCAGAAATCACTGTGTTCATCATCAAATTAGAATGTTGGTTCTTTTCCTTCTG CCTTTTTGGGAGAGAGACAGGAAAGATTCACTTGAAAACATAAATGAACGTCAAGACTGAAGGCAATAGAAATTAAAGAATGTGAGAAAGTTCTGGTGGGCCGGCAGGATTG CCGCACAAGTTTATATGATGGTCGTATATATATCCCTGTTAAAAACTGGGATGAAGATGTGCAAAGTCACAGAATGTAATGGAAGTCCTGATGGTTACAGAGTAAGTGAAAG GGTGCCTGCGCTGACGTGAGAGAAAGGAATCTGTAAACAGTGGAAACACTGTGGGAGTTTCCCATGGTGTTTTGAAGAGTGGAACGAAGGCGATATGAACTGAAGGGGTGAA GACTTGATTTTGGAGAGGGCAACAAAACAAGGGTGTGTGTGCATAGGAGAATGGCCCACTCCAAATACGAAGTGAGATCCTGAGTCTTTGGGTGCTTCATGATTTCCTACCA TATTCAGGCCTAAAGACATTGAAAAAGCATCTTTTCTTGAGATCATGGTCATATGAGGTCCTAATGAAGTACTACAGTTTTCATTCTTTCAAGGGTAGACTAAAATATAGTT TATAAΔTCGGCAGTACAGTATTATGAAACCAAGAAAGGGTTTCTTGAAAAGCTTGTCGGTTCAAAGAGGAAAGATGAATTTCAATGTGAAAACACGTTTTGTTGAGGGCTGT ACTTTTTACCCCCTTTAAGTGCTTTAACAGGATATACGTTTGATTTTCCTCATATCTTATTTACCTAGGAGCATGTCAGAGAAAGAAGGGAGAGAAAAGGTTGCATCTGCAG
TGCTGCTGTTTACAGCCACAGTCTCATCTATCACTAAATATGAAACTGGGCCAAGGGGAAAATTCAGTAAGTTAGCGTTAAATGGAAGTAAATATATGTATACCTAAGAGAA TGTCAAAATAAACACCAAACCAAAAGAAGGTAGGAGTGCCATTTTTAGAAAAGACACAACTTTAATTCCTGTCAAGAGACCTAGGTCTACTGATGGCAGTCACTGCATTGTA CATTATTCCAGTTCTTCAGTAATTCTGTTTAAACTGTGATTTTCTTTATTGTGTTGGTGCAATATTTTATTATCATTTAACCTCAGGATATTCAGACCAACAGGATTGTGTT GCTGCTGAAAGTCTGAGCAGTGTTTTACCGTCCCCAGCCCCCCTCCCACATGGTCACATGTTCACTTGCTTTTCCTTCCATCTGTTGGTTTTGTGAGCTGAGAGCATCTCTG GACACATGGAAGGGAGCCAGGGATTCCTGTGATACAGATTTTGAACCAGCAGAGTACTTTGGTTTTCTTCATGTCCTAAGGGTTTGATCCAGAAACCCTGGTGCTTCCCCTG CAGAATACTGTACTTCATTTAACAGAATGATTGATTTTTCTTTCAATCAGCATGTTCACCAAAAATAGAAAAGTTCTTCTAAGGTTAAATTTTGTATTTAAAAGTTAGTTGG CCATTTGATCAGGGAATTTTCTACACACATTAGGCAAATGTATGCTTTTCATCCTCTGGGCTTACCTCTCTCCTCIGCAATCCTGGAAGCATTGTGCATAGTTCTTTCATTG TAAGCCGCTATTTAAATTCCCACAATGCAAAACTGTTAGACCAGTAATTGTGCTACTGAAATTGTCACAAAACGTTATTCCTTGATTTGGTTTTTAAATTTTGCTTTTGTGT GTGTGTCTTTAAACAGGTAATGTGTATTTAAGTGTTGTCTAAACAGTTGATTTTTACTTTAGAAAAGATCATCTTCAACTGTTTATTGACTTCTGAGTTATATAGTTCATGC CCTGCCAAGGCATTGTTCGACTCCATGATACTAAAACATAATGAAAGAAACAAACTCCAGTATGGAGAAGAGAAAG TTAATTATTTGGTTCCATCTAGAAAAGCAACAACT TAAAGGAATCCTTCCCTAGGATTGTCTTATCACCTTTATTAGATAAATCATGAAGTGTCCCTGTGAAATTGAAGTGAAACTATCTCTGTAGGACTTAAGAGAATAGCTAAAA GβTGTGACTTGCCTTATTGAACTGATACTGGCATATCTGACTGτAAGCAGTAGGTTGAAGATATCATTTTATGAATGTGGAGAATTCTACATTGAAACAGAAAATACCTGGG AATGAAGATTAAAAATGTAGCTGCTGTTATTTGCTTGGTGATTCCCCTCTTGCTCTCTTTAGTTGAAAAAAAAAAAAAAAA
193
MPSFDEALQRVGEFGRFQRRVFLLLCLTGVTFAFLFVGVVF GTQPDHYWCRGPSAAALAERCGWSPEEEWNRTAPASRGPEPPERRGRCQRYLLEAANDSA8AT8ALSCAD PL-^FPNRSAPLVPCRGG RYAQAHSTIVSEFDLVCVNAWMLDLTQAILN GFLTGAFTLGYAADRYGRIVIYLLSCLGVGVTGVVVAFAPNFPVFVIFRFLQGVFGKGTWM TCYVIVTEIVGSKQRRIVGIVIQ FFTLGI IILPGIAYFIPNWQGIQLAITLPSFLFLLYY WPE8PRWLITRKKGDKA QILRRIAKCNGKY S8NYSEITVTDEEVSNP SFLD VRTPQMRKCTLI MFA FTSAWYQG VMRLGIIGGNLYIDFFISGWELPGALLILLTIERLGRRLPFAASNIVAGVACLVTAFLPEGIAWLRTTVATLGRLGITM AFEIVY VNSE YPTTLRNFGVS CSG CDFGGIIAPFL FR AAVW ELP IIFGIIiASICGG -VMLLPETKGIALPETVDDVEKLGSPHSCKCGRNKKTPVSRSH
194
CTGCGGGCGGCGGGCGGCGGGCGCACCATGCCCTCCTTCGACGAGGCGCTGCAGCGGGTGGGCGAGTTCGGGCGCTTCCAGAGGCGCGTGTTTTTGCTGCTGTGCCTGACGG GCGTCACCTTCGCCTTCCTCTTCGTCGGCGTGGTCTTCCTGGGCACGCAGCCCGACCACTACTGGTGCCGCGGGCCAAGTGCCGCGGCGCTGGCCGAGCGCTGCGGCTGGAG CCCGGAGGAGGAGTGGAACCGCACGGCGCCCGCCTCCCGCGGCCCAGAGCCCCCCGAGCGCCGCGGCCGCTGCCAGCGCTACCTCCTGGAGGCGGCCAACGACAGCGCCTCC GCCACTAGCGCTCTCAGCTGCGCGGACCCACTCGCCGCCTTCCCCAACCGTTCGGCTCCCCTTGTGCCGTGCCGCGGCGGCTGGCGCTACGCCCAGGCCCACTCCACCATCG TCAGCGAGTTTGACCTTGTCTGTGTCAATGCGTGGATGCTGGACCTCACCCAAGCCATCCTGAACCTCGGCTTCCTGACTGGAGCATTCACCTTAGGCTATGCAGCAGACAG GTATGGCAGGATCGTCATTTACTTGCTATCCTGCCTTGGTGTTGGCGTCACTGGGGTTGTGGTGGCCTTTGCACCAAACTTCCCTGTGTTTGTGATCTTCCGCTTCCTGCAA GGTGTATTTGGAAAGGGGACGTGGATGACTTGCTACGTGATTGTGACAGAAATAGTAGGTTCGAAACAAAGGAGGATTGTGGGAATCGTGATTCAAATGTTCTTTACCCTTG GAATCATAATTCTCCCTGGAATTGCCTACTTCATCCCCAACTGGCAAGGAATCCAGTTAGCCATCACGCTGCCCAGCTTTCTCTTCCTCCTT'IATTACTGGGTGGTCCCTGA GTCTCCCCGTTGGCTGATTACTCGGAΔGA AGGAGATAAAGCATTACAGATCCTGAGACGCATTGCTAAGTGCAΔTGGGAAATACCTCTCATCAAATTACTCAGAGATCACT GTTACAGATGAGGAAGTTAGTAATCCATCCTTTTTAGATCTGGTGAGAACTCCCCAAATGAGGAAATGCACACTTATTCTTATGTTTGCTTGGTTCACAAGCGCAGTGGTGT ATCAAGGACTTGTCATGCGCCTGGGAATTATAGGGGGCAACCTCTATATAGACT'ITTTCATCTCGGGCGTGG'IGGAACTGCCAGGAGCTCTCTTGATCTTACTAACCATTGA GCGCCTTGGACGACGCCTCCCCTTTGCGGCAAGCAATATAGTGGCAGGGGTGGCATGCCTTGTCACTGCGTTCTTACCAGAAGGAATAGCATGGTTGAGGACCACAGTGGCT ACATTGGGAAGACTAGGGATAACCATGGCCTTTGAAATTGTTTATTTGGTAAATTCAGAATTGTACCCAACAACATTACGAAATTTCGGAGTTTCGCTCTGTTCAGGTCTGT GTGATTTTGGGGGAATCATAGCCCCATTTCTGCTCTTTCGGCTAGCAGCCGTGTGGCTAGAACTACCTCTGATCATCTTTGGTATCCTGGCATCCATCTGTGGTGGCCTTGT GATGCTTTTGCCTGAAACCAAGGGTATTGCCTTGCCAGAGACAGTGGATGATGTAGAAAAACTTGGCAGTCCACATTCCTGTAAATGTGGCAGGAATAAGAAAACCCCAGTT TCCCGCTCTCACCTTTGAGGCCCCCGACAAAGACAGAAAGAAGGAGCTATCCAGGAGCTGATCCTCCTTGCAAAGCTGTGCCTTGCAGAGATGCACGTGTGCATTTCAGCTA CATCATGCCGCGCTGTTGTAATACTGTATAAAGACCTCAATCTATCCAGAGTATTTTTATATAATGTTGGATGAGTTAGGATTTGTAATGCTGTTGAAGTTTCTGGGAACAC
GCCCCCAACCTGATTCTCATGACAGCTCCATCAAGAATGTGGGATGTGCCGACCAAGGATTTGAGAAAGTTGTACAGAAATGTGTTCATCAAATCTGGTCAAGGGACTAAGC ΓCCTAGCTGACCATTCATTCTGAAGATTGCATGGAGGATGAACATCTGGGAATCCTGTTAATGAGAAGGCTGAATCACAGGCACCTGGGCCAAAGGGTGTGAGCATTCATGT ΓCTCTGCTCACCTTGGTTTCCGCACACCTTCGCAATGTGAACAGGTCAGGAGTCCCTCCCGTCCACCTCCTCTGTAACAGCTGGGGTTCCAGGCATGGTTTAGGCCCTGTTC CAGCAATAAGAACCAATCTGCTGTACAATCTGAGGACTTGGCTGTGTTATTTACAAAATGATGCTGTGGTTCTGAGATTATTTGGGACATTTTTGGCTCTCCTTTAGTGGAC
ACCTAGAGCCACAGATTCCCTTCTTTACTAAACAAATCCCATGGATTCTGATTTCTGGGTCTTAGGATTTTAAAAGTGAAGGGATATTTTTCTTATA'ITTGTGAGTTCAGTT CCGATGGTGCCCGTGGTCAAAAGCGAAAAACATGGACAATTCCTATTCATTCITAGCACTTTGACATGTCTTGGGGAAAAGCTTTACATTTTAATTTAAAAGAAAGATCAAT TATATCCATGCTTAACAGGATCAGCAGGAGCTTTATAAATGACTTTACAGAGACTAATAAGGGATTGATCTTTCTTTTTTTGTTATCGAGGCTTTTGAAA GTGGAACTTGT GTGTTCTGCTTTATA GTTATATTCAATATCTTTTCAGATGCAGTCTATATTTTATGCTGAGTTTTAAAAATGAAATACTTTATGCAAACAGGCAAAATTGGTACCAAAGGG AAACATTAACCATGAGGAAGAGCATTTTTCTAAGGAGAACAGGTGACAATATACACATGTCGCGTAATCGTAAAATGAGCATCTTAGTCTTTAAAACACATCAGAATTGAAT ACGAATAATCTATTTGTCGATGAAATAAACACAACTCTTTGAGGATTTGAGACTACATTCACCCTTTATTCACAGTCACTTGCAGTTTTGCTTTTCTCTCCATTTCTCTGCT GTAAGATGACTGTTGCATTGTTGAATTGTATTTTGAGTGGATATTTTTGTTTGGTAACAATTAAAATTTTAAATCGT
195 MAKKSAENGIYSVSGDEKKGPLIAPGPDGAPAKGDGPVGLGTPGGRLA.VPPRETWTRQMDFIMSCVGFAVG GNVWRFPYLCYKNGGGVFLIPYVLIALVGGIPIFFLEIS GQFMKAGSINV NICPLFKGLGYASMVIVFYCNTYYIMVLAWGFYYLVKSFTTTLPWATCGHTWNTPDCVEIFRHEDCANASLANLTCDQLADRRSPVIEF ENKVLRLSGG LEVPGALN EVTLC LACWVLVYFCV KGVKSTGKIVYFTATFPYVV VV VRGVLLPGALDGIIYYLKPDWSKLGSPQV IDAGTQIFFSYAIGLGALTALGSYNRFN N CYKDAIILALINSGTSFFAGFVVFSI GFMAAEQGVHISKVAESGPG AFIAYPRAVTLMPVAPLWAALFFFMLLLLG DSQFVGVEGFIΓG LDLLPASYYFRFQREISVA LCCΛLCFVIDLSMVTDGGMYVFQLFDYYSASGTTLLWQAFWECVVVAWVYGADRFMDDIACMIGYRPCPWMK CWSFFTPLVCMGIFIFNVVYYEP VYNNTYVYP WGEAM G AFALSSMLCVPLHLLGCLLRAKGTMAERWQHLTQPIWGLHHLEYRAQDADVRGLTTLTPVSEESKWWESVM
196
TAGTCGGAGCGAGGTGGCGAGTCGCTGAGCCCGCCGCGGCCCCGAGAGCGGCTGCAGCCGCCGCCGCCGGGAAGGAGAGGGCGAGGCGCGCCCGAGCCGCCGCCGCCGCCGC CACCGCCGCCGCCGCCACCACCGCCACCGGAGTCGCGGGCCAGCCGGGCAGCCTCCGCGGGCCCCGGCCGGGGCGGGGGGCGCGGGCCACAGGCCCCTGCTCCGGCCGTCGT TTGCAGACCGCGGGCGCCGATGTCGCCCGCGCCCCGTTAGGATGAGTCTCGGGTCGGGCGAGGAGCCGCCGCAGCCGCCGCCGCCCGAGCCGCGGGCAGGAGCCTCGGGAGC CGCCGCCGCCGCCGCCGCCGCCCGGCCGGGCCCCGACGCCGCCCGCGCGCCCCCGGGCCCCCGACACACATGAGATTCTTCAGGCTCACTTTCAAGTGCTTCGTGGACTGCT TCTGACTGCGCCGCCCGCGCCCCGCACCCCGCCGTCCGCCCGCCGCCCCGTCCCCCGGCCCGGCCGCCCCCCGGCCCCCGGCCGGCCCGCGCCCTCGGGGCCCTCCCCGGTG CCGCCGGTGCCCCCCGCCTGACCGCCGCCCCCCGTGAGGCGCCGCGACCCCGGCCCGGCCGTGCGGCCCGCCGGGGCCATGGCGAAGAAGAGCGCCGAGAACGGCATCTATA GCGTGTCCGGCGACGAGAAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGCCTGGCCGΓ GCCGCCGCGCGAGACCIGGACGCGCCAGATGGACTTCATCATGTCGTGCGTGGGCTTCGCCGTGGGCTTGGGCAACGTGTGGCGCTTCCCCTACCTGTGCTACAAGAACGGC GGAGGTGTGTTCCTTATTCCCTACGTCCTGATCGCCCTGGTTGGAGGAATCCCCATTTTCTTCTTAGAGATCTCGCTGGGCCAGTTCATGAAGGCCGGCAGCATCAATGTCΓ
GGAACATCTGTCCCCTGTTCAAAGGCCTGGGCTACGCCTCCATGGTGATCGTCTTCTACTGCAACACCTACTACA'ICATGGTGCTGGCCTGGGGCTTCTATTACCTGGTCAA
GTCCTTTACCACCACGCTGCCCTGGGCCACATGTGGCCACACCTGGAACACTCCCGACTGCGTGGAGATCTTCCGCCATGAAGACTGTGCCAATGCCAGCCTGGCCAACCTC ACCTGTGACCAGCTTGCTGACCGCCGGTCCCCTGTCATCGAGTTCTGGGAGAACAAAGTCTTGAGGCTGTCTGGGGGACTGGAGGTGCCAGGGGCCCTCAACTGGGAGGTGA CCCTTTGTCTGCTGGCCTGCTGGGTGCTGGTCTACTTCTGTGTCTGGAAGGGGGTCAAATCCACGGGAAAGATCGTGTACTTCACTGCTACATTCCCCTACGTGGTCCTGGT CGTGCTGCTGGTGCGTGGAGTGCTGCTGCCTGGCGCCCTGGATGGCATCATTTACTATCTCAAGCCTGACTGGTCAAAGCTGGGGTCCCCTCAGGTGTGGATAGATGCGGGG ACCCAGATTTTCTTTTCTTACGCCATTGGCCTGGGGGCCCTCACAGCCCTGGGCAGCTACAACCGCTTCAACAACAACTGCTACAAGGACGCCATCATCCTGGCTCTCATCA ACAGTGGGACCAGCTTCTTTGCTGGCTTCGTGGTCTTCTCCATCCTGGGCTTCATGGCTGCAGAGCAGGGCGTGCACATCTCCAAGGTGGCAGAGTCAGGGCCGGGCCTGGC CTTCATCGCCTACCCGCGGGCTGTCACGCTGATGCCAGTGGCCCCACTCTGGGCTGCCCTGTTCTTCTTCATGCTGTTGCTGCTTGGTCTCGACAGCCAGTTTGTAGGTGTG GAGGGCTTCATCACCGGCCTCCTCGACCTCCTCCCGGCCTCCTACTACTTCCGTTTCCAAAGGGAGATCTCTGTGGCCCTCTGTTGTGCCCTCTGCTTTGTCATCGATCTCT CCATGGTGACTGATGGCGGGATGTACGTCTTCCAGCTGTTTGACTACTACTCGGCCAGCGGCACCACCCTGCTCTGGCAGGCCTTTTGGGAGTGCGTGGTGGTGGCCTGGGT GTACGGAGCTGACCGCTTCATGGACGACATTGCCTGTATGATCGGGTACCGACCTTGCCCCTGGATGAAATGGTGCTGGTCCTTCTTCACCCCGCTGGTCTGCATGGGCATC TTCATCTTCAACGTTGTGTACTACGAGCCGCTGGTCTACAACAACACCTACGTGTACCCGTGGTGGGGTGAGGCCATGGGCTGGGCCTTCGCCCTGTCCTCCATGCTGTGCG TGCCGCTGCACCTCCTGGGCTGCCTCCTCAGGGCCAAGGGCACCATGGCTGAGCGCTGGCAGCACCTGACCCAGCCCATCTGGGGCCTCCACCACTTGGAGTACCGAGCTCA GGACGCAGATGTCAGGGGCCTGACCACCCTGACCCCAGTGTCCGAGAGCAGCAAGGTCGTCGTGGTGGAGAGTGTCATGTGACAACTCAGCTCACATCACCAGCTCACCTCT GGTAGCCATAGCAGCCCCTGCTTCAGCCCCACCGCACCCCTCCAGGGGGCCTGCCTTTCCCTGACACTTTTGGGGTCTGCCTGGGGGAGGAGGGGAGAAAGCACCATGAGTG CTCACTAAAACAACTTTTTCCATTTTTAATAAAACGCCAAAAATATCACAACCCACCAAAAATAGATGCCTCTCCCCCTCCAGCCCTAGCCGAGCTGGTCCTAGGCCCCGCC TAGTGCCCCACCCCCACCCACAGTGCTGCACTCCTCCTGCCCCTGCCACGCCCACCCCCTGCCCACCTCTCCAGGCTCTGCTCTGCAGCACACCCGTGGGTGACCCCTCACC CCAGAAGCAGCAGTGGCAGCTTGGGAAATGTGAGGAAGGGAAGGAGGGAGAGACGGGAGGGAGGAGAGAGAGGAGAAGGGAGGCAGGGGAGGGGCAGCAGAACCAAGGCAAA TATTTCAGCTGGGCTATACCCCTCTCCCCATCCCTGTTATAGAAGCTTAGAGAGCCAGCCAGCAATGGAACCTTCTGGTTCCTGCGCCAATCGCCACCAGTATCAATTGTGΓ GAGCTTGGGTGCGAGTGCACGCGTGCGTGAGTACGGAGAGTATATATAGATCTCTATCTCTTAGCAAAGGTGAATGCCAGATGTAAATGGCGCCTCTGGGCAAAGGAGGCTT GTATTTTGCACATTTTATAAAAACTTGAGAGAATGAGATTTCTGCTTGTATATTTCTAAAAAGAGGAAGGAGCCCAAACCATCCTCTCCTTACCACTCCCATCCCTGTGAGC CCTACCTTACCCCTCTGCCCCTAGCCAAGGAGTGTGAATTTATAGATCTAACTTTCATAGGCAAAACAAAAGCTTCGAGCTGTTGCGTGTGTGAGTCTGTTGTGTGGATGTG CGTGTGTGGTCCCCAGCCCCAGACTGGATTGGAAAAGTGCATGGTGGGGGCCTCGGGGCTGTCCCCACGCTGTCCCTTTGCCACAAGTCTGTGGGGCAAGAGGCTGCAATAT TCCGTCCTGGGTGTCTGGGCTGCTAACCTGGCCTGCTCAGGCTTCCCACCCTGTGCGGGGCACACCCCCAGGAAGGGACCCTGGACACGGCTCCCACGTCCAGGCTTAAGGT GGATGCACTTCCCGCACCTCCAGTCTTCTGTGTAGCAGCTTTAACCCACGTTTGTCTGTCACGTCCAGTCCCGAGACGGCTGAGTGACCCCAAGAAAGGCTTCCCCGACACC CAGACAGAGGCTGCAGGGCTGGGGCTGGGTGAGGGTGGCGGGCCTGCGGGGACATTCIACTGTGCTAAAAAGCCACTGCAGACATAGCAATAAAAACATGTCATTTTCC
197
MAKKSAENGIYSVSGDEKKGPLIAPGPDGAPAKGDGPVGLGTPGGRLAVPPRET TRQMDFIMSCVGFAVGLGNVWRFPYLCYKNGGGVF IPYVLIALVGGIPIFFLEISL
GQFMKAGSINV WICPLFKΣLG AS^WIVFYCNTYYI^WTΛ GFYY VKSF TT PWA CGHTWNTPDCVEIFRHEDCA ASLA ^ TCDQLADRRSPVIEFWENKV R SGG
LEVPGALNWEVTLCLLACWVLWFCWKGVKSTGKIWFTATFPYWLVVLLTO^
CYKDAIILALINSG1SFFAGFVVFSI GF AAEQGVHISKVAESGPGIΛFIAYPRAVTLMPVAPLWAALFFFMLLL G DSQFVGVEGFITGLLDLLPASYYFRFQREISVA CCALCFVIDLSK N:RXMMYVFQLFDYYSASGTTLLKQAF ECVVVAVFVYGADRFMDDIACMIGYRPCPVMKWC SFFTPLVCMGIFIFNVVYYEPLVYNNTYV^
GWAFALSSMLCVP HLLGCLLRAKGTMAER QHLTQPIWGLHHLEYRAQDADVRGLTTLTPVSESS VWVESVM
198
ATGGGAGGATGGGAGGGTGAGGGAATGGGGGATGGGTATGTAAATGGGCTCTGTAATTAAAGAATTTAAATTAAAATAAATGATATATTTAAAAAAGATACAAATGGTTTTA CCTATCAGGAAACCACTATCATATGAACTGGAAACACGCAAAATACATCAGAGGGTTGCCATGCAAAGCTTGGAGAACATCAGTTCTAGTGTGACATTTGTTATTTAAACAC
TTCCATGCTCCTGAGACACCTGTTTTGATGTCGGAAGAATGTAGGTTTTTGTTCATGCCATGAACAGCTCTGCTCACTCAGCACTCCTTGGCCCTGAGTGAGGGCAGGAACC TTTAAACATGACCTGCCCTTCCTGGAGTTCTCTGCTCTTGTCTTCTCTCTTCCTCTGGCCACACTCCTTGATGGACTTTCCTGAAGAAGATTTCTCTTGCTGTTCACTTGCT TGGCCCTGTGCCTGAACCTGGAAACACCCCAGTTGGTGTCACACTCAATTATACTATCTGCCACTCTCTGGTATTGCTTTTGTCTTTCTGACTGTTCCCTCCAACTTAAAAT TCAAGGGTTGGCATTAGAGAGCCTGGTGTGACATACACAGGAAGGCTGGGGACCTCTTTTCAGCTCACATCTGGAACTAGAATTTGAGGGAAATTTGCTGATTTTTCTTTCT TGGCCTTTTGTATGACTTTTCCAGTTTTCTCTCCTAGAGTCAGTTAATATAATGCAAGGACATGAGATCTGAACCTTGAGATCCAGACCTACAAAGCACAGTCAGTATTTGT AACATTTGGCTCTTGATGGACACTATACAAAAACCAAGTGTTGTGGGCTGGAGCTACGGCTCTGCAATTGAGAGCACTTTCTGCTCTTGCAGAGGACCCACATTTGGTTCCC AGCACCCACATGGCAGCTCACAATGATCTATAACICCAGCACCAGGGGATCAGATCAGGGAGCTTGAAGCTGAGGGGGGCACACTTTACCTCCCAGGCCAGGACAATGACCA CTTCCTTCCCCACCCCACCCCCAGGCTACTCTTAGCCCTAGAAAATTCTAAACAAGCTGCTCAGCTGGCGGCGGAGAGGCAGCCCAACAAGCTGGCTCTTGCTAGGGAGGCC TGGGGGGTCCTGGGGAGAGGAACACGGGGTGGGTGGGGGGCGGGCAGCCAGGACCTCAGGCCTGAGGCCTTTGGGGAAGGGTCTGTGCACCTGCCAGGCACCAGGGGGCAGC CTTGCCTTGTTCCCGCTCCAGTCCCCTCAAGTCCGAAGCCCCTACCCACTCTCACGCCAGGCAGGGGTGGGGGCCGCCGGGGTCATTTACCCGGGCCCCTTCTCTGCCTΓGA TGACAAAGTCGAGGCTTGCTCATCAGCCAGGCAGGCTCCCCTCTGCCCACTGTGGAGACACAGAGGCCTGTCACCTGAAGAGCTGGTCCCGGCCTCCAGCTTCCAGGGTAGC CGGGAAGCTGTAGCCCCCAGTGGGCAGCGGTGGAGAGAGCTCAAGGAAGGAGGGAGCACCGGGAGGAGACGGCTGCAGCCIGCCAGGAGCGGGGAGAAAGGGAGAGAAGGGG AGGCGGAGGGCTGAGGGGGCCCGGGGGACGTCTTCCCAGGGCTGGGAGGGGCCGGCCGGGAAGCCTGGGCTGCACTAGGAGCCGGCGACCCTGGGGCGAGGGGCGGCCCGGA GCCCTGCGGGAGGAGCTGGCGGCCGCCCCAGGTAGCAACCATCCTGCCTCCCGCTGGAGCGGCGTCTCCTCCCCGGGAGGAGGGCAGGGAGGAGGTGGGCGGAGTGTGACGA GGAGGGCGGGAGGGAGGGATGCGGGAGGGGGAGGGGGAGGGGGGCCGGCCGGCCGTGGGGGTGGGGCGATAGTGACATCACCCCGGAGTCGGTTTTTAAGCGGCGGCCGGCC GGGGACGGGGAAGAGAGGGATAGTCGGAGCGAGGTGGCGAGTCGCTGAGCCCGCCGCGGCCCCGAGAGCGGCTGCAGCCGCCGCCGCCGGGAAGGAGAGGGCGAGGCGCGCC CGAGCCGCCGCCGCCGCCGCCACCGCCGCCGCCGCCACCACCGCCACCGGAGTCGCGGGCCAGCCGGGCAGCCTCCGCGGGCCCCGGCCGGGGCGGGGGGCGCGGGCCACAG GCCCCTGCTCCGGCCGCCGCTTGCAGACCGCGGGCGCCGATGTCGCCCGCGCCCCGCTAGGCTGAGCCTCGGGTCGGGCGAGGAGCCGCCGCAGCCGCCGCCGCCCGAGCCG CGGGCAGGAGCCTCGGGAGCCGCCGCCGCCGCCGCCGCCGCCCGGCCGGGCCCCGCCGCCGCCCGCGCGCCCCCGGGCCCCCGACACACATGAGATTCTTCAGGCTCACTTT CAAGTGCTTCGTGGACTGCTTCTGACTGCGCCGCCCGCGCCCCGCACCCCGCCGCCCGCCCGCCGCCCCGTCCCCCGGCCCGGCCGCCCCCCGGCCCCCGGCCGGCCCGCGC CCTCGGGGCCCTCCCCGGTGCCGCCGGTGCCCCCCGCCTGACCGCCGCCCCCCGTGAGGCGCCGCGACCCCGGCCCGGCCGTGCGGCCCGCCGGGGCCATGGCGAAGAAGAG CGCCGAGAACGGCATCTATAGCGTGTCCGGCGACGAGAAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACA CCCGGCGGCCGCCTGGCCGTGCCGCCGCGCGAGACCTGGACGCGCCAGATGGACTTCATCATGTCGTGCGTGGGCTTCGCCGTGGGCTTGGGCAACGTGTGGCGCTTCCCCT ACCTGTGCTACAAGAACGGCGGAGGTGAGTTCCCCCGCCCGCCGCGGCCTCCTCCCCCAGCAGGCCGCCGGCCCCCGCCCGACCCCCGGAGCCGCCGCGGAGGGGTGAAGTC CGGGCAACX3GGTGGCCCCCGGGCACGCGGGGGTCGGGGCCGCCCCTCGTCCGCCGCTGCCGCTCGGTGGCCGGGCCGGGCGCCTCCACCCCCCTCX3CAGTCATGTGCCTGGC ATGGTGGGGGGAGGGGGCCGGCGATGCCCGCGAGGCTGCCCCCCAGACTCCCGGGCTGGGAGGAGCGATTGGCCGCCGAGGTGGGAAAGCAGGCCTGCGCCTTGGGGTCΓCC GCGAGGTAAGGAGCCCTGGCTGCCCCCACGGGTCGGGCACACAAGCGGCACATTGTGTGGGCCCCCCACGTGTGCACACACACGAACACACACACACACAATGGGCCACTCT GTCCCTCCCCCTGCCCTCCCCTCCCCTCGCGGCCCTCCCGCCCCTCCCCTCTGGCCCGGGCCTGGAACACTGGGTGCCCGAGCCAGGCT GGGAAGCCTGCGGCCTGGCCCG CCTGGCGCCGCCACTGGACACACTGCATGCACGTCCCATGCCCGCCCGCCCGCCCGCCCGCCCGGGCCCAGCTTAGCAACAGCGATGGGCACGCGTGTGTCCTGTGACTACA AAACAGCACTGGGGTTGCTGGAAGCCGAAGTGACCCGGTGATGGGTGGGAAACAGAGGTCCAGAGCAAAGGCCTTTGCCCAAGGTCAGGAGAAGGATGCTGGGACCTGGAGT CAGGCAAGTTGCAGCCAAGCTCAGCCTCTGAGTAGTGGAGCGAGCCCAGCCAGGGCAAGGGTAGGAGGCCCAGAGAGGAGAAGGGGGTAGTGGCACCCAGCTCTCCCTGCCC TTCTGCCACCCCCACCCCAGCCTGCTGGCCTCAGGAGATAGGCCTGTGTCACGCCCTGCCTATCTCCTGCAGAGCCTGACTCCCTGGCCTTGCTAAGGCCGGCCTGGCCCCΓ CTTCCGCACCTGTATCCC CTGTCCTTGCACATCGCCATCCCACCAGCAGGGGACTGTGACCCACCCACCCTCTGCCTTAGACCTCACACTTGCAGGCAAGCGTCCAAGGGC AGGACAGTCGCGCTCCCTGCCTTTGGATGAGCCCCCCAGGCCTGATCACCCAGCCTTGGCACACATGCACACATGCACGTGCCCTCACTGTGCTGCCTGAAACAGGGAATTG CAGCACTAGGGACAGCCCGCGTGTCTGAGCGTGTGTGTCCTCCATGGCCATCGCCCCAAGTGACCGTGGGGGTGGAAGCCCTGGGGGCCTAGGGCCCCTCTGCCACCCAGGG AATAGGGCTCCAATGGCTCAGGGGCTACTGTAGCCCCTCTTCAACACACTCAACCCACCCCCTCAAGACTCCACCTGGGGCCTGAGTCAGTGGCCACCCCTACACTGACTCA CCCAGTCGGAAGTTGTGATGGGGCCTTTGGAGTCTGGGCTGGCCCGCTGGGCCTGGGCAGCCTGGCTGGGGGCCACCCTGAGTCCACGCTGTGCCTCCACCCCCAGGTGTGT TCCTTATTCCCTACGTCCTGATCGCCCTGGTTGGAGGAATCCCCATTTTCTTCTTAGAGATCTCGCTGGGCCAGTTCATGAAGGCCGGCAGCATCAATGTCTGGAACATCTG TCCCCTGTTCAAAGGTGAGCAGCCCTTGGCCAGCCTCAGGGACTGCCCCCTTCTCCCAGCTGGCTCCCACTTGAGAAATCTTTTCCTGTCGTGAGCACCAGGCCTGGGGCCA CGTGATGGCGTCCCAGTCTCGAGGGGGGAGCCTGGAGGAGATGTTCAGGCCGCACAGCGAACTTGGGGAAGCGGGGACTAGAGGGGGCATAGGCAGCTCCACAAGGCAAGGA CAGGCCAGGCATAGCCGGGCTGGGGACGGGACCTGCCCAGCAGCACCCTTGGCTCTCTAGGTAGGTCCTACTGTTACTATCCCCAAGGACGCTGGGGCACAGACAGGTGGAG CGACGTACTGAGGTTGCCCACTGCAGGGGCGACTGTCTCCAACACTACCTCAGGCGACTAGAAACCCCCCCCCCCCACCACCACCATCAACACCAGCTGCTGAGGACTGGAG GCTACTGGGTGGCCAGGCAGAGGCTTGGACCTCCTGGAACCGCCATGGTGGCAGTGGGACCCACAGAAGGGGCCAGGTGTATGAGGCTGGAGACTCCACAGCACTTGGTCAG ATGGGGACAGGAGGAGAGGGGCTCGCTCTGCCTTGGGTCTAGGGGGCGGCTGGAGGAGAGGAGACAGGCTGGGGAGTCAGCGCAGTGTTGGGGCTCACACAAGGGGGAGCCC AGGGGAGTCAGGAGCACCACAAACAAGGCTCCAGGAGGACAGATGGTGGGAGCACGGCCAGCCTGGGTGGGGACATAAAGGGGTGGCAGGGGGAGGTGGCCAGGGAAGAAΓC TACATGGCAAGGACTTCCCGGCCCCAGGCCTGGGCTACGCCTCCATGGTGATCGTCTTCTACTGCAACACCTACTACATCATGGTGCTGGCCTGGGGCTTCTATTACCTGGT CAAGTCCTTTACCACCACGCTGCCCTGGGCCACATGTGGCCACACCTGGAACACTCCCGACTGCGTGGAGATCTTCCGCCATGAAGACTGTGCCAATGCCAGCCTGGCCAAC CTCACCTGTGACCAGCTTGCTGACCGCCGGTCCCCTGTCATCGAGTTCTGGGAGTGAGTCCGGCACCTCTGGGCCAAQCCCATCCCATCCCCCAGGTCTCCCTCATGTTGCC CGGCTCCAGGGGAGTGGCCCTGAGGGGGCACCAGGGTGTTGCCTGGCAGTCCATCCTGGACCCTGCCTGCCCTTGCCTGTCCTCGGAGAGTCCTGGGGCCAGCCTCGCTCCT GGGTTCGGCAGCCGATCACTGTCCTGGTCACTCCCCCCTGATGGGGGAGCTGGGGCTGCATGTGAGGTGGGATGGGAGTGGCCTCCCAATGGCCAGGGGATCGTGGGCTCCA GGCCCAGCCCAATTGGACAAGAGGGACCCGCTGAACCCTGGGCTGTGGGAGAGAAGGGAGCCACAACTCCTGGGGGTGGACCCTGTGGCTCCATCCTCTGCTGGCACAGGCC TCATGGGACCTCCCTCCCTCCCCTAGGAACAAAGTCTTGAGGCTGTCTGGGGGACTGGAGGTGCCAGGGGCCCTCAACTGGGAGGTGACCCTTTGTCTGCTGGCCTGCTGGG TGCTGGTCTACTTCTGTGTCTGGAAGGGGGTCAAATCCACGGGAAAGGTACCACTAGAGGCATGCAGCGGGGAGGGTGGCTCAGCCCTGGGAGCCGGATGTCTGTGCCAGGO ACACCTGTGGCAACGGGAGGTGACCAGACAGAGTCTAGCCCTAAGGAAGGGGGAGGTACTGAAAGCCAAGCAATGCTCCCCACCCTGCAAATCCAGGGCCCAGCAGCCΓTTG CTCCTGGGGATAGAGGCCCTGGCAGGCACTGTCCCTTCCCTGTGCCCATCACCCCCACTGGTGCCCTCCTGCCAGTCTCTGACTCTTGTGACAGTCTGGTGGACCTGGTCTG GCCATCTGTTACCTATCTTGCCTTGGGGACCCAGAGCAGAGTCTGGCCACATCCCTTGGGGGCTCCTGGTCAGGCTGGGGAGTCACCTGAACAAAGAAGACAGTGTCTAGAG CTGTGGGACATGGCCAGCTCCCTGGGGGACAAGGTCCCCAGAGCAGCATGTGGGAAGAGGGGGCAGACAGTGTGGCAGCTGCATCTCGCCTGCCTCTGCCTGGCCCAGTTCC ACTCTCCACCTGCTCAACCCCCACCTCTCTCCAGAAGAGGAGGGGGACCCGACCCGGATCCAATATCCCGCTCCCTGCCTGGGCCTCCCACACCTGCACTGCCCACACACTC ATACAGCTCTCACTCCCCACGTGCTCCACGCCTCCTGTCCCCACTGAGGAGAGCTCCCAGAGGCTCGCCTGCTCCCCACCGACACGCGTCCCTGCAGACAAACGAGGCGCCC AGGGAGCTTCCCCACTGCACTTGGCCAGGGCTGCCGGGGCGCAGCCTTGCCCCTAGCTTCCTCTGGCGGGAGCCATGGCTCGGAGGACAATGGGGACCTCTGAACATACCTG CCCGCAAGGGGGACCGGAGGCGCTGGGAGTGGGGGTGTGAGGGAGGTGGTGCCACAGCCTCCGCTGAGCAGCCTGGCCCCCCAGATCGTGTACTTCACTGCTACATTCCCCΓ ACGTGGTCCTGGTCGTGCTGCTGGTGCGTGGAGTGCTGCTGCCTGGCGCCCTGGATGGCATCATTTACTATCTCAAGCCTGACTGGTCAAAGCTGGGGTCCCCTCAGGTGAG GTGGAGGTGGAGAGGCTGCAGCAGGGCGCTGCGGGGGAGCCCTGCAGGCCCCTCATGCCTGCGCTCTCCGGCCCTTCTCTAGGTGTGGATAGATGCGGGGACCCAGATTTTC TTTTCTTACGCCATTGGCCTGGGGGCCCTCACAGCCCTGGGCAGCTACAACCGCTTCAACAACAACTGCTACAAGTAAGCACCGCCGCCCTGCCACCCGTGCCCTGTCCTGC CCTGCCCCGCCCTGCCCAGCAGCCTAACCCATCCACTCTGGCCCCTCCACCCCTCAGGGACGCCATCATCCTGGCTCTCATCAACAGTGGGACCAGCTTCTTTGCTGGCTTC GTGGTCTTCTCCATCCTGGQCTTCATGGCTGCAGAGCAGGGCGTGCACATCTCCAAGGTGGCAGAGTCAGGTAGGGCCCIACCCCCAGCCCCGCCTCCAGAGCAGCGAGTGC TACCCAGATGCATGATGTACAGGAACATGCAATAGAAATGCTGAAAAGTGACGAGGATTCAAACGGAACTTGTCAGATTGTGGGCCTGTGGGGGCAGGTCCTGGGATTTGTC AATGTTGACAGAGAAAGGACCTCCCAGCCCCTGCCGCACGACCCAGGGTTGACAGCGCCTCTGAGGCAGGCGTGGGCATGGGCGCGAGTGTTGCAGGCAGGGCTCAGGGTGC GCACAGGGCAGGACATCGGCTACAAGGTCTAGAGCCTGCACCTTTCCCACAGGGCCGGGCCTGGCCTTCATCGCCTACCCGCGGGCTGTCACGCTGATGCCAGTGGCCCCAC TCTGGGCTGCCCTGTTCTTCTTCATGCTGTTGCTGCTTGGTCTCGACAGCCAGGTTTGCATGGGGCTCTGGGACAGGGAGCCAGGAGGGGGGCGGAGGGAGGGCTGCAGGCA AGGAAAGGGGTGGAGGGCGGTGCGGGGCTCGGCCTGAGCTGCCCTGGCCACAGTTTGTAGGTGTGGAGGGCTTCATCACCGGCCTCCTCGACCTCCTCCCGGCCTCCTACTA CTTCCGTTTCCAAAGGGAGATCTCTGTGGCCCTCTGTTGTGCCCTCTGCTTTGTCATCGATCTCTCCATGGTGACTGATGTGAGTGGGGTGGGGGGTCTGCCTGTGACCTCT GGTGGCCGTCTGCCATCCTCCCTGACTGGGCTCTGTCCCCCAGGGCGGGATGTACGTCTTCCAGCTGTTTGACTACTACTCGGCCAGCGGCACCACCCTGCTCTGGCAGGCC TTTTGGGAGTGCGTGGTGGTGGCCTGGGTGTACGGTAGGTCATGGCTGAGGGCTGGGCTGGGGGATGGTGGCGGGGAAGGCAGGTCTCCAGCTTGGCCCTCCCGCCTCACCT CGCCGCAGGAGCTGACCGCTTCATGGACGACATTGCCTGTATGATCGGGTACCGACCTTGCCCCTGGATGAAATGGTGCTGGTCCTTCTTCACCCCGCTGGTCTGCATGGTA AGGGCTGGGGGAGGTGGGGCAGGGCGGGGGGCGAGGCAGGGCGGGGTAGGGGCCCCATTAACCGCAGCATTCTGGTCCGTAGGGCATCTTCATCTTCAACGTTGTGTACTAC GAGCCGCTGGTCTACAACAACACCTACGTGTACCCGTGGTGGGGTGAGGCCATGGGCTGGGCCTTCGCCCTGTCCTCCATGCTGTGCGTGCCGCTGCACCTCCTGGGCTGCC TCCTCAGGGCCAAGGGCACCATGGCTGAGGTAAGGCTCCCGCCCGGCCCGCCCTCCCCTCCCCTGCTGTGAACATTCAACCCAGCCTGCTTCCTAGCCAGGGAGTGGCCCCG CTAGGGTGGCAGGCAGTGGGAACCGGAGAGAGGCAGAGGAAGTCACCGTGGGGACGΔGCAGGTGACCCTGGGGGCTTCAGCATGTCCTCCTCTCCTGCAGCGCTGGCAGCA CCTGACCCAGCCCATCTGGGGCCTCCACCACTTGGAG ACCGAGCTCAGGACGCAGATGTCAGGGGCCTGACCACCCTGACCCCAGTGTCCGAGAGCAGCAAGGTCGTCGTG GTGGAGAGTGTCATGTGACAACTCAGCTCACATCACCAGCTCACCTCTGGTAGCCATAGCAGCCCCTGCTTCAGCCCCACCGCACCCCTCCAGGGGGCCTGCCTTTCCCTGA CACTTTTGGGGTCTGCCTGGGGGAGGAGGGGAGAAAGCACCATGAGTGCTCACTAAAACAACTTTTTCCATTTTTAATAAAACGCCAAAAATATCACAACCCACCAAAAATA GATGCCTCTCCCCCTCCAGCCCTAGCCGAGCTGGTCCTAGGCCCCGCCTAGTGCCCCACCCCCACCCACAGTGCTGCACTCCTCCTGCCCCTGCCACGCCCACCCCCTGCCC ACCTCTCCAGGCTCTGCTCTGCAGCACACCCGTGGGTGACCCCTCACCCCAGAAGCAGCAGTGGCAGCTTGGGAAATGTGAGGAAGGGAAGGAGGGAGAGACGGGAGGGAGG AGAGAGAGGAGAAGGGAGGCAGGGGAGGGGCAGCAGAACCAAGGCAAATATTTCAGCTGGGCTATACCCCTCTCCCCATCCCTGTTATAGAAGCTTAGAGAGCCAGCCAGCA ATGGAACCTTCTGGTTCCTGCGCCAATCGCCACCAGTATCAATTGTGTGAGCTTGGGTGCGAGTGCACGCGTGCGTGAGTACGGAGAGTATATATAGATCTCTATCTCTTAG CAAAGGTGAATGCCAGATGTAAATGGCGCCTCTGGGCAAAGGAGGCTTGTATTTTGCACATTTTATAAAAACTTGAGAGAATGAGATTTCTGCTTGTATATTTCTAAAAAGA GGAAGGAGCCCAAACCATCCTCTCCTTACCACTCCCATCCCTGTGAGCCCTACCTTACCCCTCTGCCCCTAGCCAAGGAGTGTGAATTTATAGATCTAACTTTCATAGGCAA AACAAAAGCTTCGAGCTGTTGCGTGTGTGAGTCTGTTGTGTGGATGTGCGTGTGTGGTCCCCAGCCCCAGACTGGATTGGAAAAGTGCATGGTGGGGGCCTCGGGGCTGTCC CCACGCTGTCCCTTTGCCACAAGTCTGTGGGGCAAGAGGCTGCAATATTCCGTCCTGGGTGTCTGGGCTGCTAACCTGGCCTGCTCAGGCTTCCCACCCTGTGCGGGGCACA CCCCCAGGAAGGGACCCTGGACACGGCTCCCACGTCCAGGCTTAAGGTGGATGCACTTCCCGCACCTCCAGTCTTCTGTGTAGCAGCTTTAACCCACGTTTGTCTGTCACGT CCAGTCCCGAGACGGCTGAGTGACCCCAAGAAAGGCTTCCCCGACACCCAGACAGAGGCTGCAGGGCTGGGGCTGGGTGAGGGTGGCGGGCCTGCGGGGACATTCTACTGTG CRAAAAAGCCACTGCAGACATAGCAATAAAAACATGTCATTTTCCAAAGCAGGCTCCTGCTTCCGCCTCTGCTGCTCTAAGGAAGGGGTCGGGGTACAGGAGGCAGGGGGAA CCRCCTCCAGCTGGAGCTGCTGCCGTGAGCAAGGCTCTGCTCTGGAGGCCTCTGCGGCCGGCACCCTTCTGGGGACTGGGAAGGGGGCAGGGAAGGCAGCAGCCCAGGGGAA GGCCTTGTCCCCCTGGAGCCGAGGCAGTTGGGGAGAGCAGGACGAGAGTGAGCTGGAGAGCAGCCACACCCGCGGGGAAGGGTGGCGTAAAGCCATGGGTGCTGAAATTTTC AAAATGTTACCCCAAGAATTTGΓC
199
MVKHSTIYPSPEELEAVQNMVSΓVECALKHVSD LDETNKGTK EGETEVKKDEAGENYSKDQGGRT CGVMRIGLVAKGLLIKDD DLELV MCKDKPTETLLNTVKDNLP IQIQKLTEEKYQVEQCV EASIIIR TKEPTLTLKVILTSPLIRDELEKKDGENVS KDPPDLLDRQKCLNALASLRHAKWFQARANGLKSCVΪVLRILRDLCNRVPTWAPL
KG PLELICEKSIGTCNRPLGAGEALRRVMECLASGILLPGGPGLHDPCERDPTDALSYMTIQQKEDITH8AQHALRLSAFGQIYKV1JEMDPLPSSKPFQ Y8 8VTDKEGA
GSSALKRPPEDGLGDDKDPNKICMKPJtfLRKILDSKAIDL NAIJdRL^
CMSSDEKSDNESKNETVSSNSSrrøTGNSTTETSSTLEVRTGGPILTASGKNPVMELNEKRRG KYELIS^
FSGPNAANNKKKKIIPQAKGWNTAVSAAVQAVRGRGRGTLITRGAFVGATAAPGYIAPGYGTPYGYSTAAPAYGLEKRMVLLPVMKFPTYPVPHYSFF
200
CCGGAGCCGCGAGCGCCACCAGGGCAGCAGCCGCCGCAGCCGCCGCCGCTGGGCAGAGGAGCCGGAGACGCGAGCGGGCGAGGTGGCGGCGGCGGCGGAGCGGGAGCGGGTA
CCGGGCGCGGGCAGAGCGCGGCGGCGCGGGTGTGTTCCAGAGAACAAGCCTTCAGACAΓTTGCTATATTGACGCTGAGCTGTCAGGGGACTCAGGCTTATGAGGAGGTATTG TΓACACAAAACAGΓGΓCTAGΓGAAGACGACAAGAAAGAGGGGAAAGGATCGGAAAAAGAAGCTAAAATACTATAGAAAACCATGATAAACAAGAACAAAAGAGGCAAGACTG TTCATAAAAAATTGAGAARGRTTTAGTTTGCGATGGACTTCAAAACAAAATATTTACCATGTACTAACATATAATTTCATAGATCTATTCGATCTTTTGCTAATGATGATCG CCATGTTATGGTGAAACARRCAACAATCTATCCATCTCCGGAGGAACTTGAAGCTGTTCAGAATATGGTATCTACTGTTGAATGTGCTCTTAAACATGTCTCAGATTGGTTG GATGAAACAAATAAAGGCACAAAAACAGAGGGTGAGACAGAAGTGAAGAAAGATGAGGCCGGAGAAAACTATTCCAAGGATCAAGGTGGTCGGACATTGTGTGGTGTAATGA GGATTGGCCTGGTTGCAAAAGGCTTGCTGATTAAAGATGATATGGACTTGGAGCTGGTTTTAATGTGCAAAGACAAACCCACAGAGACCCTGTTAAATACAGTCAAAGATAA TCΓTCCTATTCAGATTCAGAAACTCACAGAAGAGAAATATCAAGTGGAACAATGTGTAAATGAGGCATCTATTATAATTCGGAATACAAAAGAGCCCACGCTAACTTTGAAG GΓGATACTTACCTCACCTCTAATTAGGGACGAATTGGAGAAGAAGGATGGAGAAAATGTTTCGATGAAAGATCCTCCGGACTTATTGGACAGGCAGAAATGCCTGAACGCCT TGGCGTCTCTTCGACATGCCAAATGGTTTCAGGCAAGGGCAAATGGATTAAAATCATGTGTAATTGTCCTCCGCATTCTGCGTGATTTGTGCAACAGAGTCCCCACATGGGC ACCATTGAAAGGATGGCCACTAGAACTTATATGTGAAAAGTCTATAGGTACTTGTAATAGACCTTTGGGCGCTGGGGAGGCCTTGAGACGAGTAATGGAGTGTTTGGCATCT
GGAATACTACTTCCTGGGGGTCCTGGTCTTCATGATCCTTGTGAGCGAGACCCAACAGATGCTCTGAGCTATATGACCA'ICCAGCAAAAAGAAGATATTACCCACAGTGCAC AGCATGCACTCAGACTATCAGCCTTTGGTCAGATTTACAAAGTGCTGGAGATGGACCCCCTTCCATCTAGTAAGCCTTTTCAGAAGTATTCCTGGTCAGTTACTGATAAAGA AGGTGCTGGGTCTTCAGCTCTAAAGAGGCCATTTGAAGATGGATTAGGGGATGATAAAGACCCCAACAAGAAGATGAAACGAAACTTAAGGAAAATTCTGGATAGTAAAGCA
ATAGACCTTATGAATGCACTAATGAGGCTAAATCAGATCAGGCCTGGGCTTCAGTA-RAAGCTCCTATCTCAGTCTGGCCCCGTTCATGCCCCAGTCTTCACAATGTCTGTAG ATGTGGATGGCACAACATATGAAGCCTCAGGACCATCCAAGAAAACAGCAAAACTTCACGTAGCGGTGAAGGTATTGCAGGCAATGGGATATCCAACAGGCTTTGATGCAGA ΓATTGAATGTATGAGTTCCGATGAAAAATCAGATAATGAAAGTAAAAATGAAACAGTGTCTTCAAACTCAAGCAATAATACTGGAAATTCTACAACTGAAACCTCCAGTACC ΓTAGAGGTAAGAACTCAGGGCCCTATCCTCACAGCAAGTGGCAAAAACCCTGTAA'IGGAGCTCAATGAAAAAAGAAGAGGTCTCAAGTATGAACTCATCTCAGAGACTGGTG GAAGCCATGACAAGCGCTTTGTAATGGAGGTAGAAGTAGATGGACAGAAATTCAGAGGCGCAGGTCCAAATAAGAAAGTGGCAAAGGCGAGTGCAGCTTTAGCTGCCTTGGA GAAACTGTTTTCTGGACCCAATGCGGCAAATAATAAGAAAAAGAAGATTATCCCTCAGGCAAAGGGCGTTGTGAATACAGCTGTGTCTGCAGCAGTCCAAGCTGTTCGGGGC AGAGGAAGAGGAACTCTAACAAGGGGAGCTTTTGTTGGGGCGACAGCTGCTCCTGGCTACATAGCTCCAGGCTATGGAACACCATATGGTTACAGCACAGCTGCCCCTGCCT ATGGTTTACCCAAGAGAATGGTTCTGTTACCCGTTATGAAATTTCCAACATATCCTGTTCCCCACTACTCATTCTTTTAGCAAATGACAGAAGCTAATTCCTATTGAACAAC ATACAGTACAACACAGAATGTTAGAGAAAAAGCCTTTTTATCCTGCTTTCTTTGAACACATACTTGATCAAAATTATTTGTAAAGAACATCTTTCCTACTTTTTGATTTTA ACAAATGCAAATTTAGTTCTCTAAAACTTGAAAAAAAAAAAAGAAACCAGTTCTGTGAAAACGGTACCTCATTTCTGGAAAATAACTTATACCAGCCCTTCTGTTCTAGGGA ATAAAAGTCTAGCAGTTCAAAGTTTAAGTTTTAAGAGACGTATCAGATTATGTAAAATTAAATTTGTGAAGGATGTATAGAGTCTCAAACACTGATCACAAATAAACTGCT RTGTTGTAACACAGAGTACTGCCTGGTTCCTGATGCAGTCACTGATTCTTAGTTGATTGATATGTATTTGCCCCAGGGCACTTTAATTTGGGCTGTAGTTATTTTTTTTAAT ACAATAGAGACTTTTCATTTAACTTTAACTTTGTAAATATTGAAGTGTGTAATAAAGCCAATAAAATATGGGTTTGAAAAAAAAAAAAAAAAAAAAAA
201
MLRGPGPG LLAVQCLGTAVPSTGASKSKRQAQQMVQPQSPVAVSQSKPGCYDNGKHYQINQQ ERTYLGNALVCTCYGGSRGFNCESKPEAEETCFDKYTGNTYRVGDTY ERPKDSMIWDCTCIGAGRGRISCTIANRCHEGGQSYKIGDT RRPHETGGYM ECVCLGNGKGEWTCKPIAEKCFDHAAGTSYWGETWEKPYQGWMMVDCTCLGEGSGRIT CΓSRNRCNDQDTRTSYRIGDTWSKKDNRGNLLQCICTGNGRGEWKCERHTSVQTTSSGSGPFTDVRAAVYQPQPHPQPPPYGHCVTDSGWYSVGMQWLKTOGNKQMLCTCL GNGVSCQETAVTQTYGGNSNGEPCVLPFTYNGRTFYSCTTEGRQDGH WCSTT8NYEQDQKYSFCTDHTVLVQTQGGNSNGALCHFPF YNNHNYTDCTSEGRRDNMKWCGT TQNYDADQKFGFCPMAAHEEICTTNEGVMYRIGDQWDKQHDMGHMMRCTCVGNGRGEWTCIAYSQLRDQCI'VDDITYNVNDTFHKRHEEGHMLNCTCFGQGRGRWKCDPVDQ CQDSETGTFYQIGDS EKYVHGVRYQCYCYGRGIGEWHCQPLQTYPSSSGPVEVFITETPSQPNSHPIQ NAPQPSHISKYI R RPKNSVGR KEATIPGHLNSYTIKGLK PGVVYEGQ ISIQQYGHQEVTRFDFTTTSTSTPVTSNTVTGETTPFSP VATSESVTEITASSFWSVFVSASDTVSGFRVEYE SEEGDEPQYLDLPSTATSVNIPDLLPGR KYIVNVYQISEDGEQSLILSTSQTTAPDAPPDPTVDQVDDTSIWRWSRPQAPITGYRIVYSPSVEGSSTELNLPETANSVTLSDI.QPGVQYNITIYAVEENQESTPWIQQ ETTGTPRSDTVPSPR1DLQFVEVTDVKVTIM TPPESAVTGYRVDVIPVNLPGEHGQRLPISRNTFAEVTGLSPGVTYYFKVFAVSHGRESKPLTAQQTTKLDAPTN QFVNE RDSTVLVR TPPRAQITGYRLTVGLTRRGQPRQYNVGPSVΕKYPLRNLQPASEYTVSLVAIKGNQESPKATGVPTTLQPGSΕIPPYNTEVTETTIVITWTPAPRIGFKLGVR P8QGGEAPREVTSDSGSIVVSG TPGVEYVYTIQVLRRX3QERDAPIVNKVVTPLSPPTNLHLEANPDTGVLTV8WERSTTPDITGYRITTTPTNGQQGNSLEEVVHADQS8C TFDNLSPGLEYNVSVYTVKDDKESVPISDTIIPAVPPPTDLRFTNIGPDTMRVTWAPPPSIDLTNFLVRYSPVKNEEDVAELΕIΕPSDNAWLTNLLPGTEYWSVSSVYEQ HESTPLRGRQKTGLDSPTGIDFSDITANSFTVH IAPRATITGYRIRHHPEHFSGRPREDRVPHSRNSITLTN TPGTEYWSIVA NGREESPLLIGQQSTVSDVPRDLEV VAATPTSLLISWDAPAVTVRYYRITYGETGGNSPVQEFTVPGSKSTATISGLKPGVDYTITVYAVTGRGDSPASSKPISINYRTEIDKPSQMQVTDVQDNSISVKWLPSS8P VTGYRVTTTPK GPGPTKTKTAGPDQTEMTIEGLQPTVEYWSVYAQNPSGESQPLVQTAVTNIDRPKGLAFTDVDVDSIKIAWESPQGQV8RYRVTYSSPEDGIHELFPAP DGEEDTAE QGLRPGSEYTVSWA HDDMESQPLIGTQSTAIPAPTDLKFTQVTPTSLSAQWTPPNVQLTGYRVRVTPKEKTGPMKEINLAPDSSSVWSGLMVATKYEVSV YALKDT TSRPAQGWTTLE VSPPRRARV DATETTITIS RTKTETITGFQVDAVPANGQTPIQRTIKPDVRSYTITGLQPGTDYKIYLYTLNDNARSSPWIDASTAID APSNLRFLATTPNSLLVSWQPPRARITGYIIKYEKPGSPPREWPRPRPGVTEATITG EPGTEYTIYVIALKNNQKSEPLIGRKKTDE PQ VTLPHPNLHGPEILDVPST VQKTPFVTHPGYDTGNGIQLPGTSGQQPSVGQQMIFEEHGFRRTTPPTTATPIRHRPRPYPPNVGEEIQIGHIPREDVDYHLYPHGPGLNPNASTGQEALSQTTIE APFQD TSEYIISCHPVGTDEEPLQFRVPGTSTSATLTGLTRGATYNIIVEALKDQQRHKVREEWTVGNSVNEGLNQPTDDSCFDPYTVSHYAVGDE ERMSESGFK CQCLGFGS GHFRCDSSRWCHDNGVNYKIGEKWDRQGENGQMMSCTCLGNGKGEFKCDPHEATCYDDGKTYHVGEQWQKEYLGAICSCTCFGGQRGWRCDNCRREGGEPSPEGTTGQSYNQ YSQRYHQRTNTNVNCPIECF PLDVQADRED8RE
202
GAAGAGCAAGAGGCAGGCTCAGCAAATGGTTCAGCCCCAGTCCCCGGTGGCTGTCAGTCAAAGCAAGCCCGGTTGTTATGACAATGGAAAACACTATCAGATAAATCAACAG TGGGAGCGGACCTACCTAGGTAATGTGTTGGTTTGTACTTGTTATGGAGGAAGCCGAGGTTTTAACTGCGAAAGTAAACCTGAAGCTGAAGAGACTTGCTTTGACAAGTACA CTGGGAACACTTACCGAGTGGGTGACACTTATGAGCGTCCTAAAGACTCCATGATCTGGGACTGTACCTGCA'ICGGGGC'IGGGCGAGGGAGAATAAGCTGTACCATCGCAAA CCGCTGCCATGAAGGGGGTCAGTCCTACAAGATTGGTGACACCTGGAGGAGACCACATGAGACTGGTGGTTACATGTTAGAGTGTGTGTGTCTTGGTAATGGAAAAGGAGAA TGGACCTGCAAGCCCATAGCTGAGAAGTGTTTTGATCATGCTGCTGGGACTTCCTATGTGGTCGGAGAAACGTGGGAGAAGCCCTACCAAGGCTGGATGATGGTAGATTGTA CTTGCCTGGGAGAAGGCAGCGGACGCATCACTTGCACTTCTAGAAATAGATGCAACGATCAGGACACAAGGACATCCTATAGAATTGGAGACACCTGGAGCAAGAAGGATAA TCGAGGAAACCTGCTCCAGTGCATCTGCACAGGCAACGGCCGAGGAGAGTGGAAGTGTGAGAGGCACACCTCTGTGCAGACCACATCGAGCGGATCTGGCCCCTTCACCGAT GTTCGTGCAGCTGTTTACCAACCGCAGCCTCACCCCCAGCCTCCTCCCTATGGCCACTGTGTCACAGACAGTGGTGTGGTCTACTCTGTGGGGATGCAGTGGTTGAAGACAC AAGGAAATAAGCAAATGCTTTGCACGTGCCTGGGCAACGGAGTCAGCTGCCAAGAGACAGCTGTAACCCAGACTTACGGTGGCAACTTAAATGGAGAGCCATGTGTCTTACC ATTCACCTACAATGGCAGGACGTTCTACTCCTGCACCACGGAAGGGCGACAGGACGGACATCTTTGGTGCAGCACAACTTCGAATTATGAGCAGGACCAGAAATACTCTTTC TGCACAGACCACACTGTTTTGGTTCAGACTCAAGGAGGAAATTCCAATGGTGCCTTGTGCCACTTCCCCTTCCTATACAACAACCACAATTACACTGATTGCACTTCTGAGG GCAGAAGAGACAACATGAAGTGGTGTGGGACCACACAGAACTATGATGCCGACCAGAAGTTTGGGTTCTGCCCCATGGCTGCCCACGAGGAAATCTGCACAACCAATGAAGG GGTCATGTACCGCATTGGAGATCAGTGGGATAAGCAGCATGACATGGGTCACATGATGAGGTGCACGTGTGTTGGGAATGGTCGTGGGGAATGGACATGCATTGCCTACTCG CAACTTCGAGATCAGTGCATTGTTGATGACATCACTTACAATGTGAACGACACATTCCACAAGCGTCATGAAGAGGGGCACATGCTGAACTGTACATGCTTCGGTCAGGGTC GGGGCAGGTGGAAGTGTGATCCCGTCGACCAATGCCAGGATTCAGAGACTGGGACGTTTTATCAAATTGGAGATTCATGGGAGAAGTATGTGCATGGTGTCAGATACCAGTG CTACTGCTATGGCCGTGGCATTGGGGAGTGGCAT'RGCCAACCTTTACAGACCTATCCAAGCTCAAGTGGTCCTGTCGAAGTATTTATCACTGAGACTCCGAGTCAGCCCAAC TCCCACCCCATCCAGTGGAATGCACCACAGCCATCTCACATTTCCAAGTACATTCTCAGGTGGAGACCTAAAAATTCTGTAGGCCGTTGGAAGGAAGCTACCATACCAGGCC ACTTAAACTCCTACACCATCAAAGGCCTGAAGCCTGGTGTGGTATACGAGGGCCAGCTCATCAGCATCCAGCAGTACGGCCACCAAGAAGTGACTCGC'RTTGACTTCACCAC CACCAGCACCAGCACACCTGTGACCAGCAACACCGTGACAGGAGAGACGACTCCCTTTTCTCCTCTTGTGGCCACTTCTGAATCTGTGACCGAAATCACAGCCAGTAGCTTT GTGGTCTCCTGGGTCTCAGCTTCCGACACCGTGTCGGGATTCCGGGTGGAATATGAGCTGAGTGAGGAGGGAGA'IGAGCCACAGTACCTGGATCTTCCAAGCACAGCCACTT CTGTGAACATCCCTGACCTGCTTCCTGGCCGAAAATACATTGTAAATGTCTATCAGATATCTGAGGATGGGGAGCAGAGTTTGATCCTGTCTACTTCACAAACAACAGCGCC TGATGCCCCTCCTGACCCGACTGTGGACCAAGTTGATGACACCTCAATTGTTGTTCGCTGGAGCAGACCCCAGGCTCCCATCACAGGGTACAGAATAGTCTATTCGCCATCA GTAGAAGGTAGCAGCACAGAACTCAACCTTCCTGAAACTGCAAACTCCGTCACCCTCAGTGACTTGCAACCTGGTGTTCAGTATAACATCACTATCTATGCTGTGGAAGAAA AΓCAAGAAAGTACACCTGTTGTCATTCAACAAGAAACCACTGGCACCCCACGCTCAGATACAGTGCCCTCTCCCAGGGACCTGCAGTTTGTGGAAGTGACAGACGTGAAGGT CACCATCATGTGGACACCGCCTGAGAGTGCAGTGACCGGCTACCGTGTGGATGTGATCCCCGTCAACCTGCCTGGCGAGCACGGGCAGAGGCTGCCCATCAGCAGGAACACC TTGCAGAAGTCACCGGGCTGTCCCCTGGGGTCACCTATTACTTCAAAGTCTTTGCAGTGAGCCATGGGAGGGAGAGCAAGCCTCTGACTGCTCAACAGACAACCAAACTGG ATGCTCCCACTAACCTCCAGTTTGTCAATGAAACTGATTCTACTGTCCTGGTGAGATGGACTCCACCTCGGGCCCAGATAACAGGATACCGACTGACCGTGGGCCTTACCCG AAGAGGCCAGCCCAGGCAGTACAATGTGGGTCCCTCTGTCTCCAAGTACCCCCTGAGGAATCTGCAGCCTGCATCTGAGTACACCGTATCCCTCGTGGCCATAAAGGGCAAC CAAGAGAGCCCCAAAGCCACTGGAGTCTTTACCACACTGCAGCCTGGGAGCTCTATTCCACCTTACAACACCGAGGTGACTGAGACCACCATCGTGATCACATGGACGCCTG CTCCAAGAATTGGTTTTAAGCTGGGTGTACGACCAAGCCAGGGAGGAGAGGCACCACGAGAAGTGACTTCAGACTCAGGAAGCATCGTTGTGTCCGGCTTGACTCCAGGAGT AGAATACGTCTACACCATCCAAGTCCTGAGAGATGGACAGGAAAGAGATGCGCCAATTGTAAACAAAGTGGTGACACCATTGTCTCCACCAACAAACTTGCATCTGGAGGCA AACCCTGACACTGGAGTGCTCACAGTCTCCTGGGAGAGGAGCACCACCCCAGACATTACTGGTTATAGAATTACCACAACCCCTACAAACGGCCAGCAGGGAAATTCTTTGG AAGAAGTGGTCCATGCTGATCAGAGCTCCTGCACTTTTGATAACCTGAGTCCCGGCCTGGAGTACAATGTCAGTGTTTACACTGTCAAGGATGACAAGGAAAGTGTCCCTAT CTCTGATACCATCATCCCAGC GTTCCTCCTCCCACTGACCTGCGATTCACCAACATTGGTCCAGACACCATGCGTGTCACCTGGGCTCCACCCCCATCCATTGATTTAACC AACTTCCTGGTGCGTTACTCACCTGTGAAAAATGAGGAAGATGTTGCAGAGTTGTCAATTTCTCCTTCAGACAATGCAGTGGTCTTAACAAATCTCCTGCCTGGTACAGAAT ATGTAGTGAGTGTCTCCAGTGTCTACGAACAACATGAGAGCACACCTCTTAGAGGAAGACAGAAAACAGGTCTTGATTCCCCAACTGGCATTGACTTTTCTGATATTACTGC CAACTCTTTTACTGTGCACTGGATTGCTCCTCGAGCCACCATCACTGGCTACAGGATCCGCCATCATCCCGAGCACTTCAGTGGGAGACCTCGAGAAGATCGGGTGCCCCAC TCTCGGAATTCCATCACCCTCACCAACCTCACTCCAGGCACAGAGTATGTGGTCAGCATCGTTGCTCTTAATGGCAGAGAGGAAAGTCCCTTATTGATTGGCCAACAATCAA CAGTTTCTGATGTTCCGAGGGACCTGGAAGTTGTTGCTGCGACCCCCACCAGCCTACTGATCAGCTGGGATGCTCCTGCTGTCACAGTGAGATATTACAGGATCACTTACGG AGAAACAGGAGGAAATAGCCCTGTCCAGGAGTLCACTGTGCCTGGGAGCAAGTCTACAGCTACCATCAGCGGCCTTAAACCTGGAGTTGATTATACCATCACTGTGTATGCR GTCACTGGCCGTGGAGACAGCCCCGCAAGCAGCAAGCCAATTTCCATTAATTACCGAACAGAAATTGACAAACCATCCCAGATGCAAGTGACCGATGTTCAGGACAACAGCA TTAGTGTCAAGTGGCTGCCTTCAAGTTCCCCTGTTACTGGTTACAGAGTAACCACCACTCCCAAAAATGGACCAGGACCAACAAAAACTAAAACTGCAGGTCCAGATCAAAC AGAAATGACTATTGAAGGCTTGCAGCCCACAGTGGAGTATGTGGTTAGTGTCTATGCTCAGAATCCAAGCGGAGAGAGTCAGCCTCTGGTTCAGACTGCAGTAACCAACATT GATCGCCCTAAAGGACTGGCATTCACTGATGTGGATGTCGATTCCATCAAAATTGCTTGGGAAAGCCCACAGGGGCAAGTTTCCAGGTACAGGGTGACCTACTCGAGCCCTG AGGATGGAATCCATGAGCTATTCCCTGCACCTGATGGTGAAGAAGACACTGCAGAGCTGCAAGGCCTCAGACCGGGTTCTGAGTACACAGTCAGTGTGGTTGCCTTGCACGA TGATATGGAGAGCCAGCCCCTGATTGGAACCCAGTCCACAGCTATTCCTGCACCAACTGACCTGAAGTTCACTCAGGTCACACCCACAAGCCTGAGCGCCCAGTGGACACCA CCCAATGTTCAGCTCACTGGATATCGAGTGCGGGTGACCCCCAAGGAGAAGACCGGACCAATGAAAGAAATCAACCTTGCTCCTGACAGCTCATCCGTGGTTGTATCAGGAC TTATGGTGGCCACCAAATATGAAGTGAGTGTCTATGCTCTTAAGGACACTTTGACAAGCAGACCAGCTCAGGGTGTTGTCACCACTCTGGAGAATGTCAGCCCACCAAGAAG GGCTCGTGTGACAGATGCTACTGAGACCACCATCACCATTAGCTGGAGAACCAAGACTGAGACGATCACTGGCTTCCAAGTTGATGCCGTTCCAGCCAATGGCCAGACTCCA ATCCAGAGAACCATCAAGCCAGATGTCAGAAGCTACACCATCACAGGTTTACAACCAGGCACTGACTACAAGATCTACCTGTACACCTTGAATGACAATGCTCGGAGCTCCC CTGTGGTCATCGACGCCTCCACTGCCATTGATGCACCATCCAACCTGCGTTTCCTGGCCACCACACCCAATTCCTTGCTGGTATCATGGCAGCCGCCACGTGCCAGGATTAC CGGCTACATCATCAAGTATGAGAAGCCTGGGTCTCCTCCCAGAGAAGTGGTCCCTCGGCCCCGCCCTGGTGTCACAGAGGCTACTATTACTGGCCTGGAACCGGGAACCGAA TATACAATTTATGTCATTGCCCTGAAGAATAATCAGAAGAGCGAGCCCCTGATTGGAAGGAAAAAGACAGACGAGCTTCCCCAACTGGTAACCCTTCCACACCCCAATCTΓC ATGGACCAGAGATCTTGGATGTTCCTTCCACAGTTCAAAAGACCCCTTTCGTCACCCACCCTGGGTATGACACTGGAAATGGTATTCAGCTTCCTGGCACTTCTGGTCAGCA ACCCAGTGTTGGGCAACAAATGATCTTTGAGGAACATGGTTTTAGGCGGACCACACCGCCCACAACGGCCACCCCCATAAGGCATAGGCCAAGACCATACCCGCCGAATGΓA GGACAAGAAGCTCTCTCTCAGACAACCATCTCATGGGCCCCATTCCAGGACACTTCTGAGTACATCATTTCATGTCATCCTGTTGGCACTGATGAAGAACCCTTACAGTTCA GGGTTCCTGGAACTTCTACCAGTGCCACTCTGACAGGCCTCACCAGAGGTGCCACCTACAACATCATAGTGGAGGCACTGAAAGACCAGCAGAGGCATAAGGTTCGGGAAGA GGTTGTTACCGTGGGCAΔCTCTGTCAACGAAGGCTTGAACCAACCTACGGATGACTCGTGCTTTGACCCCTACACAGTTTCCCATTATGCCGTTGGAGATGAGTGGGAACGA ATGTCTGAATCAGGCTTTAAACTGTTGTGCCAGTGCTTAGGCTTTGGAAGTGGTCATTTCAGATGTGATTCATCTAGATGGTGCCATGACAATGGTGTGAACTACAAGATTG GAGAGAAGTGGGACCGTCAGGGAGAAAATGGCCAGATGATGAGCTGCACATGTCTTGGGAACGGAAAAGGAGAATTCAAGTGTGACCCTCATGAGGCAACGTGTTACGATGA TGGGAAGACATACCACGTAGGAGAACAGTGGCAGAAGGAATATCTCGGTGCCATTTGCTCCTGCACATGCTTTGGAGGCCAGCGGGGCTGGCGCTGTGACAACTGCCGCAGA CCTGGGGGTGAACCCAGTCCCGAAGGCACTACTGGCCAGTCCTACAACCAGTATTCTCAGAGATACCATCAGAGAACAAACACTAATGTTAATTGCCCAATTGAGTGCTTCA TGCCTTTAGATGTACAGGCTGACAGAGAAGATTCCCGAGAGTAAATCATCTTTCCAATCCAGAGGAACAAGCATGTCTCTCTGCCAAGATCCATCTAAACTGGAGTGATGTΓ AGCAGACCCAGCTTAGAGTTCTTCTTTCTTTCTTAAGCCCTTTGCTCTGGAGGAAGTTCTCCAGCTTCAGCTCAACTCACAGCTTCTCCAAGCATCACCCTGGGAGTTTCCΓ GAGGGTTTTCTCATAAATGAGGGCTGCACATTGCCTGTTCTGCTTCGAAGTATTCAATACCGCTCAGTATTTTAAATGAAGTGATTCTAAGATTTGGTTTGGGATCAATAGG AAAGCATATGCAGCCAACCAAGATGCAAATGTTTTGAAATGATATGACCAAAATTTTAAGTAGGAAAGTCACCCAAACACTTCTGCTTTCACTTAAGTGTCTGGCCCGCAAT ACTGTAGGAACAAGCATGATCTTGTTACTGTGATATTTTAAATATCCACAGTACTCACTTTTTCCAAATGATCCTAGTAATTGCCTAGAAATATCTTTCTCTTACCTGTTAT TTATCAATTTTTCCCAGTATTTTTATACGGAAAAAATTGTATTGAAAACACTTAGTATGCAGTTGATAAGAGGAATTTGGTATAATTATGGTGGGTGATTATTTTTTATACT GTATGTGCCAAAGCTTTACTACTGTGGAAAGACAACTGTTTTAATAAAAGATTTACATTCCACA
203
SVCWEDRY KARMEESF SRAPSRGGVNFLNVARTYIPNTKVECHYTLPPGTMPSASDWIGIFKVEAACVRDYHTFVWSSVPESTTDGSPIHTSVQFQASYLPKPGAQLYQF
RYVNRQGQVCGQSPPFQFREPRPMDE VTLEEADGGSDILLWPKATVIjQNQLDESQQERND MQ KLQLEGQVTEI.RSRVQELERALATARQEHTELMEQYKGISRSHGEI
TEERDILSRQQGDHVARI ELEDDIQTISEKVLTKEVELDRLRDTVKALTREQEKLLGQLKEVQADKEQSEAELQVAQQENHHLNLDLKEAKS QEEQSAQAQRLKDKVAQM
KDT GQAQQRVAE EPLKEQLRGAQE AASSQQKATLLGEE ASAAAARDRTIAE HRSR EVAEVNGRLAELGLHLKEEKCQWSKERAG LQSVEAEKDKI KLSAEILRL
EKAVQEERTQNQVFKTE AREKDSS VQ SESKRELTELRSA RV QKEKEQ QEEKQELLEYMRK EARLEKVADEKWNEDATTEDEEAAVGLSCPAALTDSEDESPEDMR
LPPYGLCERGDPGSSPAGPREASPLWISQPAPISPH SGPAEDSSSDSEAEDEKSVLMAAVQSGGEEANL LPELGSAFYDMAR
204
GCTGATCCGTCTGTTGGGAGGACAGATATCTCAAGGCCAGGATGGAAGAATCACCACTAAGCCGGGCACCATCCCGTGGTGGAGTCAACTTTCTCAATGTAGCCCGGACCTA CATCCCCAACACCAAGGTGGAATGTCACTACACCCTTCCCCCAGGCACCATGCCCAGTGCCAGTGACTGGATTGGCATCTTCAAGGTGGAGGCTGCCTGTGTTCGGGATTAC CACACATTTGTGTGGTCTTCCGTGCCTGAAAGTACAACTGATGGTTCCCCCATTCACACCAGTGTCCAGTTCCAAGCCAGCTACCTGCCCAAACCAGGAGCTCAGCTCTACC AGTTCCGATATGTGAACCGCCAGGGCCAGGTGTGTGGGCAGAGCCCCCCTTTCCAGTTCCGAGAGCCAAGGCCCATGGATGAACTGGTGACCCTGGAGGAGGCTGATGGGGG CTCTGACATCCTGCTGGTTGTCCCCAAGGCAACTGTGTTACAGAACCAGCTCGATGAGAGCCAGCAAGAACGGAATGACCTGATGCAGCTGAAGCTACAGCTGGAGGGACAG GTGACAGAGCTGAGGAGCCGAGTGCAGGAGCTCGAGAGGGCTCTGGCAACTGCCAGGCAGGAGCACACGGAGCTGATGGAACAGTACAAGGGGATTTCCCGGTCCCATGGGG AGATCACAGAAGAGAGGGACATCCTGAGCCGGCAACAGGGAGACCATGTGGCACGCATCCTGGAGCTAGAGGATGACATCCAGACCATCAGTGAGAAAGTGCTGACGAAGGA AGTGGAGCTGGACAGGCTTAGAGACACAGTGAAGGCCCTGACTCGGGAACAAGAGAAGCTCCTTGGGCAACTGAAAGAAGTACAAGCAGACAAGGAGCAAAGTGAGGCTGAG CTCCAAGTGGCACAACAGGAGAACCATCACTTAAATTTGGACCTGAAGGAGGCGAAGAGCTGGCAAGAGGAGCAGAGTGCTCAGGCTCAGCGACTGAAAGACAAGGTGaCCC AGATGAAGGACACCCTAGGCCAGGCCCAGCAGCGGGTGGCCGAGCTGGAGCCCTTGAAGGAGCAGCTTCGAGGGGCCCAGGAGCTTGCAGCCTCAAGCCAGCAGAAAGCCAC CCTTCTTGGGGAGGAGTTGGCCAGCGCAGCAGCAGCCAGGGACCGCACCATAGCCGAACTACACCGCAGCCGCCTGGAAGTGGCTGAAGTTAACGGCAGGCTGGCTGAGCTC GGTTTGCACTTGAAGGAAGAAAAATGCCAATGGAGCAAGGAGCGGGCAGGGCTGCTGCAGAGTGTGGAGGCAGAGAAGGACAAGATCCTGAAGCTGAGTGCAGAGATACTTC GATTGGAGAAGGCAGTTCAGGAGGAGAGGACCCAAAACCAAGTGTTCAAGACTGAGCTGGCCCGGGAGAAGGATTCTAGCCTGGTACAGTTGTCAGAAAGTAAGCGGGAGCT GACAGAGCTGCGGTCAGCCCTGCGTGTGCTCCAGAAGGAAAAGGAGCAGTTACAGGAGGAGAAACAGGAATTGCTAGAGTACATGAGAAAGCTAGAGGCCCGCCTGGAGAAG GTGGCAGATGAGAAGTGGAATGAGGATGCCACCACAGAGGATGAGGAGGCCGCTGTGGGGCTGAGCTGCCCGGCAGCTCTGACAGACTCAGAGGACGAGTCCCCAGAAGACA TGAGGCTCCCACCCTATGGCCTTTGTGAGCGTGGAGACCCAGGCTCCTCTCCTGCTGGGCCTCGAGAGGCTTCTCCCCTTGTTGTCATCAGCCAGCCGGCTCCCATTTCTCC TCACCTCTCTGGGCCAGCTGAGGACAGTAGCTCTGACTCGGAGGCTGAAGATGAGAAGTCAGTCCTGATGGCAGCTGTGCAGAGTGGGGGTGAGGAGGCCAACTTACTGCTT CCTGAACTGGGCAGTGCCTTCTATGACATGGCCAGGTGAGTTCAACCAGCAAGGCCAGGAGGGAGGTGGGAGGAGGTCAGAGGGAAAGGGCATCTGTGTGGACAGTCACCAG GCCCTGCTCCCAACCCCTGCCCTTCTTGGCCTCAGCCAAGAAAAGGAGATACAGGTATGGTTAACAAGGAAAATGACTCACTGCTCCAAATCCCAGATGCCTTCAGGTAATC CCTACCCCTATCTTATCAATGCACTCAGAGGTCCTGCCTTTAACTGGCTTCTATGTTGTTCTAGCACCATCTTCTGCAGAGCCCAAATTGCCCTGCTTCCCCTCTCTCCTGC CTCTACCCCTTCCCCAACCACCAGGTAGGTACCTAGGGTCCTCCGGGGAGGAAGGGAGGTGACCATGGCCCCCAGGGATAGGAGCAGAGAGAAGACTGGGATCCAGCATCCA TCTGGCTACAACTGAAATGCTTTCCCTCTTCCCTGACTTCCCTGGGTAACCCTTAGGGAAGGGAACCTATAGAGGTGGGGGTTTCAGGTATCAGATTGTCCCCTTCTGCCTT CCCTTTTATTCCCAGGTTCAAGGGGGCAGGCACAGGGAAGAGAGATTTGATCATCTAGTCCCGGTTTTGCCTGGATGTGAGATGGGCTCAGGGCAGGGAGGGGGTGATGCTG TCATCCTTCTCGGCTGGAGCAGGAAGATGAAGGACGATGTCAGACTCATTTTCAGCCTCATTAGGCAGCAGACGGAGATGGAGGGAGGAGAGCAGGAGGCTGGGGGATGGGC TCTGCACTGCAGAGACCAGCAGGGACTAAAGAAGAGAGGACATGGGGAACTGGAAAAATAAGCCTTCCAGGATTGTGGGGAGAAAGACACTGTGGGAGAGGCCAGGATGCTG CATTAGGCACAGGATAACCTGGGAACCCAGGCACATGGGTCCTGCTCTCCGAAGTCTGCAAGTCAAGAAGGGAACAGAGCACGCCGACCCTCTCCCTTTCCCCTCTGTCTCT CTTAGTGGCTTTACAGTGGGTACCCTGTCAGAAACCAGCACTGGGGGCCCTGCCACCCCCACATGGAAGGAGTGTCCTATCTGTAAGGAGCGCTTTCCTGCTGAGAGTGACA AGGATGCCCTGGAGGACCACATGGATGGACACTTCTTTTTCAGCACCCAGGACCCCTTCACCTTTGAGTGATCTTACTCCCTCGTACATGCACAAATACACACTCATGCACA CACACACTCACACACATGCATACACTTAGGTTTCATGCCCATTTTCTATCACACTGGGCTCCATGATATTCTGTTCCCTAAGAACTGCTTCTGTGTGCCCTGTTTTCATCCC AAGATTTCTCACITCATCCTCTCCTACCTGGCTCTTTTGTCCCAGGGAGGGGTCCTGTTCGGAAGCAGTGGCTGAATTTATCCCCTGAAAGTGGTTTTGGAGGAACCGGGAT GGAGGAGGCCTTCCCCTGTGGGAATAGAATCGTCCACTCCTAGCCCTGGTTGCTTCTGATACACAGCCACTGCACACACACACTCACACTCACACTCCCTTGTCTGATGCCC CAAAGCCAATTCCTGGGGCACCCTACCCTCTCTTATTTGGAGTTTCCGTTGGTTTACCTGAGTTTTCTCTGGGGTCTGCACΔGAGGCAGCAGCATGGACATCATGGCCTCTC AGGTCCCTTTTGGTTCTCAGTTTCATTGGTTCCTCTTTCTGTTCCCCCATTGACTTCTGTGCCCCACCCTAGCCTTTTCCATAACCTTAGGTATTCAGTTTGGAGGGGTTTT TTGTATTTTTGAGGATTCCTGTATTCTGTATCCTCTCCTCGCATCTCCTCACATGGAAAGAAATAATGTATTTGTGCCTTCTGTGAGGAATGGGGGGAACAAGTGGTCCCAG GTATCCCCATTTCCAAGGCCCCCCTCCCTCTCCAGGTCCCCCCACAGCAATAAAAGCTTCCCCCTGATATCCATCCCTTTGTAGTTTGAACAAATATATTTATATGATATGT
205
^mPIG KAVVGEKI^fflD IKKVKKKGEWl V VDQLεMPJ LSSCCKMTDIMTEGI IVEDINKRREP PSLEAVYLI PSEKSVHSLISDFKDPPTAKYPJW TVFFTDSCPD
A FMELVKSRAAKVIKTLTEINIAFLPYESQVYSLDSADSFQSFYSPHKAQMKNPILERLAEQIATLCATLKEYPAVRYRGEYKDNAL AQLIQDKLDAYKADDPTMGEGPD
KARSQLLILDRGFDPSSPVLHELTFQAMSYDL PIENDVYKYETSGIGEARVKEV LDEDDDLWIA RHKHIAEVSQEVTRSLKDFSSSKRMHTGEKTTNRDLSQM KKMPQ
YQKELSKYSTH HLAEDCMKHYQGTVDKL ;RVEQDLAMGTDAEGEKIKDP RAIVPIL DANVSTYDKIRI IL YIFLKNGITEENLNKLIQHAQIPPEDSEIITNMAHLGV PIVTDSTLRRRSKPERKERI8EQTYQL8R TPIIKDIMEDTIEDKLDTKHYPYISTRSSASFSTTAVSARYGHMHKHKAPGEYRSGPRLIIFIL.GGVS NEMRCAYEVTQAN GKWEVLIGSTHILTPTKFLMDLRHPDFRE8SRVSFEDQAPTME
206
CTGACGCGCGGCTGCGGGGCGGAGAGCTGCGGCTGGCCCAGCGCGCCCACCTGAGGAGGCGGCGGGGTCCGCAGGCGTCGCGGGACGAGGAGATCGGAGCCGGGAGACTCGC GCAGCGCCATGGCCCCCATTGGCCTCAAAGCRGTRGTCGGAGAGAAGATTATGCATGATGTGATAAAGAAGGTCAAGAAGAAGGGGGAATGGAAGGTGCTGGTGGTGGATCA GTTAAGCATGAGGATGCTGTCCTCCTGCTGCAAGATGACAGACATCATGACCGAGGGCATAACGATTGTGGAAGATATCAATAAGCGCAGAGAGCCGCTCCCCAGCCTGGAG GCTGTGTATCTCATCACTCCATCCGAGAAGTCCGΓCCACTCTCTCATCAGTGACTTTAAGGACCCGCCGACTGCTAAATACCGGGCTGCACACGTCTTCTTCACTGACTCTT GTCCAGATGCCCTGTTTAATGAACTGGTAAAATCCCGAGCAGCCAAAGTCATCAAAACTCTGACGGAAATCAATATTGCATTTCTCCCGTATGAATCCCAGGTCTATTCCTT
GGACTCTGCTGACTCTTTCCAAAGCTTCTACAGTCCCCACAAGGCTCAGATGAAGAATCCTATACTGGAGCGCCTGGCAGAGCAGATCGCGACCCTTTGTGCCACCCTGAAG
GAGTACCCGGCTGTGCGGTATCGGGGGGAATACAAGGACAATGCCCTGCTGGCTCAGCTAATCCAGGACAAGCTCGATGCCTATAAAGCTGATGATCCAACAATGGGGGAGG GCCCAGACAAGGCACGCTCCCAGCTCCTGATCCTGGATCGAGGCTTTGACCCCAGCTCCCCTGTGCTCCATΒAATTGACTTTTCAGGCTATGAGTTATGATCTGCTGCCTAT CGAAAATGATGTATACAAGTATGAGACCAGCGGCATCGGGGAGGCACGGGTGAAGGAGGTGCTCCTGGACGAGGACGACGACCTGTGGATAGCACTGCGCCACAAGCACATC GCAGAGGTGTCCCAGGAAGTCACCCGGTCTCTGAAAGATTTTTCTTCTAGCAAGAGAATGAATACTGGAGAGAAGACCACCATGCGGGACCTGTCCCAGATGCTGAAGAAGA TGCCTCAGTACCAGAAAGAGCTCAGCAAGTACTCCACCCACCTGCACCTTGCTGAGGACTGTATGAAGCATTACCAAGGCACCGTAGACAAACTCTGCCGAGTGGAGCAGGA CCTGGCCATGGGCACAGATGCTGAGGGAGAGAAGATCAAGGACCCTATGCGAGCCATCGTCCCCATTCTGCTGGATGCCAATGTCAGCACTTATGACAAAATCCGCATCATC CTTCTCTACATCTTTTTGAAGAATGGCATCACGGAGGAAAACCTGAACAAACTGATCCAGCACGCCCAGATACCCCCGGAGGATAGTGAGATCATCACCAACATGGCTCACC TCGGCGTGCCCATCGTCACCGATTCCACGCTGCGΓCGCCGGAGCAAGCCGGAGCGGAAGGAACGCATCAGCGAGCAGACCTACCAGCTCTCACGGTGGACTCCGATTATCAA GGACATCATGGAGGACACTATTGAGGACAAACTTGACACCAAACACTACCCTTATATCTCTACCCGTTCCTCTGCCTCCTTCAGCACCACCGCCGTCAGCGCCCGCTATGGG CACTGGCATAAGAACAAGGCCCCAGGCGAGTACCGCAGTGGCCCCCGCCTCAΓCAΓTTTCATCCT GGGGGTGTGAGCCTGAATGAGATGCGCTGCGCCTACGAGGTGACCC AGGCCAACGGAAAGTGGGAGGTGCTGATAGGTTCRACTCACATTCTTACTCCCACCAAATTTCTCATGGACCTGAGACACCCCGACTTCAGGGAGTCCTCTAGGGTATCTTR GAGGATCAGGCTCCAACAATGGAGTGAGAGCCAAAGAAACAAAGATCCACACACATCCTCACCCCACAGAAACTGCTGGACACACTGAAGAAACTGAATAAAACAGATGAA GAAATAAGCAGTTAAAAAAATAAGTCGCCCCTCCAAAACACGCCCCCATCCCACAGCGCTCCGCAGCTTCCCACCACCGCCCGCCTCAGTTCCTTTGCGTCTGTTGCCTCCC CAGCCCTGCACGCCCTGGCTGGCACTGTTΒCCGCTGCATTCTCGTGTTCAGRGATGCCCTCTTCTTGTTTGAAACAAAAGAAAATAATGCATTGTGTTTTTTAAAAAGAGTA TCTTATACATGTATCCTAAAAAGAGAAGCTCATGΓGCAATTGGTGCACAGCAGGAGAAATTTCTGGACTGTTAGGATGAATGGACGCCTTCTCCCCGTTATTTAAGATTTGΓ GACCTTGTACATAACCCTGGGTGACGTGCACATTGCTTGGGTATGGAACΒGTAGAAATTTGGGTGTTTTTAAAACCTTGTTTGGGGTTGTTCCTGTCCTTGTTGAGAATCAT AGAGATGTCTGTGTTCTTGGAGTATTTCACACTGAGGACTAATCTGCTATCTΓCATTCCAGTCCCTACCCCTCAGTGCCTGCTCTCATCCAAATAACCTGGGAGGTGACAAT CAGGATATCTCAGGAGGTCCAAGGTGGAACAGACCTCTTTGCCTTTCCCAGCGTCTCATACCCCCGGTAGTGCAGCTGTGGGTGGAGGCTGGGGTGTCTGCACGAAGTCAGG CCAGCGTCCTCCTCCACAGCCTGTCACTGCCCCCTCCCCAGCCTGTGTCCACAGTGCTGTGATCCCGAGGGAAGΓCCTCCAGTCTAAGTCACAGTGCCCTGACAGGTGAGAA GCAAACTCCCGCTGGAAGCCTCCATCTCTΓTGGAAAAACAGTTAGTCTGGAGCCTGTGGCCCAGGCCCTTCTGTCCCCAGGCATCATCCCAACAGCTCATTTTCCCTAGTCC GCCTTCGTTCAAGGGTCAGGAATGGACCAGAACAGATGGGTTCTGGAGGCCCCTGAACAGAGGGCTATGGCΓGTGGAGAAGGTTCTTGGCCCGTTGGACTCACACAGACCCT GTACCCTCTCGGCAAGCATCTTCAGTCAGATTAΓCCTCAGTTTCAGATACTTCATAATACCTTGTGTTGTGTGGGGTCATACATCATCGTGTTTGTAAGAGAAGATGGTCAT TTTATTCTCTGTATAAAACTTAGCTCTAAAGCAGAAACTAAAGCAGCAAATGCAGGAAGGCTGTCTCGCCAΓCCΓCAAGACTCAGCAGCTCTCATTCTCCAGTGGTGAGCAC ACCATTTGTGCTGCTGCTGTTGTCGTGAAATATAATAACAGTGGAAGTCACAAAAATGTCCCCTGCCCAGCCCCCTCGCCGCCCTTGACCTCCTGCAGGCCATGTGTGTATT ACTTGTCTAGTGATGTCCTCTCAAAGTGCΓGTACGCGAGCTCGGCGCCACCTCCGCCTCCCTTTCAGAGCCTGCΓCCCCGCCCTCTCTGCTCGCTGCATTGTGGTGTTCTCT TCTCAAGGCTTTGAAATCTCCCCTTGCACTGAGATTAGTCGTCAGATCTCTCCCCGTCTCCCTCCCAACTTATACGACCTGATTTCCTTAGGACGGAACCGCAGGCACCTGC GCCGGGCGTCTTACTCCCGCTGCTTGTTCTGTCCCCTCCCTCGGACCAAACAGTGCTCATGCTTCAGGACCTTGRTTGTCGAAGATGTTGGTTTCCCTTTCTCTGTTATTTA TATAAAAATAATTTATCAAAAGGATATTTRAAAAAAGCTAGTCTGTCTTGAAACTTGTTTACCTTAAAATTARCAGAATCTCAGTGTTTGAAAGTACTGAAGCACAAACATA TATCATCTCTGTACCATTCTGTACTAAAGCACTTGAGTCTAATAAATAAAGAAATCAGCACCCCTTCCCGΣRGTCCAGGGGGAAAAAAAAA
207
MELIQDTSRPPLEYVKGVPLIKYFAEALGPLQSFQARPDDLLISTYPKSGTT VSQILDMIYQGGDLEKCHRAPIFMRVPFLEFKAPGIPSGMETLKDTPAPRLLKTHLPLA
LLPQT LDQKVKVVYVAFJSAKDVAVSYYHFYHMAKVHPEPGT DSFLEKFMVGEVSYGS YQHVQE ELSRTHPVLY FYEDMKENPKREIQKI1.EFVGHSLPEETVDFMV
QHTSFKEMKKNPMTNYTTVPQEFMDHSISPFMRKGMAGD KTTFTVAQNERFDADYAEKMAGCSL8FRSEL
208
TTGCTGCCAGCTGCCTCTCCCTCCTTGTCTCTTACCTGCCTGCTGCCTGGGACAGGATGAAGCGGGGCCCTTGTG'TTGCCCCAACCCTΒGCTGTTGGCTAAGAGCCCACGTG ATCTGCCTGTGAGAGGAGTTCCTTCCGGAAGAACCAGGGCAGCTTCTGCCCCTAGAGGGCCAATGCCCTAGCTGAGTGCAGTCCCCCGGCCCCAGCCTGGTCCAGCTTTGGG AAGAGGGTGCCCAGTTGTGCAATCCAGGCCGGGGCAGCCGTGTCCTGATCTTGGTATTCAGGGCTGAGCCTGGAGGGGGCTTGTGATGCCTGACTCTGTCTCTCTCTCTGGC CCCATGCCTTGGTAΒCTGTGAGGCGTCACTGCTTTΒGGΤGACCTGATCTΒGCTGTGATGGATGAGCACGGGGGAAATAGTGGAAGACTCGGAATTAGAAGACGTGAGTGGGC TTTGGCCCCAGCCTCCCTACCCCACTCCCTGTCCTGGGCTGCCTGTGACCAACCTTGTTTCTGCAGGCACACTGGATAGCCCTGCTGGAGCTCAGTGTCCCTAATCCCCTCC AGATACTGGTGGCCTAGGGGAGGTCATCAAAGACCGGTGGGACATCGACCTCAGCCCGTTTCCACGCTTTTTTTTGTTTTTTTTTTTTTTTTGAGACCGAGTTTCACTCTTG TTGCCCAGGCTGGAGTGCAATGGCGTGAΓCTTGGCTCACCGCAACCTCCGCCTCCTGGGTTCAAGCGATTCTCCΓGCCTCAGCCTCCCAAGTAGCTGGGATTACAGGCGTGT GCCACCAGGCTTGACTAATTTTCTATTTTTAGTAGAGACAAGGTTTCTCCATGTTGGTCAGGCTGGTCTCAAACTCCCGACTTCAGGTGATCTGCCTGCCTCGGCCTCCCAA AGTGCTGGGATTACAGGAGTGAGCCACCGTGCCAGGCCTTCTCCAGGCΓCTTGGCACCTTAGCCAGAAACAATTΓAAGGACAAGTGCAAAAGTCATGAATGTAGGCAGAΓTT CCTGCAGAGTAAAGGGACTCACTCAAGAAGAΒGAACGTGGGGGTCCTCAAGAGAGTGTCTCATGCCCTACAAΒGTΒTGGGΒCTGACCTTTATGGΒCTTCTTCAACTAAAGAΒ GGGTATATTCATGAAGAGTCCAGGAAAAGGTAAAGATTΤCTCAAGACCGTGGTΒCCACAATTTACACCCAAATACAGΒTGTTCCTGGAGCCGTCTTGGCACTGGTGΣGTGTA CGGTTTCATATGTTACTGATCATACAATGAGATCCTAGGTGAAACCTACATCAAATACAGCGCCATGTTGTGTCTGGTTGGTCGTAGCCAGCTTGGTCCTCATCCTATTRRT CAGGGACTTATTGGCCCTTAGCGCATGCAGCTATTTCAAGTTTCCTTCTTCTCCTCATGTGAAACTGCTGCCTGGGATTTTGTATTCACTTGCTACCACTCTATTAATCTCA CATTCTCGCCTCTTTTCTGTGTCACCCCGTGTGGGTCCGACAGGTTGTTACTAGAG GCAATACAAAGTCTTAGTCAAGGGAACCTCCTGAGGGTTGCTGAGGGCAGGGGTG GAGCTAGTAGCCTGAGGACCTGCCAGTCACGGGGATTCCTCATGGGCACAΒAΒΒAGGGAGGAGGGGTCCATGGCCCTAGCATATGAGAAGCCTCTCCTCTGCCTGGAATTCC CATGCCTCAGCTTCCCCCACACTCCCACCTGTCCGCTTGCCTCTGAACTCACGCATTTCTTGGAAGTCTTGGGAGATTCACCTTTACTCAGATGGTTGTTTACCTGTCTCGT GCACAGCTTGACCTTGGACTTTAAAGTGAGGATAAAGAACGAGGAGGATGGGGGGATGCCCCCCTTCCACGGGGCCCTGTGGCTTCCAAACCTCGGCCTCCTCTGGTCTCTT GTCTGTGGAGCCTCCTTCAAACCCAGGGAAATAAAACCACCTGCCACGGGRΤGTGGTTCTTCTAGGATCTTCTATCAATGTTCTCTGAGGTCCCCAGGAGCCATGAAGCTGG GGCTGACTCCCAGGGCAATGGGACTGCAGTGTCCTTGTTCTTTCTTGTTCTATGCATCCATGCTCTGCTCCACCCCTGCCCCTTCACTCTGCCCACACACATCCCTCTAGAC TGGCCTTΒTGGTCAGAGCCTGGAGTGCATGGGCTGCTGGGGGCCTGTGGGCTGCACTGGGCCAGAACCCCTΒΒCACCTTCAAGACTGGCCTGGAGCCAGCAGGTAGGTGACC TTTCCAGGGCCTGCCTATCCCAGCTTTCTCCTCCAATCCCTCCCCTCTCTTGCCTGGGTCAATTAGAGAGAGCTTGTCTGTTGGCTGCCTGGCAGGGTGGAGTTCAGGGGCA GGTCAGGAGCCCAGTGACAGCTCGGAAAAAAAAAAAAAAAAAAAAAAAACAGAAAAAAAAACCTACAAAAACAAACCCACCATTGGGCCTTTCCCCTTTCATTCTTCTGTTT TCTACACAGCAAACTCAGTCGTGGCTTTGGAGATCACTTTAAGCTTGTCTCCAGCTGGCACACTAAGGAGGGTAATGGAGAAGCTCCCCCACCCCCAACCCCACCCCTTCCT TCCGGAAGCAAATCTAAGTCCAGCCCCGGCTCCAGATCCCTCCCACAGTGGACCTAGGAAACCCTCAGCTCAGAGAACAACCCTGCATTCCCCACACAGCACCCACAATCAG CCACTGCGGGCGAGGAGGGCACGAGGCCAGGTTCCCAAGAGCTCAGGTGAGTΒACACAGTGGAACGGCCCAGGGCGCCCTCACCCTGCTCAGCTTGTGGCTCTAACATTCCA GAAGCTGAGGCCTCTGGCA'ICCCTGCCCTΓTCCCCATGGATATCCCATTTCAGACAACCCTGGCCTGCGTGAATCCCCCTCCCTTCCCTTGTTTGTTTGTTTTTTTCCCCGG GGAGGCCAGGTCTTGCTGTCACCCAGGCTGGAGTGCTGTGGGATCCTGGCCACTGCAGCCTTGAATTCCTGGGCTCAAGTGATTCTCTTGCCTCAGCCTCTGGAGTAGCTAG GACTACAGGCCCTCATCATCCTGCCTGGTΓAATGTTTAAGAATTTTTTTAAAGATTTTTAGAGATGGGGTCTTGCAATGCTGCACCAGGTTGGTCTCCAACTCCTGGCCΓCA GCCTCCCTAGGGTCTGGGATTATAGGTGGGAGCCACCCTGCCTAGGCCTGTGCTTTTGCTGAGTCATCAGAGTTTTGTTCATTCCCACAGCAGCTCTGGCCCCTAGTAGCAG CTCAGTTCCTCAATGGGCCGTGTTTGTCCRGGAΒCCCAGATGGACTGTGGCCAGGCAAGTGGATCACAGGCCTGΒCTGGCCTGGGCGGTTTCCACATGTGAGGGGCTGAGGG GCTCAAGGAGGGGAGCATCTCCACTGGGTGGAGGCTGGGGGTCCCAGCAGGAAATGGTGAGACAAAGGGCGCTGGCTGGCAGGGAGACAGCACAGGAAGGTCCTAGAGCTTC CTCAGTGCAGCTGGACTCTCCTGGAGACCΓTCACACACCCTGATATCTGGGCCTTGCCCGACGAGGGΓGCTTTCACTGGTCTGCACCATGGCCCAGGCCCTGGGATTTΓGAA CAGCTCCGCAGGTGAATGAAAGGTGAGGCCAGGCTGGGGAACCACCGCATTAGAGCCCGACCTGGTTTTCAGCCCCAGCCCCGCCACTGACTGGCTTTGTGAGTGCGGGCAA GTCACTCAGCCTCCCTAGGCCTCAGTGACTTCCCTGAAAGCAAGAATTCCACTTTCTTGCTGTTGTGATGGTGGTAAGGGAACGGGCCTGGCTCTGGCCCCTGACGCAGGAA CATGGAGCTGATCCAGGACACCTCCCGCCCGCCACTGGAGTACGTGAAGGGGGTCCCGCTCATCAAGTACTTTGCAGAGGCACTGGGGCCCCTGCAGAGCTTCCAGGCCCGG CCTGATGACCTGCTCATCAGCACCTACCCCAAGTCCGGTAAGTGAGGAGGGCCACCCACCCTCTCCCAGGTGGCAGTCCCCACCTTGGCCAGCGAGGTCGTGCCCTCAGCCT GCTCACCCCCCATCTCCCTCCCTCTCCAGGCACCACC GGGTGAGCCAGATTCTGGACATGATCTACCAGGGTGGTGACCTGGAGAAGTGTCACCGAGCTCCCATCTTCATG CGGGTGCCCTTCCTTGAGTTCAAAGCCCCAGGGATTCCCTCAGGTGTGTGAGTGTGTCCTGGGTGCAAGGGGAGTGGAGGAAGACAGGGCTGΒGGCTTCAGCTCACCAGACC TTCCCTGACCCACTGCTCAGGGATGGAGACTCTGAAAGACACACCGGCCCCACGACTCCTGAAGACACACCTGCCCCTGGCTCTGCTCCCCCAGACTCTGTTGGATCAGAAG GTCAAGGTGAGGCAGGGCACAGTGTTTCACATCCA'IAATCCCAGCACTTTGGGAGGCTGAGGCAGGCAGATCACCTGAGGTTGGGAGTTTGAGAGCACCCTGAGCAACATAG AAGAACCTTGTCTCTACTAAAAATACAGAATTAGCCGGGTGTGGTGGCGGGTGCCTGTAATCCCAGCTACTCCGAAGCCIGAGACAGGAGAATCACTTGAACCCGGGAGAAG GAGGTTGTGGTGAGCCAGAGATCCCACCATTGCATTCCAGCCTGAGCAACAAGAGCAAAACTCACAAAAATAAATAAATAAATAGATATATAAATAAAAATAAAACTGTGGC ACCTGTGGTGGCTCACTGCTGTAATGCCAGCACTTTGGGAGGCCAAATTGGGTGGATCACTTGAGCTCAGGAGTTACAGACCAGCCCGGGAAACATGGGGAACTTCCATCTC TATAAAAATGCAAAATATCAGCAGGGCATGGTGGCATGGCGCTGTAGTTCCAGCTACTGGAAAGTCTGAGGTTGGAGGATTGCTTGAGCCTGGGAGGTCAAGGTTGCAGTGA GTTATTATCACTCCAGTGCACTCCAACCTGGGCGACAGAAAAAAAGAAAGACCAAGGTCTTTTTTCTTTTTTGAGATTGTCTCAATAAATAAATAAATGAATAAATAAAAAT AAAATAAAGTAAAATAAATCCCACAATTAAAAGAAAAAGCAAAGGTCCAGGTGTGGGGCATGTGAATCCAGGGAAGGAGGCCCTGGCTCAGCCCAGCTTTGGTCCTGTTCTT CTGGGAAAGTCGCCTCACTTCCTCCAGCCTTGTCTCATCTTCTGCGGCGGGGACTGTCTGCCTCTTGCTCTGATGACCAAGAACGTAAGGCTCTTCAGTGTAGACCTAAGAA AGCTAGAGGGTGGGTCCTCACAGGCCCACAAAAT'ITGGTGGCGGTGGGATCACGGCTGGTGGAGCGTGCCTTGCTCCAGATCGGGGTGTGACGCATTGATGCAGATTATATT GCTATAGAATATGATGGTCTCAGGGACCAGGCAGGACTTTGGCTTCTGAGCAGGGTTCAGATCCTGACTTGGCCCTACCGGTGCCGTGAGATCTCAAACAAGTCΛGCCTCTA AGCCTCAGGTTCCTCCTTTGCCAATCCAAGAGATGAGCIGGCCTGGGGCAGGCTGTGTGGTGATGGTGCTGGGGTTGAGTCTTCTGCCCCTGCAGGTGGTCTATGTTGCCCG CAACGCAAAGGATGTGGCAGTTTCCTACTACCACTTCTACCACATGGCCAAGGTGCACCCTGAGCCTGGGACCTGGGACAGCTTCCTGGAGAAGTTCATGGTCGGAGAAGGT GGGTTTGATGGGAGGAAGGAAAGTGTGGAGCCGAGGGGTGGTGGCTACAACGCACAGCAACCCTGTGTTGGCACCCCTTGCCTGCTTCTCCAGTGTCCTACGGATCCTGGTA CCAGCACGTGCAGGAGTGGTGGGAGCTGAGCCGCACCCACCCTGTTCTCTACCTCTTCTATGAAGACATGAAGGAGGTGAGACCACCTGTGAAGCTTCCCTCCATGTGACAC CTGGGGGCCGGCACCTCACAGGGACCCACCAGGGTCACCCAGCCCCCTCCCTTGGCAGCCCCCACAGCAGGCCCGGATTCCCCATCCTGCCTTCTTGGCCCAGGCCTCCCCG CTACAGGCCCCACCIGGCAGCGGGCCCCACACGGCTCTCATCACCCACATCTGAGTCAGCTGCATGGGGGGCCACGGATCAGAAACTTAGTCCTATTGCTACTCCCTGCCAA AGGGTGTGCCACCCAGGGCCACAGTCATGGAAGAAGACCATCACGGTCCTCACCCATAGGAGCCAAGCCCAGCTCATGATGGGATCACAGGGCAGACAGCAATTCTTTTTAC CCCCGGGACTGGGGCCCTGGGGGTTGAGGAGT'IGGCTCTGCAGGGTCTCTAGGAGAGGTGGCCAGATCGCCTCTGAGGTTAGAGAAGGGGACCCCTTTTACTTTTCCTGAAT CAGCAATCCGAGCCTCCACTGAGDAGCCCTCTGCTGCTCAGAACCCCAAAAGGGAGATTCAAAAGATCCTGGAGTTTGTGGGGCACTCCCTGCCAGAGGAGACCGTGGACTT CATGGTTCAGCACACGTCGTTCAAGGAGATGAAGAAGAACCCTATGACCAACTACACCACCGTCCCCCAGGAGTTCATGGACCACAGCATCTCCCCCTTCATGAGGAAAGGT GGGTGCTGGCCAGTACGGGGGTTTGGGGCGGGTGGGAGCAGCAGCTGCAGCCTCCCCATAGGCACTCGGGGCCTCCCCTGGGATGAGACTCCAGCCTTGCTCCCTGCCTTCC CCCCCCAGGCATGGC'IGGGGACTGGAAGACCACCTTCACCGTGGCGCAGAATGAGCGCT'ICGATGCGGACTATGCGGAGAAGATGGCAGGCTGCAGCC'ICAGCTTCCGCTCT GAGCTGTGAGAGGGGCTCCTGGGGTCACTGCAGAGGGAGTGTGCGAATCAAACCTGACCAAGCGGCTCAAGAATAAAATATGAATTGAGGGCCTGGGACGGTAGGTCAΓGTC TGTAATCCCAGCAAT'ITGGAGGCTGAGGTGGGAGGATCATTTGAGCCCAGGAGTTCGAGACCAACCTGGGCAACATAGTGAGATTCTGTTAAAAAAATAAAATAAAATAAAA CCAATTTTTAAAAAGAGAATAAAATATGATTGTGGGCCAGGCATAGTGGCTCATGCCTGTAATCCCAGCAATTTGAGAAGTTGAGGCTAGAGGATCACTGGAGGACAGGAGT TTGGGACCAGCCTGTTCAACATTACAAGACATCATCCCTACAAAAATTTGAGAAAATTATCTGTACGTGATGGTGGGCACCTGTAGTCCCAGCTACTTGACAAGTGAAGGCA GTAGGATCGCCTGAGCCAGGGAGGTTATGGCTGCAGTGGGCTGACTGGGCTAA'ICCACTCAAGCCTGAGGGACAGAGCAAATCTTGCTTGAGAAATAAATAAAATACAATTT ACTTAACATAAATTATGATTCAGGACCAGTCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAAAAAAAAAAGATACAAAAATTAGCCGGGCATGGTGGCAGACACCTGT AACCTCAGCTACTCTGGAGGCTGAGGCAGGAGAATTGCTCGAACCCAGGGACGGATGATGCAGTGAGCCAAGATCATGCCACTTCACTCCAGCCTGGGCATAAGAGCAAAAC TCTGGCTTGAAAATAAATAAATAATTAAATTAAATTAAGGTATTATTTGACCTGGGCTCGGTGGCTTATGCCTGGAATCTCAGCACTTCAGCCTGGCAGATCACTTGAGGTC AGGAGTTCAAGACCAGGCTGGCCAGCATGGGAAAACCCCATCTCTACTAAAAATACAAAAATTAGCTGGGCATGATGATGGGCGCCTGTAATCCCAGCTACTCCAGAGGCΓG AGGTGGGAGAATCGATTGAATCCATGAGGTGGAGGTTTCATTGAACCGGGATCACACCACTGCACTCCAGTCTGGGCGACAGAGCAAGACTCAGTCTTAAAACAACAACAAC AACAACAACAACAACACAACTATGATTTGTGTTCAATGCAGAGTCTCTATTCCAAGCCAAGAGAAACCCTGAGCTGAAAGAGTGATCGCCCACTGGGGCCAAATACGGCCAC CTCTCCGCTCCAGCTCCTCAACTTGACCTGT'ΓTGGAGAGGGGAGAGGGTCTGGAGAAGTAAAACCCAGGAGACGAGTGGAGGGGGAATGTGTTTAATCCCAGCACATCCTTT GCTGTCCTGCCCTGTGTCGTTGGTGGATGGCGAAGTCCGCCAGGCAGCGTCACTTTTTCTTGGGCTCCTTACAAGCCACCACCTACCTCTGGGCCACGCTGAGGGGAGGGGA ATGCTTGAAGACACTCAAGCATAGGAGTGTCTTCAAACAGGACCAAGTAGTCATCCTGGGGCTGTGGGGCAGGCAGACAGGAGGGGCTGCTCAGAGATCCCCAGGCCATGAC TCAGGGACTCTGTGTTCAGAGGACCGAGGGCAGCCCAGATGGTGGCAA
209
MSVSRTMEDSCELDLVYVTERIIAVSFP8TANEENFRSNLREVAQMLKSKHGGNYLLFNLSERRPDITKLHAKVLEPGWPDLHTPALEKIC8ICKAMDTWLNADPHNVVVLH
NKGNRGRIGWIAAYMHY8NISASADQALDRFANKRFYEDKIVPIGQP8QRRYVHYFSGLLSGSIKINNKPLFLHHVIMHGIPNFESKGGCRPFLRIYQAMQPVYTSGIYNI
PGDSQTSVCITIEPGLLLKGDILLKCYHKKFRSPARDVIFRVQFHTCAIHDLGWFGKEDLDDAFKDDRFPEYGKVEFVFSYGPEKIQGMEHLENGPSVSVDYNTSDPLIR
DSYDNFSGHRDDGMEEWGHTQGPLDGSLYAKVKKKDS HGSTGAVNATRPTLSATPNHVEHTLSVSSDSGNSTASTKTDKTDEPVPGASSATAALSPQEKRE DR SGFG
LEREKQGAMYHTQHLRSRPAGGSAVP88GRHWPACVHVNGGALASERETDILDDELPNQDGHSAGSMGT SSLDGVTNTSEGGYPEA SP TNG DKSYPMEPMVNGGGYP
YESASRAGPAHAGHTAPMRPSY8AQEGLAGYQREGFHPAWPQPVTTSHYAHDPSGMFRSQSFSEAEPQLPPAPVRGGSSREAVQRGLNSWQQQQQQQQQPRPPPRQQERAHL,
ESLVASRPSPQPLAETPIPS PEFPRAASQQEIEQSIETLNMLMLDLEPASAAAPLHKSQSVPGAWPGASPLSSQPLEGSSRQSHPLTQSRSGYIPSGHSLGTPEPAPRAS
ESVPPGRSYSPYDYQPCIiAGPNQDFHSKSPASSSIjPAF PTTHSPPGPQQPPASLPGLTAQPLLSPKEATSDPSRTPEEEPLNLEG VAHRVAGVQAREKCPAEPPAPLRRR
AASDGQYEMQSPEATSERSPGVRSPVQCVSPELALTIALNPGGRPKEPHLHSYKEAFEEMEGTSPSSPPPSGVRSPPG AKTPLSALGLKPHNPADILLHPTGVTRRRIQPE
EDEGKVWRLSEEPRSYVEEVARTAVAGPRAQDSEPKSFSAPATQAYGHEIPLRNGTLGGSFVEPEPLSTEEPILSADETSVGSFPEGEEEDQGPRTPTQPLLESGFRSGSL
GQPSPSAQRNYQεεΞPLPTVGSSYSεPDYSLQHFSSSPESQARAQFSVAGVHTVPGεPQARHRTVGTNTPPSPGFGRRAINPSMAAPSSPSLSHHQMMGPPGTGFHGSTVSS
PQSSAATTPGSPS CRHPAGVYQVSG HNKVATTPGSPSLGRHPGAHQGNLASGLHSNAIASPGSPSLGRHLGGSGSWPGSPCLDRHVAYGGY8TPEDRRPTLSRQSSASG
YQAPSTPSFPVSPAYYPGLSSPATSPSPDSAAFRQGSPTPA PEKRRMSVGDRAGELPNYATINGKVASPVPSGMSSPSGGSTVSFSHT PDFSKYSMPDNSPETRAKVKFV
QDTSKYWYKPEISRECAIALLKDQEPGAFIIRDSHSFRGAYG AMKVSSPPPTIMQQNKKGDMTHE VRHFLIETGPRGVKLKGCPNEPNFGS SA λTYQHSIIPLA PCK
VIPNRDPTDESKDSSGPANSTADL KQGAACNVLFINSVDMESLTGPQAISKATSETLAADPTPAATIVHFKVSAQGITLTDNQRK FFRRHYPLNTVTFCD DPQERKWMK
TEGGAPAKLFGFVARKCGSTTDNACH FAELDPNQPASAIVNFVSKVMLNAGQKR
210
CTGCTCCTTGCACCCCGC CCCTGCCTGGACACAGGCTCACTCGCTGCCTTCTTCTGGGGGAAACCAGCTTCTTGCCAGCCACAGCTGCTGCCTCCGCCACTGGCCACCGCC
CCTGTCCXGGGAGTCCCTTGGCCCAGACACCCACCTGACTTAGTGGCTCCTCTGCAGGAAAGGTGGCTGCCCCCTGCGTTCCTCCATCCAACCATGAGCTGGTGCCCATCAC
CACTGAGAATGCACCAAAGAATGTAGTGGACAAGGGAGAAGGAGCCTCCCGGGGTGGAAACACACGGAAAAGCCTCGAGGACAACGGCTCCACCAGGGTCACCCCGAGTGTC
CAGCCCCACCTCCAGCCCATCAGAAACATGAGTGTGAGCCGGACCATGGAGGACAGCTGTGAGCTGGACCTGGTGTACGTCACAGAGAGGATCATCGCTGTCTCCTTCCCCA
GCACAGCCAATGAGGAGAACTTCCGGAGCAACCTCCGTGAGGTGGCGCAGATGCTCAAGTCCAAACATGGAGGCAACTACCTGCTGTTCAACCTCTCTGAGCGGAGACCTGA
CATCACGAAGCTCCATGCCAAGGTACTGGAATTTGGCTGGCCCGACCTCCACACCCCAGCCCTGGAGAAGATCTGCAGCATCTGTAAGGCCATGGACACATGGCTCAATGCA
GACCCTCACAATGTCGTTGTTCTACACAACAAGGGAAACCGAGGCAGGATAGGAGTTGTCATCGCGGCTTACATGCACTACAGCAACATTTCTGCCAGTGCGGACCAGGCTC
TGGACCGGTTTGCAATGAAGCGGTTCTATGAGGATAAGATTGTGCCCATTGGCCAGCCATCCCAAAGAAGGTACGTGCATTACTTCAGTGGCCTGCTCTCCGGCTCCATCAA
AATAAACAACAAGCCCTTGTTTCTGCACCACGTGATCATGCACGGCATCCCCAACITTGAGTCTAAAGGAGGATGTCGGCCATTTCTCCGCATCTACCAGGCCATGCAACCT
GTGTACACATCTGGCATCTACAACATCCCAGGAGACAGCCAGACTAGCGTCTGCATCACCATCGAGCCAGGACTGCTCTTGAAGGGAGACATCTTGCTGAAGTGCTACCACA
AGAAGTTCCGAAGCCCAGCCCGAGACGTCATCTTCCGTGTGCAGTTCCACACCTGTGCCATCCATGACCTGGGGGTTGTCTTTGGGAAGGAGGACCTTGATGATGCTTTCAA
AGATGATCGATTTCCAGAGTATGGCAAAGTGGAGTTTGTATTTTCTTATGGGCCAGAGAAAATTCAAGGCATGGAGCACCTGGAGAACGGGCCGAGCGTGTCTGTGGACTAT
AACACCTCTGACCCCCTCATCCGCTGGGACTCCTACGACAACTTCAGTGGGCATCGAGATGACGGCATGGAGGAGGTGGTGGGACACACGCAGGGGCCACTAGATGGGAGCC
TGTATGCTAAGGTGAAGAAGAAAGACTCCCTGCACGGCAGCACCGGGGCTGTTAATGCCACACGTCCTACACTGTCGGCCACCCCCAACCACGTGGAACACACGCTTTCTGT
GAGCAGCGACTCGGGCAACTCCACAGCCTCCACCAAGACCGACAAGACCGACGAGCCTGTCCCCGGGGCCTCCAGTGCCACTGCTGCCTTGAGTCCCCAGGAGAAGCGGGAG
CTGGACCGCCTGCTGAGTGGCTTTGGCTTAGAGCGAGAGAAGCAAGGCGCCATGTACCACACCCAGCACCTCAGGTCCCGCCCAGCAGGGGGCTCGGCTGTGCCCTCCTCTG
GACGCCACGTTGTCCCAGCCCAGGTTCATGTCAATGGTGGGGCGTTAGCATCTGAGCGGGAGACAGACATCCTGGACGATGAATTGCCAAACCAGGATGGTCACAGTGCGGG
CAGCATGGGCACACTCTCTTCTCTGGACGGGGTCACCAACACCAGTGAGGGGGGCTACCCAGAGGCCCTGTCCCCACTGACCAACGGTCTGGACAAGTCCTACCCCATGGAG
CCTATGGTCAATGGAGGAGGCTACCCCTACGAGTCTGCCAGCCGGGCGGGGCCTGCCCATGCTGGCCACACGGCCCCCATGCGGCCCTCCTACTCTGCACAGGAGGGTTTAG
CTGGCTACCAGAGGGAGGGGCCCCACCCAGCCTGGCCACAGCCAGTGACCACCTCCCACTATGCCCATGACCCCAGCGGTATGTTCCGCTCTCAATCCTTTTCGGAAGCTGA
ACCCCAGCTGCCCCCAGCTCCGGTCCGAGGGGGAAGCAGCCGGGAGGCTGTGCAAAGGGGACTGAATTCGTGGCAGCAGCAGCAGCAGCAGCAGCAGCAGCCTCGCCCACCT
CCACGCCAGCAGGAAAGAGCCCACTTGGAGAGTCTTGTAGCCAGCAGGCCCAGCCCTCAGCCATTGGCAGAGACCCCCATCCCCAGTCTCCCTGAGTTCCCGCGAGCAGCCT
CCCAGCAGGAGATTGAACAGTCCATCGAAACACTCAATATGCTGATGCTGGACCTGGAGCCAGCCTCCGCTGCTGCCCCACTACACAAGTCCCAGAGTGTCCCCGGGGCCTG
GCCAGGGGCTTCTCCACTCTCCTCCCAGCCCCTCTCTGGATCCTCCCGTCAGTCCCATCCACTGACCCAGTCCAGATCTGGCTATATCCCCAGTGGGCATTCGTTGGGAACC CCTGAGCCAGCCCCACGGGCCTCTCTGGAGTCTGTCCCTCCTGGCAGGTCTTACTCACCTTATGACTATCAGCCATGTTTGGCTGGGCCTAACCAGGATTTCCATTCAAAGA GCCCAGCCTCTTCCTCCTTGCCTGCCTTCCTTCCGACCACCCACAGCCCTCCAGGGCCTCAGCAACCCCCAGCCTCTCTCCCTGGCCTCACTGCTCAGCCTCTGCTCTCACC AAAGGAAGCGACTTCAGACCCCTCCCGGACTCCAGAGGAGGAGCCATTGAATTTAGAAGGGCTGGTGGCCCACAGGGTAGCAGGGGTACAGGCTCGGGAGAAGCAGCCTGCA GAGCCCCCAGCCCCTCTGCGGAGGCGGGCGGCCAGTGATGGACAGTATGAGAACCAGTCTCCAGAAGCCACATCCCCTCGTAGCCCTGGGGTTCGCTCCCCTGTCCAGTGTG TCTCCCCGGAGCTGGCTCTTACCATCGCTCTCAATCCTGGAGGGCGGCCCAAAGAGCCCCATTTGCACAGCTACAAGGAGGCCTTCGAGGAGATGGAGGGAACCTCCCCGAG CAGCCCACCACCCAGTGGGGTGCGGTCCCCCCCGGGTCTGGCCAAGACACCCCTGTCTGCTCTGGGCCTGAAACCTCACAACCCAGCGGACATCCTGTTGCACCCCACAGGA GTTACCAGAAGACGGAΓCCAGCCAGAGGAAGATGAGGGGAAGGTGG GGTCAGGCTGTCAGAAGAGCCCCGGAGCTATGTGGAGTCTGTGGCACGGACAGCGGTGGCTGGAC CCCGAGCTCAGGACTCTGAGCCCAAGAGCTTTAGTGCTCCAGCCACCCAGGCCTATGGCCATGAGATACCCCTGAGGAACGGGACCCTGGGTGGCTCCTTTGTCTCCCCCAG CCCCCTCTCCACCAGCAGCCCCATCCTCAGTGCTGACAGCACTTCAGTGGGGAGTTTCCCGTCGGGAGAGAGCAGTGACCAGGGTCCCCGGACGCCCACCCAGCCTCTGTTG GAGTCTGGCTTCCGCTCAGGCAGCCTGGGACAGCCCAGCCCATCTGCCCAGAGAAACTACCAGAGCTCTTCTCCTCTCCCGACTGTGGGCAGTAGCTACAGCAGCCCCGACT ACTCACTTCAGCATTTCAGCTCCTCTCCGGAAAGCCAGGCCCGAGCTCAGTTCAGTGTGGCTGGCGTCCACACGGTGCCTGGGAGCCCTCAGGCGCGCCACAGAACAGTGGG CACCAACACTCCCCCTAGTCCTGGCTTCGGCCGGCGGGCCATCAATCCCAGCATGGCTGCCCCCAGCAGTCCCAGTTTGAGCCATCACCAGATGATGGGTCCACCAGGCACT GGCTTCCATGGTAGCACΓGTCTCCAGCCCCCAGAGCAGTGCAGCGACCACCCCGGGGAGCCCCAGCCTGTGTCGGCACCCAGCAGGGGTCTACCAGGTTTCTGGCCTCCACA ACAAAGTGGCCACCACCCCGGGGAGTCCCAGCCTGGGCCGGCACCCTGGGGCTCACCAAGGCAACC GGCCTCCGGTCTTCATAGCAATGCAATAGCCAGCCCTGGAAGCCC CAGCCTGGGCCGTCACCΓCGGAGGGTCTGGATCTGTGGTTCCCGGCAGCCCCTGCTTGGACCGGCATGTGGCCTATGGCGGCTATTCTACCCCGGAGGATCGGAGACCCACA CTGTCCCGGCAGAGCAGΓGCCTCTGGCTACCAGGCTCCTTCCACGCCCTCCTTCCCTGTCTCCCCTGCCTACTACCCTGGCCTGAGCAGCCCTGCCACCTCCCCGTCACCAG ACTCCGCAGCCTTCCGGCAAGGGAGCCCAACACCAGCCTTGCCAGAGAAGCGAAGGATGTCAGTGGGAGACCGGGCAGGCAGCCTCCCCAACTATGCCACCATCAATGGGAA GGTTGCTTCGCCTGTGCCCAGCGGCATGTCCAGTCCCAGCGGGGGCAGCACCGTCTCCTTCTCCCACACTCTGCCCGACTTCTCCAAGTACTCCATGCCAGACAACAGCCCG GAGACGCGGGCTAAAGRGAAGTTTGTCCAGGACACTTCTAAGTATTGGTACAAGCCTGAGATCTCCAGGGAGCAGGCCATCGCGCTCCTCAAGGACCAGGAGCCGGGGGCCT ΓCATCATCCGCGACAGΓCACTCCTTCCGAGGCGCGTACGGGCTGGCCATGAAGGTGTCTTCGCCACCTCCAACCATCATGCAGCAGAATAAAAAAGGAGACATGACCCATGA GCTGGTCAGGCATTTTCΓGATAGAGΔCTGGCCCCAGAGGAGTCAAGCTCAAGGGCTGCCCCAATGAGCCAAACTTCGGATCGCTGTCTGCCCTGGTCTACCAGCACTCCATC ATCCCATTGGCCCTGCCΓTGCAAGCTGGTCATTCCAAACCGAGACCCCACAGATGAATCGAAAGATAGCTCCGGCCCTGCCAACTCAACTGCAGACCTGCTGAAACAAGGGG CAGCCTGCAATGTGCTCΓTCATCAACTCTGTGGACATGGAGTCACTCACTGGGCCACAGGCCATCTCTAAAGCCACATCTGAGACGTTGGCTGCAGACCCCACGCCAGCTGC CACCATCGTTCACTTCAAAGTCTCTGCCCAGGGAATCACTCTGACTGACAACCAGAGAAAGCTCTTTTTCAGACGCCACTACCCTCTCAACACIGTCACCTTCTGTGACCTG GATCCACAGGAAAGAAAGTGGATGAAAACAGAGGGTGGTGCCCCTGCTAAGCTCTTCGGCTTCGTGGCCCGGAAGCAGGGCAGCACCACGGACAACGCCTGCCACCTCTTTG CTGAGCTTGACCCCAACCAGCCGGCCTCTGCCATCGTCAACTTCGTCTCCAAGGTCATGCTGAATGCCGGCCAAAAGAGATGAACCCTGCCCCTTGCCCAGGGCCAGTGCCA TGGGGAAGGGGCTTGTGSGGAGGGGACCCATGAATCCTGACCACTCTTGAACCCAGAAGGAGGACTTTGGGCCAATTTCGGAGGAGAGAAGAAAGTGCAACGTGGGGAGAGG GAAGTGAATTGCAGAGGGGAGGGGGAAAAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAAAGATGGAGGAGAAGAACTTGGATTCCCCTGGGTAGATGGAAACT GCAAAAACCCAAAGCCTCCAAAACTAACCAGGTCCACCTAACACCCCCTCCCTCCCCTAAGAAGATGGATGTCCTCAAAAGAGAAGGAACAAACCTCCTTGGGAATCCACAT TTTTTGGGGGAATGGAAAAGCTCTGTCTCCCTAACTCAACTGCTTTGCAAGGGGAAATCAAGCTGGGAGAATCTTTTTCTGGCCACCTGTAGGGTAGGTTGTCAAACCAAAC AGAGCCACCGTGGGACAΓCAAGTGGAAGAACTTGTT GCTTGAAAGTATCTCAGACCCAAGGCACCTCAGGTCTCTTTG
211
MEYASDASLDPEAPWPPAPRARACRVLP ALVAGLTJJLLLLAAACAVFLACP AVSGARASPGSAAEPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNV LIDGPLEWYSD PG AGVS TGG SYKEDΓKE WAKAGVYYVFFQLE RRWAGEGSGSVSLALH QPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARH AWQ TQGATVLG FRVTPEIPAGLPSPRSE
212
GTCATGGAATACGCCTCΓGACGCTTCACTGGACCCCGAAGCCCCGTGGCCTCCCGCGCCCCGCGCTCGCGCCTGCCGCGTACTGCCTTGGGCCCTGGTCGCGGGGCTGCTGC ΓGCTGCTGCTGCTCGCTGCCGCCTGCGCCGTCTTCC CGCCTGCCCCTGGGCCGTGTCCGGGGCTCGCGCCTCGCCCGGCTCCGCGGCCAGCCCGAGACTCCGCGAGGGTCC CGAGCTTTCGCCCGACGATCCCGCCGGCCTCTTGGACCTGCGGCAGGGCATGTTTGCGCAGCTGGTGGCCCAAAATGTTCTGCTGATCGATGGGCCCCTGAGCTGGTACAGT GACCCAGGCCTGGCAGGCGTGTCCCTGACGGGGGGCCTGAGCTACAAAGAGGACACGAAAAAGCTGGTGG GGCCAAGGCTGGAGTCTACTATGTCTTCTTTCAACTAGAGC RGCGGCGCGTGGTGGCCGGCGAGGGCTCAGGCTCCGTTTCACTTGCGCTGCACCTGCAGCCACTGCGCTCTGCTGCTGGGGCCGCCGCCCTGGCTTTGACCGTGGACCTGCC ACCCGCCTCCTCCGAGGCTCGGAACTCGGCCTTCGGTTTCCAGGGCCGCTTGCTGCACCTGAGTGCCGGCCAGCGCCTGGGCGTCCATCTTCACACTGAGGCCAGGGCACGC CATGCCTGGCAGCTTACCCAGGGCGCCACAGTCTTGGGACTCTTCCGGGTGACCCCCGAAATCCCAGCCGGACTCCCTTCACCGAGGTCGGAATAACGCCCAGCCTGGGTGC AGCCCACCTGGACAGAGΓCCGAATCCTACTCCATCCTTCATGGAGACCCCTGGTGCTGGGTCCCTGCTGCTTTCTCTACCTCAAGGGGCTTGGCAGGGGTCCCTGCTGCTGA CCTCCCCTTGAGGACCCΓCCTCACCCACTCCTTCCCCAAGTTGGACCTTGATATTTATTCTGAGCCTGAGCTCAGATAATATATTATATATATTATATATATATATATATTT CTATTTAAAGAGGATCCTGAGTTTGTGAATGGACTTTTTTAGAGGAGTTGTTTTGGGGGGGGGGTCTTCGACATTGCCGAGGCTGGTCTTGAACTCCTGGACTTAGACGATC CTCCTGCCTCAGCCTCCCAAGCAACTGGGATTCATCCTTTCTATTAATTCATTGTACTTATTTGCCTATTTGTGTGTATTGAGCATCTGTAATGTGCCAGCATTGTGCCCAG GCTAGGGGGCTATAGAAACATCTAGAAATAGACTGAAAGAAAATCTGAGTTATGGTAATACGTGAGGAATTTAAAGACTCATCCCCAGCCTCCACCTCCTGTGTGATACTTG
GAGGCTCAGGTGATCCRCCCATCTCAGCCTCTCGAGTAGCTGAGACCACAGTTGTGTGCCACCACACTTGGCTAACTTTTTAATTTTTTTGCGGAGACGGTATTGCTATGTT GCCAAGGTTGTTTACATGCCAGTACAATTTATAATAAACACTCATTTTTCC
213
MASSGMADSANHLPFFFGNITREEAEDYLVQGG SrXSLYL RQSRNYLGGPALSVAHGRKAHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQG
VQPKTGPFEDLKEN IREYVKQTWNLQGQALEQAIISQKPQLEK IATTAHEKMPWFHGKISREESEQIVLIGSKTNGKFLIRARDNNG8YALCLLHEGKVLHYRIDKDKTG
K SIPEGKKFDTLWQLVEHYSYKADGL RVLTVPCQKIGTQGNVNFGGRPQLPGSHPAT SAGGIISRIKSYSFPKPGHRKSSPAQGNRQESTVSFNPYEPELAP AADKGP
QREALPMDTEVYESPYADPEEIRPKEVYLDRKLLTLEDKE GSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAEANVMQQLDNPYIVRMIGICEAESWMLVM
EMAE GP NKYLQQI^HWaJKNIIE VHQVSMGMKYLEESNF fflRDLAARN ΛLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYAPECINYYKFSSKSDV^
L^WEAFSYGQKP RGMKGSEVTAM EKGERMGCPAGCPREMYDLMN C TYDVENRPGFAAVE R RNYY DVVN
214
GAGGAAGAGCCGCGGGCCCGGCGGCTGAGGCCACCCCGGCGGCGGCTGGAGAGCGAGGAGGAGCGGGTGGCCCCGCGCTGCGCCCGCCCTCGCCTCACCTGGCGCAGGTGGA CACCTGCGCAGGTGTGRGCCCTCCGGCCCCTGAAGCATGGCCAGCAGCGGCATGGCTGACAGCGCCAACCACCTGCCCTTCTTTTTCGGCAACATCACCCGGGAGGAGGCAG AAGATTACCTGGTCCAGGGGGGCATGAGTGATGGGCTTTATTTGCTGCGCCAGAGCCGCAACTACCTGGGTGGCTTCGCCCTGTCCGTGGCCCACGGGAGGAAGGCACACCA CTACACCATCGAGCGGGAGCTGAATGGCACCTACGCCATCGCCGGTGGCAGGACCCATGCCAGCCCCGCCGACCTCTGCCACTACCACTCCCAGGAGTCTGATGGCCTGGTC TGCCTCCTCAAGAAGCCCTTCAACCGGCCCCAAGGGGTGCAGCCCAAGACTGGGCCCTTTGAGGATTTGAAGGAAAACCTCATCAGGGAATATGTGAAGCAGACATGGAACC TGCAGGGTCAGGCTCTGGAGCAGGCCATCATCAGTCAGAAGCCTCAGCTGGAGAAGCTGATCGCTACCACAGCCCAΩAAAAAATGCCTTGGTTCCATGGAAAAATCTCTCG GGAAGAATCTGAGCAAAΓTGTCCTGATAGGATCAAAGACAAATGGAAAGTTCCTGATCCGAGCCAGAGACAACAACGGCTCCTACGCCCTGTGCCTGCTGCACGAAGGGAAG GRGCTGCACTATCGCARCGACAAAGACAAGACAGGGAAGCTCTCCATCCCCGAGGGAAAGAAGTTCGACACGCTCTGGCAGCTAGTCGAGCATTATTCTTATAAAGCAGATG GTTTGTTAAGAGTTCTTACTGTCCCATGTCAAAAAATCGGCACACAGGGAAATGTTAAΓTTTGGAGGCCGTCCACAACTTCCAGGTTCCCATCCTGCGTCCTCCCCTGCCCA AGGGAACCGGCAAGAGAGTACTGTGTCATTCAATCCGTATGAGCCAGAACTTGCACCCΓGGGCTGCAGACAAAGGCCCCCAGAGAGAAGCCCTACCCA GGACACAGAGGTG ΓACGAGAGCCCCTACGCGGACCCCGAGGAGATCAGGCCCAAGGAGGTTTACCTGGACCGAAAGCTGCTGACGCTGGAAGACAAAGAACTGGGCTCTGGTAATTTTGGAACTG RGAAAAAGGGCTACTACCAAATGAAAAAAGTTGTG7AAAACCGTGGCTGTGAAAATACTGAAAAACGAGGCCAATGACCCCGCTCTTAAAGATGAGTTATTAGCAGAAGCAAA ΓGTCATGCAGCAGCTGGACAACCCGTACATCGTGCGGATGATCGGGATATGCGAGGCCGAGTCCTGGATGCTGGTTATGGAGATGGCAGAACTTGGTCCCCTCAATAAGTAT RRGCAGCAGAACAGACARGTCAAGGATAAGAACATCATAGAACTGGTTCATCAGGTTTCCATGGGCATGAAGTACTTGGAGGAGAGCAATTTTGTGCACAGAGATCTGGCTG CAAGAAATGTGTTGCTAGTTACCCAACATTACGCCAAGATCAGTGATTTCGGACTTTCCAAAGCACTGCGTGCTGATGAAAACTACTACAAGGCCCAGACCCATGGAAAGTG GCCTGTCAAGTGGTACGCTCCGGAATGCATCAACTACTACAAGTTCTCCAGCAAAAGCGATGTCTGGAGCTTTGGAGTGTTGATGTGGGAAGCATTCTCCTATGGGCAGAAG CCAΓATCGAGGGATGAAAGGAAGTGAAGTCACCGCTATGTTAGAGAAAGGAGAGCGGAΓGGGGTGCCCTGCAGGGTGTCCAAGAGAGATGTACGATCTCATGAATCTGTGCT GGACATACGATGTGGAAAACAGGCCCGGATTCGCAGCAGTGGAACTGCGGCTGCGCAAΓTACTACTATGACGTGGTGAACTAACCGCTCCCGCACCTGTCGGTGGCTGCCTT ΓGATCACAGGAGCAATCACAGGAAAAGTATCCAGAGGAAT GA TGTCAGCCACCTCCCTCTGCCAGTCGGGAGAGCCAGGCTTGGATGGAACA GCCCACAACTTGTCAC CCAAAGCCTGTCCCΛGGACTCACCCTCCACAAAGCΛAAGGCAGTCCCGGGAGAAAAGACGGATGGCAGGATCCAAGGGGCTAGCTGGATTTGTTTGTTTTCTTGTCTGTGTG ATTTTCATACAGGTTAΓΓTTTACGATCTGTTTCCAAATCCCTTTCATGTCTTTCCACΓΓCTCTGGGTCCCGGGGTGCATTTGTTACTCATCGGGCCCAGGGACATTGCAGAG TGGCCTAGAGCACTCTCACCCCAAGCGGCCTTTTCCAAATGCCCAAGGATGCCTTAGCATGTGACTCCTGAAGGGAAGGCAAAGGCAGAGGAATTTGGCTGCTTCTACGGCC ATGAGACTGATCCCTGGCCACTGAAAAGCTTTCCTGACAATAAAAATGTTTTGAGGCTTTAAAAAGAAAAAAAAAAA
215
MASKKLGADFHGTFΞYLDDVPFKTGDKFKTPAKVGLPIGFSLPDC QWREVQYDFSLEKKTIEWAEEIKKIEEABREAECKIAEAEAKVNSKSGPEGDSKMSFΞKTHSTAT PPPINPIIΛSLQHNSILTPTRVSSSATKQKVLSPPHIKADFNLADFECEEDPFDNLELKTIDEKEE RNILVGTTGPIMAQLLDNNLPRGGΕGSVLQDEEVLASLERATLD FKPLHKPNGFITLPQLGNCEKMSLSSKVSLPPIPAVSNIKSLSFPKLDSDDSNQKTAKLASTFH8TSC RNGTFQNSLKPSTQΞSASELNGHHTLGLSALNLDSGTEMPALT SSQ PSLSVLSVCIEES8PPNTGPTVTPPNFSVSQVP MPSCPQAYSELQMLSPSERQCVETWNMGYSYECVLRANKKKGENIEQILDYLFAHGQLCEKGFDPLLVEEALE MHQCSEEK MEFLQLMSKFKEMGFELKDIKEVLLLHNNDQDNA ED MARAGAS
216
ACTGGCGGTGGCCTACGGTGAGCGGCCTGGCCGGAGCGCGAGAGTTGGAGGTGGTGGCGTTCGCTCTCCCTAGGGGCTGTCGGGAGCTCAGCGNGGACCGAGCCTGGGAGGC CGGCCGGTGCCAGCACCTTTCGGCTTCTGAGACGGCGGCACAGCGGCATTCAGGTTCTAAATGGCTTCTAAGAAGTTGGGTGCAGATTTTCATGGGACTTTCAGTTACCTTG ATGATGTCCCATTTAAGACAGGAGACAAATTCAAAACACCAGCTAAAGTTGGTCTACCTATTGGCTTCTCCTTGCC'IGATTGTTTGCAGGTTGTCAGAGAAGTACAGTATGA CTTCTCTTTGGAAAAGAAAACCATTGAGTGGGCTGAAGAGATTAAGAAAATCGAAGAAGCCGAGCGGGAAGCAGAGTGCAAAATTGCGGAAGCAGAAGCTAAAGTGAATTCT AAGAGTGGCCCAGAGGGCGATAGCAAAATGAGCTTCTCCAAGACTCACAGTACAGCCACAATGCCACCTCCTATTAACCCCATCCTCGCCAGCTTGCAGCACAACAGCATCC TCACACCAACTCGGGTCAGCAGTAGTGCCACGAAACAGAAAGTTCTCAGCCCACCICACATAAAGGCGGATTTCAATCTTGCTGACTTTGAGTGTGAAGAAGACCCATTTGA TAATCTGGAGTTAAAAACTATTGATGAGAAGGAAGAGCTGAGAAATATTCTGGTAGGAACCACTGGACCCATTATGGCTCAGTTATTGGACAATAACTTGCCCAGGGGAGGC TCTGGGTCTGTGTTACAGGATGAGGAGGTCCTGGCATCCTTGGAACGGGCAACCCTAGATTTCAAGCCTCTTCATAAACCCAATGGCTTTATAACCTTACCACAGTTGGGCA ACTGTGAAAAGATGTCACTGTCTTCCAAAGTGTCCCTCCCCCCTATACCTGCAGTAAGCAATATCAAATCCCTGTCTTTCCCCAAACTTGACTCTGATGACAGCAATCAGAA GACAGCCAAGCTGGCGAGCACTTTCCATAGCACATCCTGCCTCCGCAΔTGGCACGTTCCAGAATTCCCTAAAGCCTTCCACCCAAAGCAGTGCCAGTGAGCTCAATGGGCAT CACACTCTTGGGCTTTCAGCTTTGAACTTGGACAGTGGCACAGAGATGCCAGCCCTGACATCCTCCCAGATGCCTTCCCTCTCTGTTTTGTCTGTGTGCACAGAGGAATCAT CACCTCCAAATACTGGTCCCACGGTCACCCCTCCTAATTTCTCAGTGTCACAAGTGCCCAACAIGCCCAGCTGTCCCCAGGCCTATTCTGAACTGCAGATGCTGTCCCCCAG CGAGCGGCAGTGTGTGGAGACGGTGGTCAACATGGGCTACTCGTACGAGTGTG'ICCTCAGAGCCATGAAGAAGAAAGGAGAGAATATTGAGCAGATTCTCGACTATCTCTTT GCACATGGACAGCTTTGTGAGAAGGGCTTCGACCCTCTTTTAGTGGAAGAGGCTCTGGAAATGCACCAGTGTTCAGAAGAAAAGATGATGGAGTTTCTTCAGTTAATGAGCA AATTTAAGGAGATGGGCTTTGAGCTGAAAGACATTAAGGAAGTTTTGCTATTACACAACAATGACCAGGACAATGC'ITTGGAAGACCTCATGGCTCGGGCAGGAGCCAGCTG AGACCAGGCCCTGCCTAGGCCCTGCCGCAGAACCACCATCCCTGGGAGGCCCTGCAGAGCCCACCTGTGGGGAAAGAGAAGGGGCAGCTTCCGGATTTTCTTTTGGGGGTTA GAAGGTCAGGTGTGGAGACTGCTCGCCAGTCTCTGTGAGCCTAGGCCCTGAGCTGGGGAGGTGGGGAAGATTCGGGCATGTGAGTGCCCCCAGAACTGTCCTGGCTCCTTCC GTATTAAACGCATTTGCATTTTGAGAAGTGTCCTTCCCACTTCAGCCCTCCGGAGAGACTACCCTAGTCTTTCTGGGGTGTTTATGTCCTCAGCTGAAGCCTGGCCTAGTTG CTGAGAGGGGCTGGGGAGATGGGGCGGGAGGGCCAGACTCAGTGCTGCTGTGGAGCTAGGTGCTTCCCCCTTCCCCTGAGACTGGTTGACTGAACTCCAGTCAAGTTGAGTT CAAGTGAAAGATTCTTCCAGGGTTTTATTTTTTCCCCTCCTAACAAAGTCTCATAGTGTTAACACTGGTTCTGCAATATCTCTGAGGTGCAAAGAATGCACTTTTCCCTATG GGGCCCAGAGTTTGCCTTTTCTGCCAGGCAGTCACCACGCTTCCCTACCCCAGCCTGTTTCTTTTGGCTTGGTTTGGACCACAGTCCTCTGCTACCCAGGGTTTTAGAGCCC CTGCTCTAGGAAACAGTTTAAGAAATCATTGGCCCCTTCCCAGCACATTGAATGGGTAAGCAGACAGGCCATGATTTAGTTGGCCAGCACTAACTCCACCTCTGTTCTCCTT GAACAGCTTCCCCTCCAGCCCACTGCTTTAGGATGACACAATGAATAACACCTAGTCATAGAAATCAGTCTCTCTGGTTTGTTTTGTATTATGTTGTACATCATTAAAGATC TAAATACAAAGGATATACAGTCTTGAATCTAAAATAATTTGCTAACTATTTTGATTCTTCAGAGAGAACTACTAATAAAAATCTAAAAGGTAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAA
217
MPI VVLLSRIIMKEKQSTKVY SLIPIISGV LATVTE SFDM G VSALAAT CFSLQNIFSKKV RDSRIHHLRLLNILGCHAVFFMIPT VLVDLSAFLVSSDLTYVY QWP LL IJAVSGFCNFAQr IAFSILNLVΞPLSYSVANATKRIWI VSLIM RNPVTεT VLGMMTAI GVFLYNKTKYDANQQARKH LPVTTADLSSKERHRSPLEKP HKGLLFPQHGDYQYGRNNILTDHFQYSRQSYPNSYS NRYDV
218
GTGCCACATCCTGGCTCTGTGCGCTGGGCTCCCGCCGCTGCTGCGCGCCTGGCGCGTGCCCCCCGCGCCGCCCGTCTCGGGCCCCGGACCCAGTCCGCATCCGTCGTCCGGC
CCGCTGCTGCCGCCGCGCTTCTACCCGCGCTACGTGCTACCGCTCGCCTTCGGCAAGTACTTCGCGTCCGTGTCAGCGCACGTCAGCATCTGGAAGGTGCCCGTGTCCTATG
CACACACCGTCAAGGCCACCATGCCCATCTGGGTGGTCCTCCTGTCCCGGATCATTATGAAGGAGAAGCAGAGCACCAAGGTATACTTGTCACTCATCCCCATCATCAGCGG
TGrCCTGCTGGCCACCGTCACCGAGTTGTCTTTTGACATGTGGGGACTCGTCAGCGCCCTCGCCGCCACGCTGTGCTTCTCGCTTCAGAACATTTTCTCCAAAAAGGTCTTG
CGAGATTCACGGATCCACCATCTCCGGCTGCTCAACATCCTGGGCTGCCACGCCGTCTTCTTTATGATCCCCACCTGGGTTCTGGTGGACCTCTCGGCTTTCCTGGTCAGCA
GCGACTTGACCTACGTCTACCAGTGGCCCTGGACGCTCCTGCTCCTGGCTGTCAGCGGCTTCTGTAACTTTGCCCAGAATGTTATCGCCTTCAGCATCCTCAACCTCGTTAG
CCCCCTGAGCTACTCGGTCGCCAATGCCACCAAAAGAATCATGGTCATCACGGTGTCCCTGATCATGCTGCGCAACCCAGTCACCAGCACCAACGTCCTGGGCATGATGACC
GCCArCCTGGGGGTCTTCCTCTATAACAAGACCAAGTACaATGCAAACCAGCAAGCCAGGAAGCACCTCCTCCCCGTCACCACAGCAGACCTGAGCAGCAAGGAGCGTCACC
GGAGCCCACTGGAGAAGCCCCACAACGGCCTCCTCTTCCCCCAGCACGGGGACTATCAGTACGGCCGCAACAACATCTTAACAGACCACTTCCAATACAGCCGGCAGAGCTA
CCCAAACTCGTACAGTTTGAACCGCTATGATGTGTAGAGTCCAAAGGACAGGACCAGACTGTTGGTGACTCCTTCCCCGGCCCCCACAGCAGTATCAGAAACTTCTGACAAT
CAGTGAATGTACAACCCAGCCGAGGGGACGGTGCATAACTCTCCATCAGAAGCCCTGGGGTTCCTGGCCCCCCGTGAGCCGCAGGAGGATGCGTTGCCTGCAGTGCAGACGG
CCGTGAGCTCTGGGCAAACCTAAACAGAGACCAGTGTCTCATGCTCTTTCTTCCTGGAGTCTGTCATCTGAGGGCCGTGTCCCTGCGGAGATCTTGGCCACGTTGTACCTTT
CCATGTGGAATTATTCCCCAAGCAGTGTAGCTCAGAGCACTTGTGTCTGCATTCCAGATAACATTCAGGACCTGTGTGAAAAGCTGGGGTCACTGTGGCTGTAGACCATGAA
CTGGCAGTGGGGGTGTCCAGGGCGGTGCTTGAGAACGTCAGACTGGCTAGTTTAATTCCCTGGCGCAGATACGCATAGGACCAACAGGGTCACCAAGCAGACAGGGAGCCCG
CGAGAATCATTCAAAACATCCCCAGCCACAGAGATGGATCCAGTTTCCTGGTCATCCCCTTAGCAGTTCACAAGTTCCTGGCAAATGTTCCAAAGCAAAAAGCGATTGCAAT
TAGCATCCAGTTCCTGCAGCCTGGTGCTCTGCCCTGCACGTCAGGGTTGGCATCCACCCAGATCCAGATGGAAGGGAAACTTCTCTCTTCTCCTTTGCCTCCTCTTCCCTCA
CCAGAGCAGGGCGCTTCTCTTGGGGTGGTGAGAAGGATCTTCGAGAAATCGTGTTCAGTATTTCAAGCTCTATTTCTGTGGCACATGTCTTTTGAGAGGCATCTTCACCTCT rCTGTGATGACTTGGTATGTTGTTTGGTAGAGAGATCTTGATTTTCGGAGGATCTTGCATTTTTCTAGGGAATATTTTGTAGTTGTGTGTGTGTGTTTTTGCCTTGGTCCCC
ATTATGGGATGCATTAGGACTGGCCTATGCATCGAAAATCTrTTTGTTTGTAAACGTTTAAAAACAAAGTTCCCCGGCCAGGCACAGTGGCTCACACCTGTAATCCCAGCAC rTTGGGAGGCCAAGATGGGCGGATCACGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATAGTGAAACCCCATCTCTACTAAAAATACAGAAATTAGCCGGGCATGGTGTC
GCGTGCCTGTAGTCCCAGCTCCTCAGGCTGCTGAGGCAGGCGAATTGCTTGAACCTGGGAGGCAGAAGTTGTGGTGAGCCGAGATTGTGCACTCCAGCCTGGGTΔΔCAGΔGC
GAGACTCCATCTCAAAAAAAAACAAAACAAAACCAAGTTCCCACTGGTGATGCCTGTCTGACACGTTTTGGTATTTAGTAGGAAATGAAGTGTTTCGAAGCTTCGAGAGAAG
CTTCAAAATTGTCACAATTGCTGAAAACAGAATGAATCGTGAACATTATCTCAATATTTTGTATAATAGACAAGACCACAGTGTTTTGGTTCCCTGACCTGTTTTTGTGTTT
ATGTTAGGATCTGAATCATGTTCTGGGTAAGGGGACGAGGAGCGAACACTGCACTAAGATTTGGTTTGCCAAATCAGATTCTTTGGTCAAGAGTCAGTTTGGGGCCAGGCGT
GGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAGGCTGAGGrGGGTGGATCACTGGAGTTTGAGACCACCCTGGCCAACATGGTGAAACCCCATCTCTACTAAAACAAAAA
TTAGCCAGGCATGGTGGCACCTGCCTGTAATCCCAGCTACrrGGGAGGCTGAGGCAGGAGAATCACTTGAGCCCAGGAGGTGGAGGTTTCAGCGAGCTGAGATCACACCACT
GCACTCCAGCCTTGGTGACAGAGTGAGACTCTGTCTC
219 TIO SAQVKGSLNITTPGLQIWRIEAMQMVPVPSSTFGSFFDGDCYI ILAIHKTASSLSYDIHYWIGQDSSI DEQGAAAIYTTQMDDFLKGRAVQHREVQGNESEAFRGYFK
QGLVIRKGGVASGMKHVE-^SYDVQRLLιHVKGKR r VAGEVEMS KSFN GDVFLLDLGK IIQ^mGPESTRMER G rLAKEIRDQERGG TYVGVVDGENELASPK ME
VM HVLGKP-RELKAAVPDTVVEPALKAALKLYHVSDSEGN VVREVATRPLTQDLLSHEDCYI DQGGLKIYV KGKKA EQEKKGAMSHALNFIKAKQYPPSTQVEVQNDG
AESAVFQQLFQKWTASbTOTSGLGKTHTVGSVAKVEQVKFDATSMHVKPQVAAQβKMVDDGSGEVQVWRIENLELVPλ DSKWLGHFYGGDCYLLLYTYLIGEKQHYLLYVWQG
SQASQDEITASAYQAVILDQK WGEPVQIRVPMGKEPPHLMSIFKGRMVVYOGG SRT^MLETGPST FQVQGTGA NTKAFE PARANFLNS DVFVLKTQSCCYLWCGK
GCSGDEREI^K WADTIS TEKQVVVEGQEPANFW ALGGKAPYAJ ^KRI^EE π ITPRLFECSNKTGRFIJVTEIPDF QDD EEDDVFLLDVWDQVFF IGKHANEEEKK
AAATTAQEYLKTHPSGRDPETPIIVVKQGHEPPTFTGHFIAWDPFK SNTKSYEDLKAESGNLRDWSQITAEVTSPKVDVFNA SNLSSGP PIFP EQLVNKPVEE PEGV
DPSRKEEHLSIEDFTQAFGMTPAAFSA PRWKQQNL.KKEKGLF
220
CATTCTCCCCCAGGCTCACTCACCATGACCAAGCTGAGCGCCCAAGTCAAAGGCTCTCTCAACATCACCACCCCGGGGCTGCAGATATGGAGGATCGAGGCCATGCAGATGG TGCCTGTTCCTTCCAGCACCTTTGGAAGCTTCTTCGAΓGGTGACTGCTACATCATCCTGGCTATCCACAAGACAGCCAGCAGCCTGTCCTATGACATCCACTACTGGATTGG CCAGGACTCATCCCTGGATGAGCAGGGGGCAGCTGCCATCTACACCACACAGATGGATGACTTCCTGAAGGGCCGGGCTGTGCAGCACCGCGAGGTCCAGGGCAACGAGAGC GAGGCCTTCCGAGGCTACTTCAAGCAAGGCCTTGTGATCCGGAAAGGGGGCGTGGCTTCTGGCATGAAGCACGTGGAGACCAACTCCTATGACGTCCAGAGGCTGCTGCATG TCAAGGGCAAGAGGAACGTGGTAGCTGGAGAGGTAGAGATGTCCTGGAAGAGTTTCAACCGAGGGGATGTTTTCCTCCTGGACCTTGGGAAGCTTATCATCCAGTGGAATGG ACCGGAAAGCACCCGTATGGAGAGACTCAGGGGCATGACTCTGGCCAAGGAGATCCGAGACCAGGAGCGGGGAGGGCGCACCTATGTAGGCGTGGTGGACGGAGAGAATGAA TTGGCATCCCCGAAGCTGATGGAGGTGATGAACCACGTGCTGGGCAAGCGCAGGGAGCIGAAGGCGGCCGTGCCCGACACGGTGGTGGAGCCGGCACTCAAGGCTGCACTCA AACTGTACCATGTGTCTGACTCCGAGGGGAATCTGGTGGTGAGGGAAGTCGCCACACGGCCACTGACACAGGACCTGCTCAGTCACGAGGACTGTTACATCCTGGACCAGGG GGGCCTGAAGATCTACGTGTGGAAAGGGAAGAAAGCCAATGAGCAGGAGAAGAAGGGAGCCATGAGCCATGCGCTGAACTTCATCAAAGCCAAGCAGTACCCACCAAGCACA CAGGTGGAGGTGCAGAATGATGGGGCTGAGTCGGCCGTCTTTCAGCAGCTCTTCCAGAAGTGGACAGCGTCCAACCGGACCTCAGGCCTAGGCAAAACCCACACTGTGGGCT CCGTGGCCAAAGTGGAACAGGTGAAGTTCGATGCCACATCCATGCATGTCAAGCCTCAGGTGGCTGCCCAGCAGAAGATGGTAGATGATGGGAGTGGGGAAGTGCAGGTGTG GCGCATTGAGAACCTAGAGCTGGTACCTGTGGATTCCAAGTGGCTAGGCCACT'ICTATGGGGGCGACTGCTACCTGCTGCTCTACACCTACCTCATCGGCGAGAAGCAGCAT TACCTGCTCTACGTTTGGCAGGGCAGCCAGGCCAGCCAAGATGAAATTACAGCATCAGCTTATCAAGCCGTCATCCTGGACCAGAAGTACAATGGTGAACCAGTCCAGATCC GGGTCCCAATGGGCAAGGAGCCACCTCATCTTATGTCCATCTTCAAGGGACGCATGGTGGTCTACCAGGGAGGCACCTCCCGAACTAACAACTTGGAGACCGGGCCCTCCAC ACGGCTGTTCCAGGTCCAGGGAACTGGCGCCAACAACACCAAGGCCTTTGAGGTCCCAGCGCGGGCCAATTTCCTCAATTCCAATGATGTCTTTGTCCTCAAGACCCAGTCT TGCTGCTATCTATGGTGTGGGAAGGGTTGTAGCGGGGACGAGCGGGAGATGGCCAAGATGGTTGCTGACACCATCTCCCGGACGGAGAAGCAAGTGGTGGTGGAAGGGCAGG AGCCAGCCAACTTCTGGATGGCCCTGGGTGGGAAGGCCCCCTATGCCAACACCAAGAGACTACAGGAAGAAAACCTGGTCATCACCCCCCGGCTCTTTGAGTGTTCCAACAA GACTGGGCGCTTCCTGGCCACAGAGATCCCTGACTTCAATCAGGATGACTTGGAAGAGGATGATGTGTTCCTACTAGATGTCTGGGACCAGGTCTTCTTCTGGATTGGGAAA CATGCCAACGAGGAGGAGAAGAAGGCCGCAGCAACCACTGCACAGGAATACCICAAGACCCATCCCAGCGGGCGTGACCCTGAGACCCCCATCATTGTGGTGAAGCAGGGAC ACGAGCCCCCCACCTTCACAGGCTGGTTCCTGGCTTGGGATCCCTTCAAGTGGAGTAACACCAAATCCTATGAGGACCTGAAGGCGGAGTCTGGCAACCTTAGGGACTGGAG CCAGATCACTGCTGAGGTCACAAGCCCCAAAGTGGACGTGTTCAATGCTAACAGCAACCTCAGTTCTGGGCCTCTGCCCATCTTCCCCCTGGAGCAGCTAGTGAACAAGCCT GTAGAGGAGCTCCCCGAGGGTGTGGACCCCAGCAGGAAGGAGGAACACCTGTCCATTGAAGATTTCACTCAGGCCTTTGGGATGACTCCAGCTGCCTTCTCTGCTCTGCCTC GATGGAAGCAACAAAACCTCAAGAAAGAAAAAGGACTATTTTGAGAAGAGTAGCTGTGGTTGTAAAGCAGTACCCTACCCTGATTGTAGGGTCTCATTTTCTCACCGATATT AGTCCTACACCAATTGAAGTGAAATTTTGCAGATGTGCCTATGAGCACAAACTTCTGTGGCAAATGCCAGTTTTGTTTAATAATGTACCTATTCCTTCAGAAAGATGATACC CCAAAAAAAAAAAA
221
EKITT QDPRKA^WQPI^H^mLH A SεTPVPQRS^4AVSQPN VIWHQHQQQ^lAPSTLSQQ HPTQNPPAGLMSMPNA TTQQQQQQK RLQ IQMERERIR IRQEELMRQE AALCRQLPMEAETLAPVQAAVNPPTMTPDMRSITNNSSDPFLNGGPYH8REQSTDSGLGLGCYSVPTTPEDFLSNVDEMDTGENAGQTPMNINPQQTRFPDFLDCLPGTNVD GT ESED IPLFNDVESALNKSEPFLT L
222
GAGAAAAAATCACCACATGGCAAGACCCTAGGAAGGCGATGAATCAGCCTCTGAA1CATATGAACCTCCACCCTGCCGTCAGTTCCACACCAGTGCCTCAGAGGTCCATGGC AGTATCCCAGCCAAATCTCGTGATGAATCACCAACACCAGCAGCAGATGGCCCCCAGTACCCTGAGCCAGCAGAACCACCCCACTCAGAACCCACCCGCAGGGCTCATGAGT ATGCCCAATGCGCTGACCACTCAGCAGCAGCAGCAGCAGAAACTGCGGCTTCAGAGAATCCAGATGGAGAGAGAAAGGATTCGAATGCGCCAAGAGGAGCTCATGAGGCAGG AAGCTGCCCTCTGTCGACAGCTCCCCATGGAAGCTGAGACTCTTGCCCCAGTTCAGGCTGCTGTCAACCCACCCACGATGACCCCAGACATGAGATCCATCACTAATAATAG CTCAGATCCTTTCCTCAATGGAGGGCCATATCATTCGAGGGAGCAGAGCACTGACAGTGGCCTGGGGTTAGGGTGCTACAGTGTCCCCACAACTCCGGAGGACTTCCTCAGC AATGTGGATGAGATGGATACAGGAGAAAACGCAGGACAAACACCCATGAACATCAATCCCCAACAGACCCGTTTCCCTGATTTCCTTGACTGTCTTCCAGGAACAAACGTTG ACTTAGGAACTTTGGAATCTGAAGACCTGATCCCCCTCTTCAATGATGTAGAGTCTGCTCTGAACAAAAGTGAGCCC1TTCTAACCTGGCTGTAATCACTACCATTGTAACT TGGATGTAGCCATGACCTTACATTTCCTGGGCCTCTTGGAAAAAGTGATGGAGCAGAGCAAGTCTGCAGGTGCACCACTTCCCGCCTCCATGACTCGTGCTCCCTCCTTTTT ATGTTGCCAGTTTAATCATTGCCTGGTTTTGATTGAGAGTAACTTAAGTTAAACATAAATAAATATTCTATTTTCATTTTCTGCAAGCCTGCGTTCTTGTGACAGATTATAC AGAATTGTGTCTGCAGGATTGATTATGCAGAATACTTTTCTCTTTCTTCTCTGCTGCCCCATGGCTAAGCTTTATGGGTGTTAATTGAAATTTATACACCAATTGATTTTAA ACCATAAAAAGCTGACCACAGGCAGTTACTTCTGAGGGCATCTTGGTCCAGGAAATGTGCACAAAATTCGACCTGATTTACAGTTTCAAAAACTGTATTGATGACAGTAGTA CCAAATGCTTTAAAAACTATTTAACTTGAGCTTTAAAAATCATTGTATGGATAGTAAAATTCTACTGTATGGAATACAATGTAATTTTGAATCCATGCIGGCTCTGATGGCT CTTATTAGTCTGTATTTATAAAGGCACACAGTCCTATTGTAGCTTATCTTTCGTTATTTTACTGCAGAGCATCTAGACAACTTAGTCCCTCCAGCGTGAAAGTAGCAGCAGC AGCATTAGTCACAGTTCTTACACTACAGATCTTGTGAAAGAGACCAGTTTGGTACTAATTATGAGCATTTTATTCAAACAAAAGTTTTTGAAATATTACAACTGGGGATTTA AAAAATTGCAGCTTAGAATCTGATGGTTTTTTTTTTTTCTTGATGTTGTTTGTTTGTTTTTGAGATCGAGTTTTGCTCTTGTTGTCCAGGCTGGAATGCAATGGCACAATCT CGGCTCACTGCAACCTCTGCCTTCTGGGTTCAAGCGATTCTCCTGCCTTAGCCTCCGGAGTAGCTGGGATTACAGGCGCCTGCCACCACGTCCGGCTAATTTTTTGTATTTT GAGTAGAGACGGGGTTTCACCATAATGGTCAGGCTGTTCTCAAACTCCTGATCTCAGGTGATCCACCCATCTCGGCCTTCCAAAGTGCTGGGATTACTGGCGTGAGCCACCG CACCCGGCCTTGATGTTTATTTTATAAAGCACTGTAATTTTGTAGCTGATGACAAAAGGCAGCCAAATGTTTTTGATAAATCAGTGGCAACTGTATTTTTGTCTTTTGAAAT AACTCTGAAAACATCAGGACAACATAGATTTCAACCTGATAGCACACCACACACAGTGAGCTGTTGCTTTTTAAATTCTGAAGCCTTGTCAGGTTTGCTTCCTAGATTTCAA GTGTTTAAAATAATTCTATCTATGAAACTGAAGGATGAAGCAGATCTCTGACTGACATGTAAAAAAAAATGCCCTTTGAGGGTGTATGGTGGAGATAAATGTTTCTGAATTC AGTAAAATTGATTCCTAAGTATATTATCCTAATCCTGTTTGCTACAGTTGGTATAAAAAGGCATGAAATATGTATTCAATACCTCTTATGTAACCAAAACCATTTTTAATTA GCTTTTAAGGACTGAGAGAGCATCATGTTCAACTGGCATGCAGTCTGCCTGCATTGCCAATGAAGTCCTCAACTGTTTAATATTTTGAACTAATATTATTTATAATCTATGA ATRTAATCTTTTTTGAAAGACTTTAATAATTTGAGTCTCTGAGAGGATACTTTCAATTTCCATGGGGGACTTATTTGTTGGGGATCTTAAATAAGATTCCTTTTGATCTACC GGAATATACATGTACAGAGTACATTGGATCATGTTGGAAAGAAGGCAAGTGAAAAGGTCAGAGATGAAGTAGCGAAGTTATGGAATATCGTGGAAAGGATACTAGTTGTGAA ATGGAAAGAGACAAGTTATAGTACCCCAAAAGCAAAACAAGCAGGAGATGCAAGAGATGCCCCAAAAGGACAAAGCAACAATTTTCTGTTGCCACCT'ITATACCGGAAGACT CTGΓTGTAGAAGAAAAGAAGGCTTTGGTGCACCTTATGTGGGAGGAGGAGGGGCAGGGCATGCTGATGCTGAGCGTACAGGCAGACAAGAGCGTAGCCTGCTGTTGCCTCCA TCACTATGAAATGACTTATTTTACCTGAAGGACCCATGGTTTATGTTCCTCTAATTCCTTTCACTCTCCCTAAGCCCTCTGAGAGAGATGAAGATAGATGATTTTATTGCTA CTAAATTGAAGGGAGCACTATTTCTTTTTGTCTTTIGTTAGCAAAAAATTGCAAAAAGAATTGTACATTCTTGCTAAAAATAAATAAATAAATAAAAAAAAAAAAAAAAA
223 GDKKSPTRPKRQAKPAADEGFWDCSVCTFRNSAEAFKCSICDVRKGT8TRKPRINSQLVAQQVAQQYATPPPPKKEKKEKVEKQDKEKPEKDKEI SPεVTKKNTNKKTKPK SDILKDPPSEANSIQSANATTKTSETNHTSRPR KITODRSTAQQLAVTVGNVTVIITDFKEKTRSSSTSSSTV SSAGSEQQNQSSSGSESTDKGSSREETPKGDMSAVNDE SF
224
GCGGGGACTAGTCTCGTCCGGAGACTGGCGGCGGCGGCGGCGGCGGCGGCCGGAGCTCGAGCCCCAGCGGCTGAGGGCGGGCGGGCGGGCGCGGGGGAGGGAGGGGGGCCGG TCCGCGACGACTCCCCGGACGGCGTTTCTCCTCCGAGCGGCGCCGGTTTCGGCTTGGGGGGGGCGGGGTACAGCCCATCCATGACCATGGGCGACAAGAAGAGCCCGACCAG GCCAAAAAGACAAGCGAAACCTGCCGCAGACGAAGGGTTTTGGGATTGTAGCGTCTGCACCTTCAGAAACAGTGCTGAAGCCTTTAAATGCAGCATCTGCGATGTGAGGAAA GGCACCTCCACCAGAAAACCTCGGATCAATTCTCAGCTGGTGGCACAACAAGTGGCACAACAGTATGCCACCCCACCACCCCCTAAAAAGGAGAAGAAGGAGAAAGTTGAAA AGCAGGACAAAGAGAAACCTGAGAAAGACAAGGAAATTAGTCCTAGTGTTACCAAGAAAAATACCAACAAGAAAACCAAACCAAAGTCTGACATTCTGAAAGATCCTCCTAG TGAAGCAAACAGCATACAGTCTGCAAATGCTACAACAAAGACCAGCGAAACAAATCACACCTCAAGGCCCCGGCTGAAAAACGTGGACAGGAGCACTGCACAGCAGTTGGCA GTAACTGTGGGCAACGTCACCGTCATTATCACAGACTTTAAGGAAAAGACTCGCTCCTCATCGACATCCTCATCCACAGTGACCTCCAGTGCAGGGTCCGAACAGCAGAACC AGAGCAGCTCGGGGTCTGAGAGCACAGACAAGGGCTCCTCCCGTTCCTCCACGCCAAAGGGCGACATGTCAGCAGTCAATGATGAATCTTTCTGAAATTGCACATGGAATTG TGAAAACTATGAATCAGGGTATGAAATTCAAAACCTCCACCTGCCCATGCTGCTTGCATCCCTGGAGAATCTTCTGTGGACATCGACCTCTTAGTGATGCTGCCAGGATAAT TTCTGCTTGCCATGGGCATCTGGCCACCAAGGAATTTCGCACCCTGACGATTACTCTTGACACTTTTATGTATTCCATTGTTTTATATGATTTTCCTAACAATCATTTATAA TTGGATGTGCTCCTGIAATCTACTTTTTATAAAAAJUIAAAAAATCTGCTGTGCACAATTTTCCATGTACATTACAACTGGTTTTTTGTTTTTGTTTTGTTGCCGGTGGGGAGG GCTGGGAGGGGGAGGGAACTTTTATTTATTGTGAACACAAACTCCATCCXTTCAGCATATCCTTTTAAGTTTAGTTCTTTCTTCCAGTTATACTATGTACTATCAGTTTTGA TARAACTATATATATATAAATATAAAATTATATATAAAGGGTTATTTGAAACCAATCCATGGCAAACGCTGGTGCTTGATACACTGTGAAGTGAATACAACATTGAACAGTT ACAGATCTGGGACAGTCCCTTCTATGAAAGTGCTGAAATTTAATTAAAATCAGTCTTACATGAAGTATGTTCCAATCCATGTGGGAACTTGACTCTCTCATCTGTCTAAAGA GTACTGGACGATATAAAAATATATATTTTTTAAACAATGTGATCTCAAATTTAAAGACTGCTCCAGATAGCCTGCATTTGCAATGGAATAACTGACAAATCACAAGTGGTTT AGTTGGGCAGGGCTTGATCATTCAAAAGTAACTAAAGTAGCTCCAGAATGCCAAGTATTCGTGTAAATTACGGTTACATGTTATCATTTGCTGTTCTTACATAAGCACTCA RGAAAATATGGTATTCTGTAACTTGAATTCCATCCATTTTCCAGACGTCTACTCATGTCTGAGGTAAATCTAGAAATTGTCTTAGTTTTAGGATTGAAACAGTCTATAAACT
GTATTTTTGGTCCATCCAGGAAGCTAGTCCCTGGTTTCTCCTTTCTACATGACATTGCAGTGGTGGTTTCTGTAATTAAAATTTGTTTeCCTCATGTCCCTTTGTCTGATAA ACCTTCACTCTACCGATTCAGTTGTGAGCATTCTTTTTTTCCTTCTCAAAACCTACTATGATTTGTTTTACTGAACAAAGGTTATCAACCACACATCCAGTCCTGACATGGA GCTTTTCAGTGTTGGJ^ACATTTCTCAATCCCCTGCTGTGGTAGGAACTCCAGTGGTGAΔCGGCTTGCGCGCCTGCAGCCAGAGTTGCAGGGGAAAGCTCGTACTTACTGCG AGCAGCATGTAATCTTRRTRCTTCCTGGACATAAAGATAGCTTGAGTAAACTGTTCTATTTCATTCTCTTCACTCTTTTTACTGTCTTGCAAAAAAAAAAAAAATAATAATA ATAATCAAAGACCACTAATAAGATTCCACCTCTCCTTATTAAAATAATTTTTTAAAATTTTGGTTTTGCTTTTGTTTTGGATTGGGTCTCTCTTCTA'ITTGACTTTTACATT TAGATACAGAGTTTGTAGTACTTCAGAGACATTTCAAGCATGAGAATTTGAGGTTACCTCTCTTTATTTGACCTTTAGGGACTCACGGGAGGGCAGCCTGATTTGTAATGAA GCACCACATTTTGGTGRRAAGAACCTGGTTTGCTTAATAATAECAGTAATTTCTGTGTGTGGAGGCAACAAATAAAAAAATTAACAGCTTGAATTGAGTAGCCAACAGGAAA GGTTCCTTTCACATTTACATΓAAAACTATTCTGTAGTCACTAATGTACCATAATTTAAATTCTTTTCTCAAAGGTATAGATTATAAAGCAGTGCCATTTGTTGCTGTGGTCC TATTCRCAAATGCATGGACAATGTTCCCCCCTTTTTAAAATAATGCTTGTGTCTGGGATGCAAGCTTTGCTTATCTTTTTAAATACATTTTTAAAGTATTTATTAATGAACC AAAGGAAATCAGATGCΓΓTCΓATAAGCATCAGAATATATAATACATAGTGATTTGACTATGAATTTTAAATCCACATTTTAATATTGGTGGGATATTGCAAAGACATTCCTT CTAAAGTTTTAATATTCCTTΓTATTAAGGGTCTCAGGGAGGGTAAATTAGTCAGCCATATTTATTTTCCAGAGGTTTAAGAAATTGCTGTTTTTAACTTTTTGAAAAAACTT AAATGCCACCAAACTCAΓGTAGGTTGCACTGCTTATTGAACCAATAACTGTTGGTATGCACTTTGTTCAGACACACTGTGTACTTTTTCAAAAACTAGTTTCATGTAAAGTG ATTGGACCCCATAGATRAGTGGAAAAAGCTGATTAACCAGCTACTCATAGGCTGCTAATTCATTCATGCCAATGTTTTGGTTTTTCAGTTTTGCCTCCGTGATAAATTAAAG AATGGGGAGGGGTCAAGGAAGGGGAAGAAGATTGCTTTAGAACAAGTGGCATGAAATTACCATCTTTGTAGAAACCGCAGCTAACAGTGGGAGTTATCTAAGCAATCAGATG TTACAGGGCCAGCCCCΓΓTAGCTGCTGTGGTGTATTCTGTTGGGTAGTGAGGTAGTAGGTACTTTATAGACTTTTAATTTTGGAAATTGATGACATCCCTCAGGCATGTATT CTGGAAATGGAATTCCΓGTAACTTCCTGTGTCTGCAGTATGCCCTACAATTAGTAGGCAGCGTGTAAAAACAC'IAGTGTAGATTATAAAGATATACATTAAAAGAGGACCAG AAAΓACTTGGTATTCAGΓGGCACAGAAAGCAGGTTAAACAAACAAAAAGCACAGTGTTACGCTTGCAAGTTTCCATTTGTTTTAATACCACGCAATCTTTCACACTCGTGCG TGTGCGCGCACACAGAGCTTACCTGACTTGCTCTGCTTGAGTCATGCAGTTACAAJΫ^AAAAAGACATCTTGACACCCACACAATATTCTAATCAAAACCTTTCAGTTTCAAT CTGGATATTTAAAAACAΓTGGCAGAAGCCTCTGTGAGTTTAGTTCCACTAAGATGTTTCACCTGCCTTATCAAGACCATTCTCAGTCTACTTTTTTAAGCTACCGTATCTTA AATTATTGAAAATTTARRAATTGCTGAATATATAATAACCTTTGCTTGTATGTAACCGAAAATGGTTTAAGAGCCAACATTTAGAGTATGACAATGGAGCTGAACAGTTTTT AATGCGCAAGCAGTTCΓGTTCTTGTGTATGACTTGTAACCTTAATTTACTGTGTAAAGATGGTTACATTATTTCCTTAGCTTTGTTTGTTGGAGACAAATAGAGAATGCTTG TTAAGTATGTCAAAACAATCTTATCTTGTGAATTTTTGTTAATGTATTATACGAGCTATATTTTTCATTTGCCCAGAAAGACAGCTTGTATAACGCTTTNGGAAGTTTCTGC TCNGTAATGTCTTTAGAGCTGACAGTCTGTTAGGTTNGTTTTTTTCTTCATGCTAAAGTGTCAGTTGGTGGTTTTGTGAACTGGTCAAAAATTCACAGGTCTTAAATGTTTT GGGGGAAATTTATATTGGACACTGCTCTTTGTCTAGCAAATAAAAGATGTTAATATATTCCTGTTACTGGCATG'IGCACGACTATGTTATTAGAAGCCACTTTATCATTTTC CTGCTTTAAATAGAAATGTCTATTTATGAATTCTGCTTGTAGTTTTTTCACAAATAAAATAGTAAAATTTAAAAAAAAAAAAAACAAAAAAAAAAAAAAAAAAAAAAA
224
GCGGGGACTAGTCTCGΓCCGGAGACTGGCGGCGGCGGCGGCGGCGGCGGCCGGAGCTCGAGCCCCAGCGGCTGAGGGCGGGCGGGCGGGCGCGGGGGAGGGAGGGGGGCCGG TCCGCGACGACTCCCCGGACGGCGTTTCTCCTCCGAGCGGCGCCGGTTTCGGCTTGGGGGGGGCGGGGTACAGCCCATCCATGACCATGGGCGACAAGAAGAGCCCGACCAG GCCAAAAAGACAAGCGAAACCTGCCGCAGACGAAGGGTTTTGGGATTGTAGCGTCTGCACCTTCAGAAACAGTGCTGAAGCCTTTAAATGCAGCATCTGCGATGTGAGGAAA GGCACCTCCACCAGAAAACCTCGGATCAATTCTCAGCTGGTGGCACAACAAGTGGCACAACAGTATGCCACCCCACCACCCCCTAAAAAGGAGAAGAAGGAGAAAGTTGAAA GCAGGACAAAGAGAAACCTGAGAAAGACAAGGAAAT AGTCCTAGTGTTACCAAGAAAAATACCAACAAGAAAACCAAACCAAAGTCTGACATTCTGAAAGATCCTCCTAG TGAAGCAAACAGCATACAGTCTGCAAATGCTACAACAAAGACCAGCGAAACAAATCACACCTCAAGGCCCCGGCTGAAAAACGTGGACAGGAGCACTGCACAGCAGTTGGCA GTAACTGTGGGCAACGΓCACCGTCATTATCACAGACTTTAAGGAAAAGACTCGCTCCTCATCGACATCCTCATCCACAGTGACCTCCAGTGCAGGGTCCGAACAGCAGAACC AEAGCAGCTCGGGGTCTGAGAGCACAGACAAGGGCTCCTCCCGTTCCTCCACGCCAAAGGGCGACATGTCAGCAGTCAATGATGAATCTTTCTGAAATTGCACATGGAATTG TGAAAACTATGAATCAGGGTATGAAATTCAAAACCTCCACCTGCCCATGCTGCTTGCATCCCTGGAGAATCTTCTGTGGACATCGACCTCTTAGTGATGCTGCCAGGATAAT ΓΓCTGCTTGCCATGGGCAΓCTGGCCACCAAGGAATTTCGCACCCTGACGATTACTCTTGACACTTTTATGTATTCCATTGTTTTATATGATTTTCCTAACAATCATTTATAA RTGGATGTGCTCCTGAATCTACTTTTTATAAAAAAAAAAAAATCTGCTGTGCACAATTTTCCATGTACATTACAACTGGTTTTTTGTTTTTGTTTTGTTGCCGGTGGGGAGG GCTGGGAGGGGGAGGGAACTTTTATTTATTGTGAACACAAACTCCATCCTTTCAGCATATCCTTTTAAGTTTAGTTCTTTCTTCCAGTTATACTATGTACTATCAGTTTTGA ΓATAACTATATATATATAAATATAAAATTATATATAAAGGGTTATTTGAAACCAATCCATGGCAAACGCTGGTGCTTGATACACTGTGAAGTGAATACAACATTGAACAGTT ACAGATCTGGGACAGTCCCTTCTATGAAAGTGCTGAAATTTAATTAAAATCAGTCTTACATGAAGTATGTTCCAATCCATGTGGGAACTTGACTCTCTCATCTGTCTAAAGA GΓACTGGACGATATAAAAATATATATTTTTTAAACAATGTGATCTCAAATTTAAAGACTGCTCCAGATAGCCTGCATTTGCAATGGAATAACTGACAAATCACAAGTGGTTT AGTTGGGCAGGGCTTTGARCATTCAAAAGTAACTAAAGTAGCTCCAGAATGCCAAGTATTCGTGTAAATTACGGTTACATGTTATCATTTGCTGTTCITACATAAGCACTCA ΓGAAAATATGGTATTCTGΓAACTTGAATTCCATCCATTTTCCAGACGTCTACTCATGTCTGAGGTAAATCTAGAAATTGTCTTAGTTTTAGGATTGAAACAGTCTATAAACT GTATTTTTGGTCCATCCAGGAAGCTAGTCCCTGGTTTCTCCTTTCTACATGACATTGCAGTGGTGGTTTCTGTAATTAAAATTTGTTTGCCTCATGTCCCTTTGTCTGATAA ACCTTCACTCTACCGATTCAGTTGTGAGCATTCTTTTTTTCCTTCTCAAAACCTACTATGATTTGTTTTACTGAACAAAGGTTATCAACCACACATCCAGTCCTGACATGGA GCTTTTCAGTGTTGGAGACATTTCTCAATCCCCTGCTGTGGTAGGAACTCCAGTGGTGAACGGCTTGCGCGCCTGCAGCCAGAGTTGCAGGGGAAAGCTCGTACTTACTGCG AGCAGCATGTAATCTTTTΓTCTTCCTGGACATAAAGATAGCTTGAGTAAACTGTTCTATTTCATTCTCTTCACTCTTTTTACTGTCTTGCAAAAAAAAAAAAAATAATAATA ATAATCAAAGACCACTAAΓAAGATTCCACCTCTCCTTATTAAAATAATTTTTTAAAATTTTGGTTTTGCTTTTGTTTTGGATTGGGTCTCTCTTCTATTTGACTTTTACATT RAGATACAGAGTTTGTAGRACTTCAGAGACATTTCAAGCATGAGAATTTGAGGTTACCTCTCTTTATTTGACCTTTAGGGACTCACGGGAGGGCAGCCTGATTTGTAATGAA ΒCACCACATTTTGGTGTTAAGAACCTGGTTTGCTTAATAATAGCAGTAATTTCTGTGTGTGGAGGCAACAAATAAAAAAATTAACAGCTTGAATTGAGTAGCCAACAGGAAA GGTTCCTTTCACATTTACATTAAAACTATTCTGTAGTCACTAATGTACCATAATTTAAATTCTTTTCTCAAAGGTATAGATTATAAAGCAGTGCCATTTGTTGCTGTGGTCC RATTCTCAAATGCATGGACAATGTTCCCCCCTTTTTAAAATAATGCTTGTGTCTGGGATGCAAGCTTTGCTTATCTTTTTAAATACATTTTTAAAGTATTTATTAATGAACC AAAGGAAATCAGATGCTTΓCTATAAGCATCAGAATATATAATACATAGTGATTTGACTATGAATTTTAAATCCACATTTTAATATTGGTGGGATATTGCAAAGACATTCCTT CTAAAGTTTTAATATTCCΓΓTΓATTAAGGGTCTCAGGGAGGGTAAATTAGTCAGCCATATTTATTTTCCAGAGGTTTAAGAAATTGCTGTTTTTAACTTTTTGAAAAAACTT AAATGCCACCAAACTCATGΓAGGTTGCACTGCTTATTGAACCAATAACTGTTGGTATGCACTTTGTTCAGACACACTGTGTACTTTTTCAAAAACTAGTTTCATGTAAAGTG ATTGGACCCCATAGATTAGTGGAAAAAGCTGATTAACCAGCTACTCATAGGCTGCTAATTCATTCATGCCAATGTTTTGGTTTTTCAGTTTTGCCTCCGTGATAAATTAAAG AATGGGGAGGGGTGAAGGAAGGGGAAGAAGATTGCTTTAGAACAAGTGGCATGAAATTACCATCTTTGTAGAAACCGCAGCTAACAGTGGGAGTTATCTAAGCAATCAGATG TTACAGGGCCAGCCCCTTRAGCTGCTGTGGTGTATTCTGTTGGGTAGTGAGGTAGTAGGTACTTTATAGACTTTTAATTTTGGAAATTGATGACATCCCTCAGGCATGTATT CTGGAAATGGAATTCCTGRAACTTCCTGTGTCTGCAGTATGCCCTACAATTAGTAGGCAGCGTGTAAAAACACTAGTGTAGATTATAAAGATATACATTAAAAGAGGACCAG AAATACTTGGTATTCAGTGGCACAGAAAGCAGGTTAAACAAACAAAAAGCACAGTGTTACGCTTGCAAGTTTCCATTTGTTTTAATACCACGCAATCTTTCACACTCGTGCG TGTGCGCGCACACAGAGCRRACCTGACTTGCTCTGCTTGAGTCATGCAGTTACAAAAAAAAAGACATCTTGACACCCACACAATATTCTAATCAAAACCTTTCAGTTTCAAT CTGGATATTTAAAAACATRGGCAGAAGCCTCTGTGAGTTTAGTTCCACTAAGATGTTTCACCTGCCTTATCAAGACCATTCTCAGTCTACTTTTTTAAGCTACCGTATCTTA AATTATTGAAAATTTAΓTAAΓΓGCΓGAATATATAATAACCTTTGCTTGTATGTAACCGAAAATGGTTTAAGAGCCAACATTTAGAGTATGACAATGGAGCTGAACAGTTTTT AATGCGCAAGCAGTTCRGRRCRTGRGTATGACTTGTAACCTTAATTTACTGTGTAAAGATGGTTACATTATTTCCTTAGCTTTGTTTGTTGGAGACAAATAGAGAATGCTTG TTAAGTATGTCAAAACAARCRRATCRTGTGAATTTTTGTTAATGTATTATACGAGCTATATTTTTCATTTGCCCAGAAAGACAGCTTGTATAACGCTTTFΑGGAAGTTTCTGC TCNGTAATGTCTTTAGAGCΓGACAGTCTGTTAGGTTNGTTTΓTTTCTTCATGCTAAAGTGTCAGTTGGTGGTTTTGTGAACTGGTCAAAAATTCACAGGTCTTAAATGTTTT GGGGGAAATTTATATTGGACACRGCTCTTTGTCTAGCAAARAAAAGATGTTAATATATTCCTGTTACTGGCATGTGCACGACTATGTTATTAGAAGCCACTTTATCATTTTC CTGCTTTAAATAGAAARGTCRATTTATGAATTCTGCTTGTAGTTTTTTCACAAATAAAATAGTAAAATTTAAAAAAAAAAAAAACAAAAAAAAAAAAAAAAAAAAAAA
225
MGDKKSPTRPKRQAKPAADEGF DCΕVCTFRNSAEAFKCSICDVRKGTΕTRKPRINSQLVAQQVAQQYATPPPPKKEKKEKVE QDKEKPEKDKEISPSVTKKNTNKKTKPK SDILKDPPSEANSIQSANATΓKTSETNHTSRPRLKNVDRSΓAQQLAVTVGNVTVIITDFKEKTRSSSTSS8TVTSSAGSEQQNQSSSGSESTDKGSSRSSTPKGDMSAVNDE
SF 227
MSDAAVDTSSEITTKD KEK EWEEAENGRDAPANGNANEENGEQEADNEVDEEEEEGGEEEEEEEEGDGEEEDGDEDEEAESATGKRAAEDDEDDDVDTKKQKTDEDD
228
CTTTGCATTGTTCCTCARCCGCCTCCTTGCTCGCCGCAGCCGCCTCCGCCGCGCGCCTCCTCCGCCGCCGCGGACTCCGGCAGCTTTATCGCCAGAGTCCCTGAACTCTCGC TTTCTTTTTAATCCCCRRCATCGGATCACCGGCGTGCCCCACCATGTCAGACGCAGCCGTAGACACCAGCTCCGAAATCACCACCAAGGACTTAAAGGAGAAGAAGGAAGTT GTGGAAGAGGCAGAAAAREGAAGAGACGCCCCTGCTAACGGGAATGCTAATGAGGAAAATGGGGAGCAGGAGGCTGACAATGAGGTAGAOGAAGAAGAGGAAGAAGGTGGGG AGGAAGAGGAGGAGGAAGAAGAAGGTGATGGTGAGGAAGAGGATGGAGATGAAGATGAGGAAGCTGAGTCAGCTACGGGCAAGCGGGCAGCTGAAGATGATGAGGATGACGA TGTCGATACCAAGAAGCAGAAGACCGACGAGGATGACTAGACAGCAAAAAAGGAAAAGΓTAAACTAAAAAAAAAAAGGCCGCCGTGACCTATTCACCCTCCACTTCCCGTCT CAGAATCTAAACGTRGGRCACCTTCGAGTAGAGAGGCCCGCCCGCCCACCGTGGGCAGRGCCACCCGCAGATGACACGCGCTCTCCACCACCCAACCCAAACCATGAGAATT GCAACAGGGGAGGAAAAAAGAACCAAAACTTCCAAGGCCCΓCCTTTTTTTCTTAAAAGΓACTTTAAAAAGGAAATTTGTTTGTATTTTTTATTTACATTTTATATTTTTGT ACATATTGTTAGGGΓCAGCCATTΓTTAATGATCTCGGAΓGACCAAACCAGCCTTCGGAGCGΓTCTC GTCCTACTTCTGACTTTACTTGTGGTGTGACATGTTCATTATAAT CTCAAAGGAGAAAAAAAACCTGTAAAAAAAGCAAAAATGACAACAGAAAAACAATCTTATTCCGAGCATTCCAGTAACTGTTTTGTGTATGTACTTAGCTGTACTATAAΒTA GTTGGTTTGTATGAGATGGTTAAAAAGGCCAAAGATAAAAGGTTTCTTTTTTTTTCCTTTTTTGCTATGAAGTTGCTGTTTATTTTTTTTGGCCTGTTTTGATGTA GTGTG AAACAATGTTGTCCAACAATAAACAGG
229
RAFLVEHNLVLAERKSPEISERIVQWPAITYKPLLDKAGLGSITEVRF GDQQRVFLSKDLLKPIQDVNSLRLSLTDNQIVSKEFQA IVKH DESHLLKGDKNLVGSEVKI YSLDP8TQ FSATWNGNPA8KTLQVNCEEIPALKIVDPSLIHVEWHDNLVTCGNSARIGAVKRK8SENNGTLVSKQAKSCSEASP8MCPVQSVPTTVPKEILLGCTAATP PSKDPRQQSTPQAANSPPNLGAKIPQGCHKQSI,PEEISΕCLNTKSEALRTKPDVCKAGLLSKSSQIGTGD KILTEPKGSCTQPKTNTDQENR ESVPQALTGLPKECLPTK ASSKAE EIANPPELQKHLEHAPSPSDVSNAPEVKAGVNSDSPNNCSGKKVEPSALACRSQNLKESSVKVDNESCCSRSNNKIQNAPSRKSV TDPAK KKLQQSGEAFVQD DSCVNIVAQLEKCRECR DS RKD EQQKDSPVFCRFFHFRR QFNLOIGV RVEGFLTPNKYDNEAIG W PLTKNVVGID DTAKYILANIGDHFCQ VISEKEAMSTIEP HRQVAWKRAVKGVREMCDVCDTTIFNLHWVCPRCGFGVCVDCYRMKRKNCQQGAAYKTFS LKCVKSQIHEPENLMPTQIIPGKALYDVGDIVHSVRAK GIKANCPCSNRQ FKLFΕKPAΕKED KCTSLAGEKPTLGAVLQQNPSVLEPAAVGGEAASKPAGSMKPACPAΕTSPLNWLADLTSGNVNKENKEKQP MPILKNEIKCLPPLPPLSKSSTVLHTF NSTILTPV8NNNSGFLRNLLNSSTGKTENGLKNTPKILDDIFASLVQNKTTSDLSKRPQG TIKPSILGFDTPHYWLCDNRLLCLQDPNNKSNWNVFREC KQGQPVMVSGV HHKLNSELWKPEΞFRKEFGEQEVDLVNCRTNEIITGAT GDF DGFEDVPNR KNEKEP^FV KLKD PPGEDFRD IMP8RFDDLMANIP PEYTRRDGKLNIIASRLPNYFVR PD GPKMYNAYGLITPEDRKYGTTN HLDVSDAANVMVYVGIPKGQCEQEEEVLKTIQDGDEDELTIKRFIEGKEKPGALWHIYAAKDTEKIREFLKKVEEEQGQENPADHD PIHDQ8WYLDRSLRKRLHQEYGVQGWAIVQF GDWFIPAGAPHQVHNLYSCIKVAEDFVSPEHVKHCF LTQEFRYLSQTHTNHEDKLQVKNVIYHAVKDAVAMLKASESS
FGKP 230
GGAGAGCATTTTTΔGTAGAACATAATTTGGTTTTAGCTGAACGAΔAGTCACCTGAAATTTCTGAACGAATTGTACAGTGGCCTGCAΔTAACGTACAAACCTCTGTTGGACAA AGCTGGTTTGGGATCCATAACTTCTGTTCGCTTTCTGGGAGATCAACAAAGAGTATTTCTTTCTAAAGACCTTTTGAAGCCTATACAGGATGTAAACAGTCTTCGACTTTCT CTTACGGATAATCAGATTGTCAGTAAAGAATTTCAAGCTTTGATTGTGAAGCATTTAGATGAAAGCCATCTTTTAAAAGGTGACAAAAACTTAGTTGGTTCAGAAGTAAAAA TTTATAGCTTGGACCCATCTACTCAGTGGTTTTCAGCAACCGTTGTAAATGGAAACCCAGCATCAAAAACTCTTCAAGTCAACTGTGAGGAGATTCCAGCACTGAAAATTGT TGATCCGTCACTGATTCATGTTGAAGTTGTACACGATAACCTTGTGACATGTGGTAATTCTGCAAGAATTGGAGCTGTAAAACGCAAGTCTTCTGAGAATAATGGAACCCTG GTTTCCAAACAAGCAAAATCTTGCTCTGAGGCCTCTCCCAGTATGTGTCCTGTGCAGTCTGTACCTACAACAGTTTTTAAGGAGATACTGCTTGGCTGTACTGCAGCAACTC CACCTAGTAAGGACCCAAGACAGCAAAGTACTCCCCAGGCTGCCAACTCTCCACCTAACCTTGGAGCAAAAATTCCTCAAGGATGTCATAAACAAAGTTTACCAGAGGAAAT TTCTTCCTGTCTAAATACAAAGTCTGAAGCTCTGAGAACAAAACCAGATGTCTGCAAAGCAGGGTTGCTCTCAAAGTCCTCTCAGATTGGAACTGGAGACTTGAAAATTCΓG ACTGAGCCAAAAGGCAGCTGTACTCAGCCTAAGACAAACACTGATCAGGAAAACAGATTGGAGTCTGTTCCACAAGCATTGACTGGCCTTCCTAAGGAGTGCTTACCTACAA AGGCTTCTTCTAAGGCAGAATTGGAAATTGCCAATCCTCCTGAACTGCAGAAGCACCTAGAACATGCACCTTCCCCATCGGATGTTTCAAATGCACCAGAAGTGAAAGCAGG TGTCAATAGTGATAGCCCTAATAACTGTTCAGGAAAAAAGGTAGAACCTTCAGCTTTAGCTTGCCGATCACAGAATTTAAAGGAATCTTCAGTAAAAGTAGATAATGAAAGC TGTTGTTCAAGAAGCAACAATAAAATCCAGAATGCCCCATCCAGGAAGTCGGTTTTGACAGACCCAGCTAAACTCAAAAAGCTGCAACAGAGTGGCGAGGCCTTCGTACAGG ATGATTCTTGTGTGAACATCGTGGCACAGTTGCCTAAATGCCGAGAGTGTCGCTTGGACAGTCTCCGCAAGGATAAGGAGCAACAGAAGGACTCACCTGTGTTTTGCCGCTT CTTTCACTTCAGGAGGTTACAATTCAACAAACATGGTGTGTTGCGGGTAGAAGGCTTCTTAACACCAAACAAGTATGACAATGAAGCAATTGGCTTGTGGTTACCTTTAACC AAAAACGTTGTGGGGATTGATTTGGACACAGCAAAGTACATCTTGGCCAACATTGGAGACCACTTCTGTCAAATGGTGATTTCTGAAAAGGAAGCTATGTCAACTATTGAGC CACACAGACAGGTTGCTTGGAAGCGAGCTGTCAAAGGTGTTCGAGAAATGTGTGATGTGTGCGACACCACCATCTTCAACCTGCACTGGGTGTGTCCTCGGTGTGGGTTTGG AGTATGTGTGGACTGCTACCGGATGAAGAGAAAGAATTGCCAACAGGGTGCTGCTTACAAGACTTTCTCTTGGCTAAAATGTGTGAAGAGTCAGATACATGAACCAGAGAAC TTAATGCCCACACAGATCATTCCTGGAAAAGCACTCTATGATGTTGGAGACATTGTTCATTCTGTAAGAGCGAAATGGGGAATAAAGGCAAACTGCCCTTGTTCAAACAGGC AATTCAAACTCTTTTCAAAGCCAGCCTCAAAGGAAGACCTAAAACAGACTTCTTTAGOTGGAGAAAAACCGACTCTTGGTGCAGTGCTCCAGCAGAATCCCTCAGTGΓTGGA GCCAGCAGCTGTGGGTGGGGAAGCAGCCTCCAAGCCAGCCGGCAGCATGAAGCCTGCCTGTCCAGCCAGCACATCTCCTCTAAACTGGCTGGCCGACCTAACCAGCGGGAAT GTCAACAAGGAAAACAAGGAAAAACAACCAACAATGCCAATTTTAAAGAATGAAATCAAATGCCTTCCACCCCTCCCACCTTTAAGCAAATCCAGCACAGTCCTCCATACGT TTAACAGCACAATTTTGACACCCGTAAGCAACAACAATTCTGGTTTCCTCCGGAATCTCTTGAATTCTTCTACAGGAAAGACAGAAAATGGACTCAAGAATACACCAAAAAT CCTTGATGACATCTTTGCCTCTTTGGTGCAAAATAAGACGACTTCTGATTTATCTAAGAGGCCTCAAGGACTAACCATCAAGCCCAGCATTCTGGGCTTTGACACTCCTCAC TATTGGCTTTGTGATAATCGCTTGCTGTGCTTGCAAGACCCCAACAATAAGAGCAACTGGAATGTGTTTAGGGAGTGCTGGAAACAAGGGCAGCCAGTGATGGTGTCTGGAG TGCATCATAAATTGAACTCTGAACTTTGGAAACCTGAATCCTTCAGGAAAGAGTTTGGTGAGCAGGAAGTAGACCTAGTTAATTGTAGGACCAATGAAATCATCACAGGAGC CACAGTAGGAGACTTCTGGGATGGATTTGAAGATGTTCCAAATCGTTTGAAAAATGAAAAAGAACCAATGGTGTTGAAACTTAAGGACTGGCCACCAGGAGAAGATTTTAGA GATATGATGCCTTCCAGGTTTGATGATCTGATGGCCAACATTCCACTGCCCGAGTACACAAGGCGAGATGGCAAACTGAATTTGGCCTCTAGGCTGCCAAACTACTTTGΓTC GGCCAGATCTGGGCCCCAAGATGTATAATGCTTATGGATTAATCACTCCTGAAGATCGGAAATATGGAACAACAAATCTTCACTTAGATGTATCTGATGCAGCTAATGTCAT GGTCTATGTGGGAATTCCCAAAGGACAGTGTGAGCAAGAAGAAGAAGTCCTTAAGACCATCCAAGATGGAGATTCTGACGAACTCACAATAAAGCGATTTATTGAAGGAAAA
GAGAAGCCAGGAGCACTGTGGCACATATATGCTGCAAAGGACACGGAGAAGA'IAAGGGAATTTCTTAAAAAGGTATCAGAAGAGCAAGGTCAAGAAAACCCAGCAGACCACG ATCCTATTCATGATCAAAGCTGGTATTTAGACCGATCATTAAGAAAACGTCTTCATCAAGAGTATGGAGTTCAAGGCTGGGCTATTGTACAGTTTCTTGGGGATGTGGTGTT TATCCCGGCAGGAGCTCCACATCAGGTTCATAACTTATATAGCTGCATCAAAGTGGCTGAAGATTTTGTTTCTCCAGAGCA'IGTTAAACACTGCTTCTGGCTTACTCAGGAA TTCCGATATCTGTCACAGACTCATACCAATCACGAAGATAAATTACAGGTGAAGAATGTTATCTACCATGCAGTGAAAGATGCAGTTGCTATGCTGAAAGCCAGTGAATCCA
GTTTTGGCAAACCTTAATCTCCCTGCACATTGGAAATGAATTACAGGCAGCTGTTCAAACTCTTCAGGCAGGATTCCTGTGGACTTTGAGATTCATGTTACCTCATCTTCTT TTTTAAACTGTACCCAACTTGTGAGGGTACTCTGTCTAATGTATATTTCTAGTGTTTACAGACAGTAAATGTGTATATGTAGTAACTATTTACAGAACATGCATCCTTAAAC TGTGACTTCTCACCTAGTGCAGAACTTTTACCAGGCTGTAAAAGCAAAACCTCGTATCAGCTCTGGAACAATACCTGCAGTTATTCTTCAGCTGTTTGGACAACTTAGATTG GGTTTATAACTATTAGGAATCACTGCACAGTTTATTTGGGTTGTGTTTTGTGTCIGAGTCCCCTCCCTCATCCCTTAGGGTCCAGAAGAGCAATGGAGGAAGTGACAGCTAA TGTTGCAGTTCTTATTGTATGGCATAGGACTGGCATTATATAGCAGAAATCAACTACTGTACAATTTCTTGGGGTTAACCATCTTTAGTTAAATGGAATTTTAATTTAAATG ACΣCTTTGCTAATTTTAAGTGTTAAGCATTTTGCATTAAAATATTCATATAAT
231
VGVVCYRVYCCCCLANVSLPGIGGTIPESKPFFYVNVADIESLEVEVSYVACTTEKIFEEKRELYDVYVDNQNVKTHHDHLQPLLKINSADREKYRR NEQRQM LYSQEVE
EDYNPCEEDLFVLFFLEQN RIFQT LEVSASQDKTLTAEHARGMGLDPQGDRSF LDLLEAYGIDVMLVIDNPCCP
232
GTGGGCGTGGTGTGCTATAGAGTGTACTGCTGCTGCTGCTTGGCCAACGTTTCACTGCCTGGCATCGGGGGCACCATTCCTGAGTCCAAACCTTTCTTCTACGTGAACGTGG CTGACATCGAGAGCCTGGAGGTAGAGGTGTCCTATGTGGCCTGCACCACAGAGAAGATATTCGAGGAGAAGCGGGAGCTGTATGACGTCTACGTGGATAACCAGAATGTGAA GACACACCACGACCACCTGCAGCCGCTGCTGAAGATCAACAGTGCTGACAGGGAGAAGTACCGCCGGCTCAACGAGCAGAGGCAGATGCTGTTGTACTCCCAGGAAGTAGAA GAAGACTACAACCCTTGTGAAGAGGACCTCTTCGTGCTGTTTTTCCTAGAACAAAACAACCGGATATTTCAGACTTTGTTGGAGGTGTCTGCCAGTCAAGACAAAACTCTGA CAGCAGAGCATGCCCGGGGCATGGGCCTAGACCCCCAAGGAGACCGGAGCTTTCTCCIGGACCTGCTGGAGGCCTATGGCATTGATGTCATGCTGGTTATCGACAACCCCTG TTGCCCGTAGGAGGAGCCAACAGGACTGGGAGCCGCTTCACGTGGGATGTCAGCAGCCCGGAGTTCACCCCAGGGCCCCAGAGGGCCTCATTTTTTATTAAGTTGACACAAA GGAATATTGTTTATACTTTCCAACAAACATAATTTTTGCAATTTCCTTTCTGCCCTTTTCCCTAGAGATAAGGTGAGATCACCTTGGTTTTGTGTCCTGCCATGTTAGGATA TTGGAATCTGCCACTTTCTCCCAGAGCTGCTGGTCCTCTGGGCTTGGTCATGGGAGTTGTATCACTAGGAGTAGGCTGAGCTCTGGAAACATTGGGATGGACTGTTCAGAAA GTCTGTGTGGTCTTTGTCCCTTGATGTATTTGAGAATAAGACAACCACCTGTCCCCTGTGGCCTTAGATGTTCATCTGCCTAAAGGCAGAAACTAGACCAGATGATCTTTTA AGGTTTTTAGTAGTTCTAGGAGTCTATAGTCTTGGGATCAAATCCCTTTTCTTGTTCATTAGGGCAACTTTATGTCTTCTCTGTTTACTTGAGTAGGGACCACAAAGAGGGA AAAJ«GGATGTTTCTGACACCAAATATGAGCTTATCTTATGGTCAGAATGAAAGAGGTTGCTTATCAGTGAGCTGAAAACTAAAATTATAGAATGAAGCCTGGAAACCTTCC TCAAAGTAACTTGATGGTGGCCATGCAATGTAATGTTCCTCTTTGTCTGAACCTTCCTCTTCTTGGGATGAATTGGTGAATTGCTAAGGGCCAATGCTGGCCTTGGAGCTTG CAAGCAAATTAATTTTCCAGTTTAGTCTCTTAAGGGTTCAATAATGCTCTTGGAGTAAGTTGGGTATTTTTAAAGGCTGAAGTTTGGACTACCGGAGGATAGAGCAATTGAA GTTCGAGCAGGATGGAGAAGCCACTCTAAGTCTCTTCATCTGGACACGAATTCTCTGGAGGCATTAGCAGCAGCACCTCTGGGTCAACACAGATTTACTGGATTCCAAAATC TAGCAAGGATCTGAGCTGGTTAACTCAGAGGGTGGAGCATGATGCTAACAAGACGGTTTATCATTTTGGACCCCTCACAAACACACTTCTCTTTAGCAGAGGTGACATTCCT TAGGCTAAATAAT GGATCCAGGGACATAACAGATTTGTTGAGAGAAAATGTGGCAGTGCCTTCACCCGGGACAGTGGTCAGGAAGCCCTGAGCATCCCTGATGGATTTATC CATCCTC TCTGAAGTGCTCTGCTCTAGGCTGGGTCCTGTTGCCACCTGCCTGTTCTCTGGTTGGCTTTTGCAGGAGGGCAGCTTACGTGTTTGTCAACCAGTTAGAAAGCC AGTTCCTGTGGGTCGAGTTTAGGCCTTTTTGGCCATAGTTGAGAATTTTGACTTGGGATACTGGGTTGTTGGTGACAAATAATGTCTTCCTTTTCCCCCTTCCCGCCTGGCT CGGTTATGGGAATAGCCGTCAGTGCATCCATGTCTGTGACCAACACCCAGCCAGACTAATGTACACAGCAGGGAGAAATAACATTCAAA GGTGGTTCACACATCTCATCTC AAGATAAGATTCTTAGGGTTCACTGCTTTATTCAAAAGTGTTTTCACTGTAGCTCCTTCATATGGAATATCAAAACTGAAGAAATTCACATGTGGAAATGCAAATAGACATT GATTAATCAAGGTAGCATCTTTATGTAAATATATAAATAAGTTTGGGCATTGAAATGTAAACTGTACAGCTAATAGACTTTTCTCCTCTGCAATGTGGGTTGCTGTCATTTC AGTAATGTGTATGTTTACAAAAGAAAAAAAAATCTGTGTTTCGAGGTTGAAGCCTCACCTTTTATTCTCCTTTACATGCAACCCTCTCTTCTTGCCTCTCAAGGGTTGAGGG GTCCTTTCTGTCAAGTAATGGTTATTTTTCGTGGTATCCTGAGGTTCAGGGTGTTTTAAGCTGGGGGTAGGTGGTTAGAGGCAGGAGTAGAAGTGAAAGGAAAGGTCTGATT CTCCTAGAGGACACAAGAAGACCTCCTTTTTCTGGAATTAGGGAATCTGCCGGAAGGAGCTGTTTGAGGCATΓTCTGCTCTGAGCCTTCTATATGCAAACACTGCAGTTTTA ACTGCAAGCTCAGAAGTGCTGGTGTAAACATAGCAGGGTGAGAATGAAGTTCCTGTTTTTTCCTTTGAATGGTGAGTCAGGGCTTCTGGGTTCCCTTAACTTTGTGCTTGTC TCGGTAGCTTTCTGTCTCACATCTCCACGTGTCCACCCTCCTGCTCATGCAGAGGGCCAGGGTATGGGTGGCCCCAGAGGAGAACGTGCCAGTGAGGCAGTGCCATGTTTCA GGTCATAGGGGCCT"IGGGCTCAGCTGACCCCAATGCAGAACTTCTCCCTTTAAGAGAGATTCCAATAAAΓTGGTCCTTCCCTACCTTGCCAGCTTCTTCATAGGACCAGAAA TCTTGTGCAGAGCCTCTGCTTGGCTGAACAGCGTGTGCTTTATCTCTTCAGTTACCTTTGCCACTGTTGAGCATCCTCAGAGTATGTCTTGCCTGGGCTATGAAGTGGAGCC TGTGGCTTCGGAAATCACCTTTCGAAGCCTTGCTCTATGCCAGATTCTGCTCCCCAACATGACAGATTAACAGGCACAACCTAGGATCCTTTGCTACCAGTTCTCTACTAGG GAATTCCACAGTGGCAGCAGAAGCTAGGAGCCATGTGGACCTGCTTTTCTGCCAGTCTTGAAATATTTTCTGAGAAACCATCTGCTTTTGTTCAGAAGAAAGTGCTGAACAT CGTTCACAGACTTCTAGGTCTGTAAGCTCTTTAGGGGCGGGCATTATGATGACCACCGGCCTCCTGGAGGAGGGTTGGATACCTGTGGTGTGACACCTTCTGCCACCATCTC CTGCCGGGCCTCAGCCCTCGCCTGCCTGAGCAGGCCTAGTTCTCCTGTGAAGCTGTCAGCCTGATCTCATGCCACACTGTGAAATGAACΓATGTGCCAGTTTGGAAATGATT GCTGACCTGAGATGCTGGCTGGGCTGCCCTGTTGTTCCTGAATAAGTCAGAAGAAGTTCCAGGTGGGAGTGGAATTCAGGTTTGGGGCTCGTTGGTATCCATGCAAAATATG ACAAAGGCCTGTTCAAGAGGGCATTTTCAATTCTGTAGGCTCAGCAGATGATACTGCCCAGCCTTTGGGAAAATGTCCAGTTGGCCCCTGGCTTAGGACTCTCCACAAGGAG TTTGAAATGGTAGGGCTTATCCCCTACCAGACTAAAAGTATGGCCCAAATTATGTGTTTAGAATTTGCTTGGCCTTTAAACACGAACCATΓCCCTATGCCTGGTAGAGACCA TTCCAGTATCAGTGTCCCACCTGGGACCTGTACAGTCCTCAGTAAATTATGATTGCAATGAATTAGAAGGCTTTTGCCTTCCATATCCATCATCCATTATAGCATCTGTGCΓ TCCACCTGGTTAGGGGGAGGGAAGCTGAAATCATTGATGTATCAATAGAAGTAATTTAGCTTAGGAACTTGCATCTATAACTTACCTTGTΓTΓGTTCCACTTTAAAGTCAAG ACAAGAAAGTTAAGATAGCACACAGGTGCACATGCTTCCAGATGCCACATGTGAACATTTGTTGATCATGTGACTACCGATGACACTTTAGCTAGAAGATAAATTAAATCTR AGCTAAATCATTGTTTTTCCTTCTGGTGGCTATGAGGATGAATTTGCTCTCAGTCTTGATGCACTGAAAGCCCTTCAAACACAGTAAAAGATGAAATCACTCATCTTTAAAC TGAGGCCTTCAGGGAAGCTTTTGTAAAGGACAGTAATGAATTAGGCTTTCAGTTTTAGGACATCAACCCΓCCGAGAAAAGGCAGAAACCCGAGGGACCATTTATTTCCCTTC GAAACTGTATAGCCCAGGGAATGGATTGAGATGCTTTCTCCAGACCCTGTATAGGTCAACCTTGCAGAGGTAAAGGAGGAGGGGCAGGTGGATGAATAAAATAGGATAATGC TCAGCTTGGCAGTGGACTTGCCTTAGTGTGATGACAGGTCTAACATGGGCAAGACAATTAGAATGGGGACCAATATGCCAGGCATGGGCTTTTATCTCCCTAGTAGATCCCA AGCTAGTAGGCTTGGATTCTGCCAAATGGCCAGCCCTCCIGTCTTCTCCCCGTACCTTGTAGTTAGACCGAGGTGAGAATCCTGCTGACCCCAGTCCCATCCCCTCTCATTT CAGGAAAACCCTTTTGTGATTCAGGTAGGGGGAGAGGAGGAGTTAAGGGCTCCGTTTACTCCCAAGTCATGGATTTTTAATATTCCATTTTTATCACTAATATACCTCTCTΓ CCTAGAAGCTACTGGAGTATTGAGTGTTGTGGGAAAAGGCTAACTGTGAATTAAGTTAATGTTTTTCTTATAAGAAATGGAAGTTTATTTTTTTATTGATATTACTATGTGA TGAACTGAGTATGCATATACTGAAATGGAAGGAAATTTTAAAACTATTATTCTAGAAGAAATGGGCAGTTTTGTAATTTGGTGGTGGCTGAGACCCCATAGAAGTTTTACTA TGTAAATAATTTGGAGAGTGAATAAGGAGATTGTGC'IATGAAATCCTGACAGCGCTCTT'RAGGAGGCAGACTTGACAGTCCTAGGAAGGTTGACATAAAAATACCAACCTTC AGTAAAGCTCTAGTACAAAAAAGGGTAAATGTCATCATTCTTATTTTTAGGCCTCTTTCTTGAGAGAGGTGGGAGTGGGAGGTAGTGTTATAACTGGCACTTTAATTTGTTT TTGGAACTAGAATTTAGGGGCAGTTGGATGAAATTGCAAATTTAGAAGGGGAATAAGAATTTTCTAGTGCTATATAAAGAAATGATGATGGAGACAAAAGCCTTGCTTTCCT CTTTTTAGAATTTATTTTCGATTTTTAGCATACTGTGGGGCTTTTAGAGCTAATATGATCTAAATTCAGAAAATTTAATTTTCATAGTAGGCCAGGTGTGAATTACTTΔTGT TTGCTATAGAATGCTTATTTAGACTAACAATAAATTTACTTTGCTTTCTAAGGCCAGTCAGCGAATGTGGGGATGAGGCAGGATGTTTTAAATGAGCCAGAGATGATCCACA AAGTGAACAGTCGACACAGAGGTCTTTGAGTTGGATGGTTGCAAATATATTGACATTAGAGTGAAAACTCCTTCCTTTGGGTAAACTAAAGAAAGATAAAGTATACTAAAAA ATTTTAAGATGGTGTTATACAAAAAAAAGTTTGGGTCTAACGTGTCCACAAAGACTGTCAAGTGAAGAATGGTGGAGATTCTTGGTGTTTGAGCAGCCAACCTGGATGAGTG
ACTTCAGGGACAGAGCAGAGGAAAGCAAAATGAATTTCC'ITTATTTACCCAAAACTTG'ITGACTGAATTTTTGTATAGGTCCGGGAAAATAAGCCTAAACAAATAGTTGTAG
CCTTAGAAAAACTGTTTTCCCATTTCTTTCTGAGTTAGAATCAGCATAGCCTCCCTGTCGCCTTAAATGTAAAAATCCTATTTTGATTAATACCCCAGCCTAAGAGTTATAG CAATACGAGAGACTGAATCTATTTTTGTTTCGGGTCTTTACCTCATAGTATGAAATTAGTAAGACACTGCATAGATTTTGCCCTGAATACTGGTGTGCCCAGGTATGCCGTG CTCTCTCTCTGT1TCCAGTGGTGGTAATTTTAAGGCCTAAAGAAAGCTGGGGTTAATCCTGAAGCTAAAAGTAAATGTTTCTTGAATTGATTTTGTTCTGTGGTACAAATAA CATCTATGAATATCATATCTGTATATATCTGAACCAAGTTGTGTGCAGAGAGGTTGATATAACTATATTTACAGAAAATGATTTTTACAATTAAAGTTCACATTTTAACATG
233
MSAAGARGLRATYHRLLDKVELMLPEKLRPLYNHPAGPRTVFF APIM WGLVCAGLADMARPAEKLSTAQSAVLMATGFI SRYSLVIIPKNWSLFAVNFFVGAAGA8QLF RIWRYNQELKΔKΔHK
234
GGGACAGCGGGCAGGGAAAGCCGCGGGAAGGGTACTCCAGGCGAGAGGCGGACGCGAGTCGTCGTGGCAGGAAAAGTGACTAGCTCCCCTTCGTTGTCAGCCAGGGACGAGA
ACACAGCCACGCTCCCACCCGGCTGCCAACGATCCCTCGGCGGCGATGTCGGCCGCCGGTGCCCGAGGCCTGCGGGCCACCTACCACCGGCTCCTCGATAAAGTGGAGCTGA TGCTGCCCGAGAAATTGAGGCCGTTGTACAACCATCCAGCAGGTCCCAGAACAGTTTTCTTCTGGGCTCCAATTATGAAATGGGGGTTGGTGTGTGCTGGATTGGCTGATAT GGCCAGACCTGCAGAAAAACTTAGCACAGCTCAATCTGCTGTTTTGATGGCTACAGGGTTTATTTGGTCAAGATACTCACTTGTAATTATTCCAAAAAATTGGAGTCTGTTT GCTGTTAATTTCTTTGTGGGGGCAGCAGGAGCCTCTCAGCTTTTTCGTATTTGGAGATATAACCAAGAACTAAAAGCTAAAGCACACAAATAAAAGAGTTCCTGATCACCTG AACAATCTAGATGTGGACAAAACCATTGGGACCTAGTTTATTATTTGGTTATTGATAAAGCAAAGCTAACTGTGTGTTTAGAAGGCACTGTAACTGGTAGCTAGTTCTTGAT TCAATAGAAAAATGCAGCAAACTTTTAATAACAGTCTCTCTACATGACTTAAGGAACTTATCTATGGATATTAGTAACATTTTTCTACCATTTGTCCGTAATAAACCATACT TGCTCGTAAAAAAAAAAAAAAAAAAAA
235
MFYVAEPKQVPHILCSPSMKNINPLTAMSY RKLDTSGFSSILVTLTKAAVALKMGDLDMHRNEMKSHSEMKLVCGFILEPRL IQQRKGQIVPTELALHLKETQPGLLVAS V GLQKNNKIGIEEADEFFKVLCAKDEDTIPQLLVDFWEAQ VACLPDWLQELFFKLTSQYIWRLSKRQPPDTTPLRTSEDLINACSHYGLIYPWVHWiεSDSIADKNYr EDLSKLQLPLFR8W8HFQKTLLPASV8 FCWHA
236
GAATTAGCAGCAAAAGTGGTTCAGATGTTTTATGTGGCTGAGCCAAAGCAAGTGCCCCATATTCTCTGTAGTCCTTCTATGAAGAATATTAATCCTTTAACTGCCATGAGCT ATCTAAGGAAGCTGGATACTTCTGGGTTTTCATCGATCTTAGTGACATTGACCAAGGCAGCAGTGGCTCTGAAAATGGGAGATCTTGACATGCACAGAAATGAAATGAAAAG CCATTCAGAGATGAAGTTGGTATGTGGCTTCATTCTGGAACCTCGGCTGTTGATTCAACAGAGAAAGGGACAGATTGTTCCAACCGAGCTTGCACTTCACTTGAAGGAAACT CAGCCTGGATTGCTTGTGGCTTCAGTTCTGGGCTTGCAGAAGAACAACAAAATTGGAATTGAAGAAGCAGATTCCTTTTTTAAGGTTCTTTGTGCTAAGGATGAAGATACAA TTCCTCAGCTCTTGGTAGACTTTTGGGAAGCTCAGCTAGTGGCATGTCTCCCAGATGTGGTACTTCAGGAACTCTTTTTCAAACTCACATCACAGTACATCTGGAGATTGTC XAAGAGGCAGCCICCTGACACCACACCATTGCGAACATCGGAGGATCTGATAAATGCCTGTAGTCATTATGGCTTAATTTATCCATGGGTTCACGTCGTAATATCATCTGAT TCTATAGCTGATAAAAATTATACAGAAGATCTTTCAAAATTACAGCTTCCATTATTCCGTTCTTGGAGCCACTTTCAGAAGACACTATTGCCGGCCTCAGTGTCCATGTTCT GTGTCGTACACGCTTGAAAGAGTATGAACAGTGCATAGACATACTGTTAGAGAGATGCCCGGAGGCAGTCATTCCATATGCTAATCATGAACTGAAAGAAGAGAACCGGATA GACTCTGTGGTGGAAAAAACTGTTGCCTGAACTTTGTCAGAGAATAAAATGTGGTGGAGAGAAGTATCAACTCTACCTGTCATCATTAAAAGCTTAATTTTCACGGGAACTG TGGAAGCTAGCAGACAGTACCACTACATTATAAATGAGGAACCTAGGACTTGGAAGATTAAGTGACTTTCTTAAAGCCACTCGAAACATTGTCAATTGTTGCTGTGGAACTA GAACTGAAGGATTTCATGAATGTTCTCCCAGAAGATGGTACTGCAACATTTTTCTTGCCATATCTTCTCTATTGCAGTCGAAAGAAACCATTGACTTAAAGGTATCATTTGA AAAATACCATAA'RGGCATTTGAGACTGAATTTCTAAAAATTGAATGCCAAAGTACAAGTAGAGGAGTTTTTTATTTTATATATNACACACACACACACACACACACACACAC ACACACACATATATGATACAAATGCTTTCAGGCTGCTTACCTTACCGTGTAGTGGTAACTATTCACTTCTTAATTTATGACCTCAATCAATTTAATTGTCTAGAATGTAAAA AGTCTTTAAGACATAAGAATTCCTCAAAGAAGCCATACATTTTTTAAGGTGGGGATTGACTTTTATTCCAAGGAACAACATCAGTTCACTGTTGTTGGAGACATGACAATCA TTTTCATCCCAAGAACACTTTAAGGAAACATTTTACAAGTATGCTTGAAAGAATGTCACTAACTGGTCCAGAATTTTATCTTCTTGATTTTTCCAGATTTCTCTATGTTTTT GAGAAAGATGTTAATGTTTTGCCATGGTAAAAGATTTCAAACCTCATTTTTTTTGTTCCTTTTCTTGTTACTTTTAAGAAAACTCATGCTCTGTTTCTCTGAATCAAATGAA GTAGAAGTTTACAAAGCTAACTTTCTTCTTGTCTAGCTATTAACATGATTTGTCAAATGCATGTTTTTTTCAGCCAAAGCCTTGTTTCCATTTTTGTTGATGTGTACTCΓΓG CTCTTTTAGCTAGAGTGTATGTGAAAATAAAGAAATACATCATTGTATTCAC
237
MRSKWQMEN8NLDL8HFKGHTVDHYNVLV WKNRPTIICYLSVCMCVCVCVCVCVCVCVISKLCSSTDSSR 238
CGCGGCCAGAGAGTGGGGTATTAGTGAGTTTAAGGTTTCAGATGTGGTGGTCCAAGGTGGTAGAAATGGGAGGCTGGCCCTTCATTTCCTGGTGTCTGTGTTCCTCAAGATG AGAACAGGGCTCAAAGACTGAGTAGACAGTGAGCCAAAATGGAAGTCCAGCAAAGCATTTAGACAGATACAGAAAGTGAGCAGAGGCTTGGCCTGGTGAGGGAAGGGCAGGA GTCCCCCCATTTCCTGAGCACTCAGTGCACACCCGATGCAGTGCTTCAAATTCTGTGGCTGCAGGAGCTGTGGGCCTTGTTCTGTGTTGGATACTCGGTGTTTGGTGTACTC TCTGGGGCTGTGTGAGCTCAGTAAATATCTGCTGAATGAATGAAGAAAATGCRTTGGCTCTGGAAATTCTCCACTATCTGAGAGATAGGTTRATTTCCCCCATTTCATGGAT GAGGAAGTAGGCCTGGAGGCATTAATTAACTTGTCAGTTTCCTATGCGTAGTAAATGGCAAATGGAGAATTCTAACΓTAGATCTGTCTCACTTCAAAGGTCACACTGTTGAT CACTACAATGTATTAGTTTGGGTGGTCAAAATGAGACCCACAATAATTTGTTATTTGTCTGTGTGTATGΓGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGA TTTCAAAACTCTGCTCAAGCACTGACAGCΓCTCGCTGAATCCAGCAGAGGGTTCTGCTGCATAGTCGGTCACCAACGAGGTGAGATTCTGTGGAAGATCCATAATGCACAGA GACAGGAAAGTGGAAAGCGTACCCAATTGCTAGAATCTGAAGCAACTGCTCTGAGAGTGTTAGGAGAGGTACAAAGAAGCACTGCAAACTCAGGTGAGTAGGACTGAAACTA GAAGAAAAGGTCGGATGTTGGAAAGGACAGCAGGAGACAGTTGTGGGACTCAGAAGGGCGTGAGGATATGGCAGAGGCCCCAGTGAGTGTCCCTGGGCCTCTGTCTGAGGCA GATTAATACCCACAAAAAGTGGGACAATCCAGATTCTCAAGGTTGCCAGGAATTTCTGTGAAAGGCCAAGGGGATGGGGAGGCACGTGATAAATTTATAAGATTCTTTTTTT AAAGCTCTCGCAATTCATAAAGGGAGCTACACTTAACTTTGAACTCAAGAAAATAAACCACAAGAGAGAAATGAAAΓGTTCTCTTTCAGACTTGCACACCTACCCCTGTGGA GCGTGCACCCTATAAGGGAGAAGTCGCCACACTGAAATCCAGAGTGACAAAAGAAGATGCCACAGCAGGGACCAGGAAACAGGCCCACCCCTGAAGTGTGTGCCATCGGTAA GGGACTGTAGGCAAGAAAAGTCTTCCTGCATGACAGCATATGAAATTAGCATCTCTCCTCATAAGGGTTGAAGAGATCAAGGTCAGAGGCTTCACAGTGATCCAAGACTCAA GGACAATTGAGCCAAGGGAAGATTGATCAAAGCAGAACATTTAGATAAGCCTTCCAGATTGTAGAAGGCCTTGGGC'RTGCTAGAGAGTCATTCTTTAAGATGTTAGGAAACA TTCAATACAGCCTTGGATAATCAACTATGAGCAAGTTGCACTAAGGAGGCTGATAACATACAGAGGGAACTACTTAAGACAGGGAGTATAATTTCATGGTCAAAATTTACAA ATGAATTAGGACCTTATCTGGAGAAATGAATCTTCATATTGTAAATACAATGGTGTTCTAAAATTTAGAATAAATGAAAAATGAATAAAATGTTGCTTTAGGGGATATAATC CTTCAGAAAAATTCTTTGATAGTATCTGATTATTTCACAGTTAGTTTTGGGAATAATATTACAGATACAGTCATTTTTGCAAAAGTATTTGAGCACTTCATCAGTTTTCTCT GTCTTTTGACATGCAGATCTTTCTTTTCTGAAGTGCCTCGTATCATCATCCTTGTCAATTTTCTTTCTTCAGTTGTCTTCTGGTCCTGCTCTCΓCAGATCCTCATTTAACAG CGGCTTTGCTGTAATTTTAGCATCTCCCTAATATCACTTCCACTGACTTCATGAAATCTACATGTTTTGCCAGTTTTGCAATTTTGCTAGGCTCTTAATTTTTTTTTAACGT GTGATATCTTTTCAGACAGTTCAACACGTGGCCATCTGCACAAGACTTAACCCCAGAGGTTGACCTAATGGACCTGGTTAGACATTTGTGΓΓAATGAGAGGCACAGTTTGAC AACGGTCTGGTTTTCTACATATTCAGGCACTGCACCTTTTCACATTTTGACAACCTCTTATTCCCTGCAΓAAATCCTGTTCCTGCAGGGAΓΓΓGGATAATGAGGGCTTGAAT GGCAAAGCCCTCTGTGCTACATGCCATGTTCTTTCATTATTGAATGTTGTGTCTTTAACAGGACTATCTAGCCCAAAGTCTCAACATTTTΓGΓCATTTTCAGACGACCAGAA TTATTCTTCTAATCTAGGATGATTTTGTTAAAAATTCAGGGAAAGATTAGCAAGAGAAAGGAATGCGATRCAATGCTATAACATGCTATTAARGACATTTATAGGAGCAGGA TTAGTGTTTACTTTGATTATAGCATTTCTTGGGGGTTAGGTTTGAATTCTGCATCTCTTTGTGAGGGAGAATGTTACAGTGAGTTCCTTTCAΓTCTCTTCAAAGGTAAAAAA ATCAGAGGAAAGGAGGCTGCCATTCCCTTCACAGCCAAACATTGTCAACCCATGGAGAAGCAGGCCTTATTCAACTCCCTAGGATCCTTTAGAAAAAATTCACCACTATAGG CTTCTTTGATTTTCTTTCAGAAGCAATTGCTGTCTTTCTCACTGTGTΓTTTGTTGCTGCATAAGATTGAAGGTATAAATTTATATTATTGTGATGGAAAGGCTGTGTGGAAA TTCATTGATGATACTTTAAAATGTCATCTTTGCTTGTACTAGATTTCΓTACTTAGAATTTTTAAAAATCATTTTCTTGTTTAAATAGTTTCTTTTTTTAAAAAAATGGTTAC ATTAGTTTTAAAATAGCTCTGTGATTTTACTTTTTATTGTAATTAATAAACATTΒAGATCTTCATTTTATACCTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA7ΛAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
239
RVRQGVGPGLQGSPQVTLAPLPLP8PTSPGFQFSAQPRRFEHGSPSYIQVTSPLSQQVQTQSPTQPSPGPGQALQNVRAGAPGPGLGLCSSSPTGDFVDASVLVRQIS SPS
SGGHFVFQDGSGLTQIAQGAQVQ QHPGTPITVRERRPSQPHTQSGGTIHHLGPQSPAAAGGAGLQP1.ASPSHITTANLPPQISSI IQGQ VQQQQV QGPP PRP GFERT
PGV LPGAGGAAGFGMTSPPPPTSPSRTAVPPG SSLPLTSVGNTGMKKVPKKLEEI PPASPEMAQMRKQC DYHHQEMQALKEVFKEY IELFFLQHFQGNMMDFLAFKER
LYGPLQAYLRQNDLDIEEEEEEHFEVINDEVKWARKHGQPGTPVAIATQLPPRTSAAFPAQQQPLQVLSDGSTVQLPRLSS GFEDSMC
240
ACGCGTCCGGCAGGGCGTGGGCCCTGGGCTCCAGGGAAGCCCACAGGTCACGCTGGCCCCACTGCCGCTCCCCAGCCCCACCTCTCCAGGCTTCCAGTTCAGCGCTCAGCCT CGGCGGTTTGAGCATGGGTCTCCATCATACATTCAGGTCACGTCCCCCTTGTCCCAGCAGGTCCAGACCCAGAGTCCCACGCAGCCCAGTCCGGGGCCGGGGCAGGCCTTGC AGAATGTGCGTGCAGGTGCCCCTGGCCCTGGGCTGGGCCTCTGCAGCAGCAGCCCTACAGGGGACTTCGTGGATGCCAGCGTGCTGGTGAGGCAGATCAGCTTGAGCCCCTC CAGTGGTGGACACTTTGTGTTTCAGGATGGGTCAGGGCTCACCCAGATCGCCCAGGGAGCCCAGGTTCAGCTCCAGCACCCGGGTACGCCCATCACAGTCCGAGAGCGGAGA CCCTCCCAGCCCCACACACAGTCAGGGGGCACCATCCACCACCTGGGACCCCAGAGCCCTGCAGCCGCGGGTGGGGCCGGCCTGCAGCCCCTGGCCAGCCCAAGCCACATCA CCACGGCTAACTTGCCACCGCAGATCAGCAGCATCATCCAGGGCCAGCTGGTTCAGCAGCAGCAGGTGCTGCAGGGGCCGCCGCTGCCCCGGCCCCTGGGCTTCGAGAGGAC GCCCGGCGTGCTGCTCCCCGGGGCTGGGGGCGCAGCGGGGTTTGGGATGACGTCCCCACCCCCGCCCACCAGCCCTTCCAGGACTGCCGTGCCCCCAGGCCTTTCCAGCCTC CCACTCACGTCTGTGGGGAACACGGGAATGAAGAAGGTTCCCAAGAAGTΓAGAGGAGATTCCCCCAGCCTCTCCGGAGATGGCACAGATGAGGAAGCAGTGCCTGGACTATC ATCACCAGGAGATGCAGGCTCTGAAGGAGGTCTTCAAGGAGTATTTGATΓGAACTGTTTTTCTTGCAACACTTTCAAGGGAACATGATGGATTTCTTAGCTTTCAAGGAGAG ACTGTATGGACCATTACAAGCATATCTTAGGCAGAATGATTTGGACATTGAAGAAGAGGAAGAGGAGCACTTTGAAGTCATTAATGATGAGGTAAAGGTTGTGGCCAGAAAG CACGGGCAGCCTGGGACTCCTGTTGCCATAGCAACCCAGCTACCGCCGAGGACTTCTGCGGCTTTTCCAGCCCAGCAGCAGCCGCTCCAGGΓACTTTCTGATGGCTCCACAG TGCAGCTCCCCAGACTTTCCTCACTCGGATTTGAGGACTCGATGTGCTGAGGCAGGACCCAGAGGGGTCCCAAGAGCCTGTCCTCTTTTGTTCAAAATACATCTTGAAACGT CTTTGTGAAGGCTCTTAGTTTTAATGCATGGATGCTGTTATTTTTCCCTACTGTTACTGAAATTAAAAAGTGTTTGTCTCTGAAAAAAAAAAAAAAAAAAAAAAAAA
241
MGSLSGLRLAAGSCFRLCERDVSSSLRLTRSSDLKRINGFCTKPQESPGAPSRTYNRVPLHKPTDWQKKILIWSGRFKKEDEIPETVSLEMLDAAKNKMRVKISYLMIALTV VGCIFMVIEGKKAAQRHETLTSLN EKKARLKEEQL
242
GGCACCAGGTCCCCGGCGAAGTTCTGCGCTGGTCGGCGGAGTAGCAAGTGGCCATGGGGAGCCTCAGCGGTCTGCGCCTGGCAGCAGGAAGCTGTTTTAGGTTATGTGAAAG
AGATGTTTCCTCATCTCTAAGGCTTACCAGAAGCTCTGATTTGAAGAGAATAAATGGATTTTGCACAAAACCACAGGAAAGTCCCGGAGCTCCATCCCGCACTTACAACAGA
GTGCCTTTACACAAACCTACGGATTGGCAGAAAAAGATCCTCATATGGTCAGGTCGCTTCAAAAAGGAAGATGAAATCCCAGAGACTGTCTCGTTGGAGATGCTTGATGCTG
CAAAGAACAAGATGCGAGTGAAGATCAGCTATCTAATGATTGCCCTGACGGTGGTAGGATGCATCTTCATGGTTATTGAGGGCAAGAAGGCTGCCCAAAGACACGAGACTTT
AACAAGCTTGAACTTAGAAAAGAAAGCTCGTCTGAAAGAGGAACAGCTATGAAGGCCAAAACAGAGTAGCAGAGGTATCCGTGTTGGCTGGATTTTGAAAATCCAGGAATTA
TGTTATAACGTGCCTGTATTAAAAAGGATGTGGTATGAGGATCCATTTCATAAAGTATGATTTGCCCAAACCTGTACCATTTCCGTATTTCTGCTGTAGAAGTAGAAATAAA
TTTTCTTAAATAATGACTGTGTTTTATTGTTTTGATCCAAGTCAAGTGTAGCCTCTCAGCCTTTTGGAGAAAAATGAAACAATTTATTTCAACTTGAATACCAACTCT CAG
AGAAGCAGGTACCATA
243
MP PL LLAVSGAQTTRPCFPGCQCEVETFGLFDSFS TRVDCSGLGPHIMPVPI PLDTAHLDLSSNRLEMVNESVLAGPGYTTLAGLDLSHNLLTSISPTAFSRLRYLES
LDLSHNGLXALPAESFTSSP SDVNLSHNQLREVSVSAFTTHSQGRALHVDLSHNLIHRLVPHPTRAGLPAPTIQ8LNLA NR HAVPNLRDLPLRYLSLDGNPLAVIGPGA
FAGLGGLTHLSLASLQR PELAPEGFRE PGLQ\rLDLSGNPKLNWAGAEVFSGLSSLQELDLSGTNLVP PEALLLHLPALQSVSVGQDVRCRRLVREGTYPRRPGSSPKVA
LHCVDTRE S AARGP I L
244
TCCAGCCCCCACCATGCCGTGGCCCCTGCTGCTGCTGCTGGCCGTGAGTGGGGCCCAGACAACCCGGCCATGCTTCCCCGGGTGCCAATGCGAGGTGGAGACCTTCGGCCTT TTCGACAGCTTCAGCCTGACTCGGGTGGATTGTAGCGGCCTGGGCCCCCACATCATGCCGGTGCCCATCCCTCTGGACACAGCCCACTTGGACCTGTCCTCCAACCGGCTGG AGATGGTGAATGAGTCGGTGTTGGCGGGGCCGGGCTACACGACGTTGGCTGGCCTGGATCTCAGCCACAACCTGCTCACCAGCATCTCACCCACTGCCTTCTCCCGCCTTCG CTACCTGGAGTCGCTTGACCTCAGCCACAATGGCCTGRCAGCCCTGCCAGCCGAGAGCTTCACCAGCTCACCCCTGAGCGACGTGAACCTTAGCCACAACCAGCTCCGGGAG GTCTCAGTGTCTGCCTTCACGACGCACAGTCAGGGCCGGGCACTACACGTGGACCTCTCCCACAACCTCATTCACCGCCTCGTGCCCCACCCCACGAGGGCCGGCCTGCCTG CGCCCACCATTCAGAGCCTGAACCTGGCCTGGAACCGGCTCCATGCCGTGCCCAACCTCCGAGACTTGCCCCTGCGCTACCTGAGCCTGGATGGGAACCCTCTAGCTGTCAT TGGTCCGGGTGCCTTCGCGGGGCTGGGAGGCCTTACACACCTGTCTCTGGCCAGCCTGCAGAGGCTCCCTGAGCTGGCGCCCAGTGGCTTCCGTGAGCTACCGGGCCTGCAG GTCCTGGACCTGTCGGGCAACCCCAAGCTTAACTGGGCAGGAGCTGAGGTGTTTTCAGGCCTGAGCTCCCTGCAGGAGCTGGACCTTTCGGGCACCAACCTGGTGCCCCTGC CTGAGGCGCTGCTCCTCCACCTCCCGGCACTGCAGAGCGTCAGCGTGGGCCAGGATGTGCGGTGCCGGCGCCTGGTGCGGGAGGGCACCTACCCCCGGAGGCCTGGCTCCAG CCCCAAGGTGGCCCTGCACTGCGTAGACACCCGGGAATCTGCTGCCAGGGGCCCCACCATCTTGTGACAAATGGTGTGGCCCAGGGCCACATAACAGACTGCTGTCCTGGGC TGCCTCAGGTCCCGAGTAACTTATGTTCAATGTGCCAACACCAGTGGGGAGCCCGCAGGCCTATGTGGCAGCGTCACCACAGGAGTTGTGGGCCTAGGAGAGGCTTTGGACC TGGGAGCCACACCTAGGAGCAAAGTCTCACCCCTTTGTCTACGTTGCTTCCCCAAACCATGAGCAGAGGGACTTCGATGCCAAACCAGACTCGGGTCCCCTCCTGCTTCCCT TCCCCACTTATCCCCCAAGTGCCTTCCCTCATGCCTGGGCCGGCTGACCCGCAATGGGCAGAGGGTGGGTGGACCCCTGCTGCAGGGCAGAGTTCAGGTCCACTGGGCTGAG TGTCCCTTGGGCCCATGGCCCAGTCACTCAGGGGCGAGTTTCTTTTCTAACATAGCCCTTTCTTTGCCATGAGGCCATGAGGCCCGCTTCATCCTTTTCTATTTCCCTAGAA CCTTAATGGTAGAAGGAATTGCAAAGAATCAAGTCCACCCTTCTCATGTGACAGATGGGGAAACTGAGGCCTTGAGAAGGAAAAAGGCTAATCTAAGTTCCTGCGGGCAGTG GCATGACTGGAGCACAGCCTCCTGCCTCCCAGCCCGGACCCAATGCACTTTCTTGTCTCCTCTAATAAGCCCCACCCTCCCCGCCTGGGCTCCCCTTGCTGCCCTTGCCΓGT TCCCCATTAGCACAGGAGTAGCAGCAGCAGGACAGGCAAGAGCCTCACAAGTGGGACTCTGGGCCTCTGACCAGCTGTGCGGCATGGGCTAAGTCACTCTGCCCTTCGGAGC CTCTGGAAGCTTAGGGCACATTGGTTCCAGCCTAGCCAGTTTCTCACCCTGGGTTGGGGTCCCCCAGCATCCAGACTGGAAACCTACCCAΓTTTCCCCTGAGCATCCTCTAG ATGCTGCCCCAAGGAGTTGCTGCAGTTCTGGAGCCTCATCTGGCTGGGATCTCCAAGGGGCCTCCTGGATTCAGΓCCCCACTGGCCCTGAGCACGACAGCCCTTCTTACCCT CCCAGGAATGCCGTGAAAGGAGACAAGGTCTGCCCGACCCATGTCTATGCTCTACCCCAGGGTAGCATCTCAGCTRCCGAACCCTGGGCTGTTTCCTTAGTCTTCATTTTAT AAAAGTTGTTGCCTTTTTAACGGAGTGTCACTTTCAACCGGCCTCCCCTACCCCTGCTGGCCGGGGATGGAGACARGTCATTTGTAAAAGCAGAAAAAGGTTGCATTTGTTC ACTTTTGTAATATTGTCCTGGGCCTGTGTTGGGGTGTTGGGGGAAGCTGGGCATCAGTGGCCACATGGGCATCAGGGGCTGGCCCCACAGAGACCCCACAGGGCAGTGAGCT CTGTCTTCCCCCACCTGCCTAGCCCATCATCTATCTAACCGGTCCTTGATTTAATAAACACTATAAAAAGTTAAAAAAAAAAAAAAAAAAAAA
245
MMAQSKANGSHYALTAIGLGMLV-^VIMAMWNLVPGFSAAEKPTAQGSNKTEVGGGILKSCT
EDSQEEEEEDEEAASRYYVPSYEEVMNTNYSEARGEEQNPRLSISLIPSYES TG DETTPTSTRADVEASPGNPPDRQNSKLAKRLKPLKVRRIKSEKLHLKDFRIN PDKN
VPPP8IEP TPPPQYDEVQEKAPDTRPPD
246
ACGCCGGCGCTCCCAGGCCGCGCTTCCTGCGTCCCCAACCCGGTCCCTGAGAGGGCACTGCGCCCTCTCCACCACTGCGTTCCCTCGGCTAAGAATCCCCCGAACCCCAGCC CCGCGATCGCGGCGCCCACCGAGGAGGCCGCCCGGGTGGGGCGCGGGGGTCGCGAAGCCCGCAGCCCCGGACCGCCCAGCCGAGACGGAGCCGGACCCGCCGCCTCCCGGGC
CCTTCCACCGCAGCTATCCGCACGGGAGGCCTCGCGATTGCTCGGAACCATCCCGCAGGAGTTCAGCTGATATTTTCTAGTGTGGGGCGAGAGATTTTGTGGAGCGCATTTA AGGGGTTTTTGTTGTGACTGCTGCCTTGTATATATTTATTTTCTTTCTTGGAACTGGGCCTCGCCCTCCTCCCACTGACATGATGGCCCAGTCCAAGGCCAATGGCTCGCAC TATGCGCTGACCGCCATCGGCCTGGGGATGCTGGTCCTTGGGGTGATCATGGCCATGTGGAACCTGGTACCCGGCTTCAGCGCGGCCGAGAAGCCAACAGCTCAGGGCAGCA ACAAGACCGAGGTGGGTGGCGGCATCCTCAAGAGCΔAGACCTTCTCTGTGGCCTACGTGCTGGTCGGGGCCGGGGTGATGCTGCTGCTGCTTTCTATCTGCCTGAGTATCAG GGATAAGAGGAAGCAGCGGCAGGGCGAGGACCTGGCCCATGTCCAGCACCCGACAGGCGCTGGGCCTCACGCCCAGGAGGAAGACAGCCAGGAGGAAGAAGAGGAGGATGAG GAGGCTGCCTCAAGGTACTATGTTCCCAGCTACGAGGAAGTGATGAACACAAACTACTCAGAAGCAAGGGGAGAGGAGCAGAACCCGAGGTTGAGCATCTCTCTCCCGTCCT ATGAGTCACTGACGGGGCTCGACGAGACCACCCCCACATCCACCAGGGCTGACGTGGAGGCCAGCCCTGGGAACCCCCCTGACAGGCAGAACTCTAAGTTGGCCAAACGACT GAAACCGCTGAAAGTTCGAAGGATTAAATCTGAAAAGCTTCACCTCAAAGACTTTAGGATCAACCTCCCAGACAAAAACGTCCCTCCTCCCTCGATAGAGCCTTTGACTCCT CCACCGCAGTATGATGAAGTCCAGGAGAAGGCCCCCGACACCCGGCCGCCCGACTGAATGGCCCCACTTGAGCCACGCTCCCTCCTGTCTCTCACACCTTTCACCCCCAAGA CTCTAACAAAGCCACATGAGCCACAGTTGAGAAGCGGAGGGGCCAGCTGTGCATGGAGCCATTTGGATGGCGGCGGGCGGGGGGGATTCTCTGTATCAGGAGTGACTTTGTT GCCCCACACAGCCTCCTGCTGCAGGTGCTTTGGAAAGAGATGCTGCCTTGGAGCTGGTGAATCTGTGGACCACATTCAAGGGTGTGGCACAGGCATCTTCCCATCCTTTTCA CTCCGAATCGCTGGCGACACATTCTCCΓTTCCAGCTAGGAAAGGGTTCCTCGCGGCTGGTTTAGATTGΓGGTTGTTTGTTTTGCTTCTACTAAGACTGTTTTGTTTCAAAAA GGAAACAAATTTTGTGTTTGCTGTCTACGCTGGAGTCCTGAACTGTGGGTAGAAAACACGACCTGGCTTTGTAGAAAGGACACAGGGCTGTTTTATGAACTAAGCGGTGAGG CTCAGGTGGCGGCTCTCACAGAGCCCCTGATGCTGTTGTTCTTTGAGGGCTTAAGGCCTGATGAACGTAGGCACGTGATGCGTAATAGTCTTCAATGGTACACTTAACTAGT CTCTTCTGTGTAACAGC
247
MAEGEDVG WRSW QQSYQAVKEKSSEA EFMKRDLTEFTQWQHDTACTIAATASWKEKLATEGSSGAΓEKMKKGLSDFLGVISDTFAPSPDKTIDCDVITLMGTPSGTA EPYDGTKAR YSLQSDPATYCNEPDGPPELFDAWLSQFCLEEKKGEISELLVGSPSIRALYTKMVPAAVSHSEFWHRYFYKVHQLEQEQARRDALKQRAEQSISEEPG EEE EEELMGISPISPKEAKVPVAKISTFPEGEPGPQSPCEENLVTSVEPPAEVTPSESSESISLVTQIANPATAPEARV PKDLSQKLLEASLEEQGLAVDVGETGPSPPIHSKP LTPAGHTGGPEPRPPARVETLREEAPTD RVFE NSDSGKSTPSNNGKKGSSTDISED EKDFDLDMTEEEVQMALSKVDASGELEDVEWED E
248
GATGTCATGCAGGCAAGATGGCGGAAGGGGAGGACGTGGGATGGTGGCGGAGCTGGCTGCAGCAGAGCTACCAAGCAGTCAAAGAGAAGTCCTCTGAAGCCTTGGAGTTTAT GAAGCGGGACCTGACGGAGTTTACCCAGGTGGTGCAGCATGACACGGCCTGTACCATCGCAGCCACGGCCAGCGTGGTCAAGGAGAAGCTGGCTACGGAAGGCTCCTCAGGA GCAACAGAGAAGATGAAGAAAGGGTTATCTGACTTCCTAGGGGTGATCTCAGACACCTTTGCCCCTTCGCCAGACAAAACCATCGACTGCGATGTCATCACCCTGATGGGCA CACCGTCTGGCACAGCTGAGCCCTATGATGGCACCAAGGCTCGCCTCTATAGCCTGCAGTCGGACCCAGCAACCTACTGTAATGAACCAGATGGGCCCCCGGAATTGTTTGA CGCCTGGCTTTCCCAGTTCTGCTTGGAGGAGAAGAAGGGGGAGATCTCAGAGCTCCTTGTAGGCAGCCCCTCCATCCGGGCCCTCTACACCAAGATGGTTCCAGCAGCTGTT CCCATTCAGAATTCTGGCATCGGTATTTCTATAAAGTCCATCAGTTAGAGCAGGAGCAGGCCCGGAGGGACGCCCTGAAGCAGCGGGCGGAACAGAGCATCTCTGAAGAGC CCGGCTGGGAGGAGGAGGAAGAGGAGCTCATGGGCATTTCACCCATATCTCCAAAAGAGGCAAAGGTTCCTGTGGCCAAAATTTCTACATTCCCTGAAGGAGAACCTGGCCC CCAGAGCCCCTGTGAAGAGAATCTGGTGACTTCAGTTGAGCCCCCAGCAGAGGTGACTCCATCAGAGAGCAGTGAGAGCATCTCCCTCGTGACACAGATCGCCAACCCGGCC ACTGCACCTGAGGCACGAGTGCTACCCAAGGACCTGTCCCAAAAGCTGCTAGAGGCATCCTTGGAGGAACAGGGCCTGGCTGTGGATGTGGGTGAGACTGGACCCTCACCCC CTATTCACTCCAAGCCCCTAACGCCTGCTGGCCACACCGGCGGCCCAGAGCCCAGGCCTCCAGCCAGAGTAGAGACTCTGAGGGAGGAGGCGCCCACAGACTTACGGGTGTT TGAGCTGAACTCGGA AGTGGGAAGTCTACACCCTCCAACAATGGAAAGAAAGGCTCAAGCACGGACATCAGTGAGGACTGGGAGAAAGACTTΓGACTTGGACATGACTGAA GAGGAGGTGCAGATGGCACTTTCCAAAGTGGATGCCTCCGGGGAGCTGGAAGATGTAGAGTGGGAGGACTGGGAGTGAGGGAGCCAGAGGGAGCAGCTCCCCCACCCATGGC ATCTCTCGCCTCCCTCGCTCGTCTCAGCCCAGCCCTGGAAGACTGAGAATGTTCCCCCAAATCTCCTCTGCCAACCAGAGCTCTGGGCACAGATTCTGGTGGCTCCCTGCTG GCCCTCTTGGGCCTCTGCTCACACCTGGGAAGGGGCTCTCTAAATCCCGGCCAGAAACTCTGACTTGTGCCAACAATAGGATGACCCAAGGGAGAGΒAAACCTATCCTCCTC ACCAGAAGAGCCTGTGTTTTTCTGCTGAACACCCACTGTTCCTGAGGACTCCTGCTGGGAAGTCCCAAGGGATAΒTTCTAGCCCTTCTGCCTGTGTAGACAGAAGCTAAACC ACCAGTCTCTCTCGGAGGAAGCTGAGACAACATACTCTGTCCATACATAAGCAGGCAGGGAGGGCCATGCCACCTACCCTTGGCTAAACAGGGACAGTGAACACATTTTGGΓ TCCTATCCCAGTGGGTAAGAGGCACTTATCTCTGGGAAATTTGCCTCTCTTGGGACTCTCCCCCTCCCAGGCATTTTCCATTCCTGGAAAGGCTCCTTTGGGGTTCAGAATC CAGAGACCAAACCCTGACCCACCTCCTTCCTTTCCTCCAGCCCACGCTGGTCTGTCCCCATGCCTTCCCAGGGCTTCTTCATGTCAGATGCACCCAAGTCCTTAGCCCAGCΓ GTGCCACCTGCAGGAGTTCGCTCTTGCGTTTCTTCCCCTCCCCAAGAAGGGAGGGGGCTACTTCAGGCCCTTCTGTGTGTTGCCTGGCAGGATACCTTGTCCAACCAGCTAC CCACCTCAACTCCCCTGTAGTTTAGGACACAAAACAGCTACCAGCGGTACAGAGCGGTGATCAAAGCCGAGTACTTACAACTCTGGTAAGCCTAGCTTCTCCGCCTCAGCCC TTCTGCTTCTGGAAGGGCTATCCTGGGGGTGAACTTGAAACTCTCATCAGGCTTCTGCAAAAGCTCTTCTTCCTGAAGACAGACCCAGCCTTTGTGCTCTCACCCTCCACTC TGGTAAAGCTGCACCTCTGGGGGAATGAGGGGCTGCAGGAATCTCTGGAGAGCCTGGTGCTTCACGATGCTGCTCTGGTGATTCTTGTACCTAATCTGGTGTGCTCACCAAT GAGTGAAAGGGATCGTGGGTCAGGGACACCGAGAGAGTGAGGTCACTTCCACTTCAAACCTTCAGTGAGGGGGTGGGATGGAGAGAATGCTGAATCTTTTTTTTGACGGGAT GGGGTTTTTCTCTTTGTAATTATTTCTTTAGTTTAATTAACCTTTTGGTTGTTTGTGCAATATTATATATTTTAAATTATAATGCATCTCCCCAGAGTATTTTGTAGCTGGG AAAAGAAAAAAGGAAAAAAAGAAAAAAAGATTCTAACAGCTGTTAGTTTTATAATTAAAAAAGAAAGAAAAAAGAACTTTGTCCTGAACCTTTTACAGACTTGCCGTTAACA GCATTAAAGTGATTCACCCGAAGCTG
249
MKGEAGHMLHNEKSKQEGHIWGSMRRTAFILGSGLLSFVAFWNSVT HLQRF GASGYFWQAQWERLLTTFEGKE ILFFIGAIQVPCLFFWSFNGLLLWDTTGKPNFISR YRIQVGKNEPVDPVKLRQSIRTVLFNQCMISFPLWVFLYPF KWWRDPCRRE PTFHWF LEIIAIFT IEEV FYYΞHR
250
AAAAAACAAGGTTAGCCTGCAGCAGAGCCGCAGCAGCAACAGCCACCAAAGCGGGGGCTGAAAGGGAAGAGAACTTAGATTTGACCTGTGCAAGGACCTCAGCAGCTTGGAC ACAGCCCACTGCAGAGATGAAAGGAGAAGCTGGACATATGCTACACAATGAAAAGTCAAAGCAGGAGGGACACATCTGGGGCTCTATGAGGAGGACAGCTTTCATCCTGGGC TCTGGACTTCTCTCATTTGTGGCCTTCTGGAACTCAGTGACATGGCATCTTCAGAGATTTTGGGGTGCTTCTGGCTACTTTTGGCAAGCCCAGTGGGAGAGGCTGCTGACTA CATTTGAAGGGAAGGAGTGGATCCTCTTCTTTATAGGTGCCATCCAAGTGCCTTGTCTCTTCTTCTGGAGCTTCAATGGGCTTCTATTGGTGGTTGACACAACAGGAAAACC TAACTTCATCTCTCGCTACCGAATTCAGGTCGGCAAGAATGAACCTGTGGATCCTGTGAAACTGCGCCAGTCTATCCGCACAGTTCTTTTCAACCAGTGCATGATATCTΓTC CCCATGGTGGTCTTCCTCTATCCCTTCCTCAAATGGTGGAGAGACCCCTGCCGCCGTGAGCTACCCACCTTCCACTGGTTCCTCCTGGAGCTGGCCATCTTCACGCTGATCG AGGAAGTCTTGTTCTACTATTCACACCGGTGAGCAGGCCCTGCCTGAGGCACAGCTGGCTCCTCATCCTGTCTAGGGCTCACTGATCAACAAGGAAACTGAGGCCAGGCTCC TTCACCACCCAACATTCTACAAGAAAATCCACAAGAAACACCATGAGTGGACAGCTCCCATTGGCGTGATCTCTCTCTATGCCCACCCTATAGAGCATGCAGTCTCCAACAT GCTACCGGTGATAGTGGGCCCATTAGTAATGGGCTCCCACTTGTCCTCCATCACCATGTGGTTTTCCTTGGCCCTCATCATCACCACCATCTCCCACTGTGGCTACCACCTT CCCTTCCTGCCTTCGCCTGAATTCCACGACTACCACCATCTCAAGTAAGGACCTTCTCCCCACAATGGGTCCCTAGGCAACAACCATCACCCTCCCTCCTTAAGCTTCTGAT AGCAGGCACTGGTATCTCAGTTTACATGTGAGTGCTAGTTGGGGAAGAGGTCTGATGGCTGGGAAAATAACCACACTGGGATGACCTTACTCTTTTCCTTCTGAAATTGGGT CCTCCTCCAACTGGGGGTTTTAAACCTTTATTTGGACTCTGGGCCCTTTGAATAAGCTCTGGACATTCTCTTTAGAAAAGTACATATATGCATAATACTCCTGCAGGCAATC ACAAGGAAGTCATGTATCTCTGAAAGCCCCAGACTTTTTCAAGTGTAGTCTACAAACCTCCTATACCAGAATCACCTGAGATGCTTGTTTAAAATATAGGCTCTTGAATTCC ACTCCAAATATGCTGAACIAAGGTATCTGGGGGAGCAGGGCCTGGAAACCTGCATTTTAGTTAAGTGTTCCAGGGGATTCTGATGCTGGTGATCTCATAC<:TGAAGAAGCCΓ AGTTCTGCTAGAGATTCTCAGACTGTGGGCATCAATCACACAGCAAGCTTTTCAAAGGAGGACTCCAGATACGGCAAATTGCAGGTTTGGAGTGGCCCCCGGGAGATGCATT GGTAGCAACTCCCCAGCTTATTCTGATGCAGATGGTCAGGATGGTGGTGACAGGTGTGGGGTAGGAGGGCTGAGAAATGTGTGAGGCTGGCACAAATGAAATGGGATCTGCA CGGAAGCCTCCAGCATGGGCACTGCAGTGCCGTCCTCTCTCTTCTAGGTTCAACCAGTGCTATGGGGTGCTGGGTGTGCTGGACCACCTCCATGGGACTGACACCATGΓTCA AGCAGACCAAGGCCTACGAGAGACATGTCCTCCTGCIGGGCTTCACCCCGCTCTCTGAGAGCATCCCAGACTCCCCAAAGAGGATGGAGTGAGAGACAGCCTAAGTGTCATC CTGGCTGTCCCTCAGCCATGGGATGCAGACACGGCTTCCTGATTGCACCTAACAATTTGCCTCCTTCGGCCACACGCCCTAATGATGGCACCACCAGGGTAGAGGGAAGGTC GGCTTCCCGGAAAAGCAGGGCCAAGGATGAGGCTTTCTTCAAACTACTGCCCTTGATGTCCCTCAATAGGATCAGGAGTTAGCTTAAGAAAAAGGAAAACACAGCTCCCCAG ACTGGAGGCTGGTCAGAGGGAGGAGACCCCTGGTCCTCTGCTGTGGAAGGAGAGGGGTTCAGCCCCAGATAACTCCTTTGTGGCCTGGGCAGGATGCAGAGAATGACAAGGC TGAAAGGAGGGGGACTGGAGGCTGCCTGGCTCCAGCGAGAGCTCCTTCTGGGACCAGAGGGTGGGACGGCCAGGTATCACTTTGCCCCTTCCTGCCCCAAAAGGCTTTCACA TACCCGACTCAGGCCAGAGCCAAGACACCCTGGCAAATCATTATAGGTCTCAATTCATGACATACCAGATGCCAGTCGCCACTTCACCCAACACACACACAAACATACACAC ACCAAACACTCTGAGTGAGTGGTAAAGGCCCCGTTTTAACTCTGGCCCACCGCAAACAAAAGGTTTCCCTCTGTGGGGGAGAAAAAGAAATCCAGGAGCTCCTCCCTGGATT AAAACCAACGAGGTGCAGACCAAACTTTAACACCTTTAGCCTTATGTGGAAACCAAAAACCAACTGOTGGGAAACTGTGAAAAGCCCTTTTACCCACAAGGGAAGGGGTCAA AGTTGCTGCCCTTTGGGGACACCCGAGACCCCTAATTAGCCTATCTGAATGAGGACCAAAGGTTAGAGCCCTCTT'RCTCCCCGAAGAAAGAGCCCGGAAAAACATGGCAGAG CAAAGAGCAAAATCCTTTCTCCCCCGAATGCTTTACCAGTTTCTCAGCAACATTTATTCAAGATGATTTTTACCAGGAACCTTATCAAAGGCAAAACCACAGCAGCTTGGGT TGAAGTCCCCATCCTGGCCTCCTCTCAGCCGCCAGACATGGCCAGGAACCCTGTGGTTCCCAAGAACAATTTAAAGATCACTCTTTGATTTGAAAGACCACCATTATCATΓT TACTAAATTCTTATATATACTTGTGCCTTTTCCAACTTTCAGTTCTCTTAAGAAAAACATCCACTGTAGCTTTATAAAATACCTTAGTATCAGCTAGGTCCAAGTCTCCAGG CAGGACTATCAAAATGGACTCCTTCTTCCTATCAGCTCTAGAACCCCAGAGGACTTGCCCAGTAGGCCAGCTGAGCATTTACCAGGCAGCATCTCCCTGGCCTTCCACAGTC TCGCCTGTCTGTCTCTGGCCTTGGTGGACCTGGCTCCCTCCCTAGGAGGCTTTTGCCCTCAGCTTGAATACAGTTCCTGGTGCATCAAAGCTGTAAGTTCTCAGCTGCTGGC CTGCGCTCATCACCTCTTCCTACAAATAAACATTTGGAAAAAAGTCCATCTTCAATATGCTTAAAGAGAAGGGTAGGAGATAAGGAGAAAGAACAGATACGGTTTTTTTCCC CTTTAAGGCCTTTAGATTTTGAGGTACTGTAAGGGGCCTAGAAGGACAAAAGGCTTTCATTCCCTCTTCCTTTTGGCAGGCAGGTTATCAGTCCTTGGCAGAAGGGCCCAGC
CCTATCCTTTTCTGTATCAAACAAAATCCTTGAGGT'IGGTATACAAGTTAAGGCTGAAAAAAGGCCTTAAATTCCCAGTAAAGAATGTGAAAGCAAGCATGTAAAATAAACT GGTCTTCATG
251
MSGGHQLQLAALWPWLLMATLQAGFGRTGLVLAAAVESERSAEQKAVIRVIP KMDPTGKLNLTLEGVFAGVAEITPAEGKLMQSHPLY CNASDDDNLEPGFISIVKLESP RRAPRPCLSI-ASKAPJWGERGASAVLFDITEDRAAAEQLQQPLG T PVVLIWGNDAEKLMEFVYKNQKAHVRIELKEPPAWPDYDVWI MTVVGTIFVI ILASVLRIRCRP RHSRPDPLQQRTAWAISQLATRRYQASCRQARGE PDSGS8CSSAPVCAICLEEFSEGQELRVISCLHEFHRNCVDPWLHQHRTCPLCVFNITEGDSFSQSLGPSR8YQEPG RRLHLIRQHPGHAHYHLPAAYLLGPSRSAVARPPRPGPFLPSQEPGMGPRHHRFPRAAHPRAPGEQQR AGAQHPYAQGWGMSHLQSTSQHPAACPVPLRRARPPDSSGSGE SYCTERSGYLADGPASDΕSSGPCHGSSSDΕWNCTDIΕLQΣVHGSSSTFCSSLSSDFDPLVYCSPKGDPQRVDMQPSVTΕRPRSLDSWPTGETQVΕΕHVHYHRHRHHHYKK
RFQWHGRKPGPETGVPQSRPPIPRTQPQPEPPSPDQQVTGSNSAAP8GRLSNPQCPRALPEPAPGPVDASSICP8TSSLFNLQKSSLSARHPQRKRRGGPSEPTPGSRPQDA
TVHPACQIFPHYTPSVAYPWSPEAHPLICGPPGLDKRLLPETPGPCYSNSQPVWLCLTPRQPLEPHPPGEGPSEWSSDTAEGRPCPYPHCQVLSAQPGSEEELEELCEQAV
252
AAAAAAAAAAAACTTTAGAGAAAGGAAGGGCCAAAACTACGACTTGGCTTTCTGAAACGGAAGCATAAATGTTCTTTTCCTCCATTTGTCTGGATCTGAGAACCTGCATTTG GTATTAGCTAGTGGAAGCAGTATGTATGGTTGAAGTGCATTGCTGCAGCTGGTAGCATGAGTGGTGGCCACCAGCTGCAGCTGGCTGCCCTCTGGCCCTGGCTGCTGATGGC TACCCTGCAGGCAGGCTTTGGACGCACAGGACTGGTACTGGCAGCAGCGGTGGAGTCTGAAAGATCAGCAGAACAGAAAGCTGTTATCAGAGTGATCCCCTTGAAAATGGAC
CCCACAGGAAAACTGAATCTCACTTTGGAAGGTG'IGT'ITGCTGGTGTTGCTGAAATAACTCCAGCAGAAGGAAAATTAATGCAGTCCCACCCACTGTACCTGTGCAATGCCA
GTGATGACGACAATCTGGAGCCTGGATTCATCAGCATCGTCAAGCTGGAGAGTCCTCGACGGGCCCCCCGCCCCTGCCTGTCACTGGCTAGCAAGGCTCGGATGGCGGGTGA GCGAGGAGCCAGTGCTGTCCTCTTTGACATCACTGAGGATCGAGCTGCTGCTGAGCAGCTGCAGCAGCCGCTGGGGCTGACCTGGCCAGTGGTGTTGATCTGGGGTAATGAC GCTGAGAAGCTGATGGAGTTTGTGTACAAGAACCAAAAGGCCCATGTGAGGATTGAGCTGAAGGAGCCCCCGGCCTGGCCAGATTATGATGTGTGGATCCTAATGACAGTGG TGGGCACCATCTTTGTGATCATCCTGGCTTCGGTGCTGCGCATCCGGTGCCGCCCCCGCCACAGCAGGCCGGATCCGCTTCAGCAGAGAACAGCCTGGGCCATCAGCCAGCT GGCCACCAGGAGGTACCAGGCCAGCTGCAGGCAGGCCCGGGGTGAGTGGCCAGACTCAGGGAGCAGCTGCAGCTCAGCCCCTGTGTGTGCCATCTGTCTGGAGGAGTTCTCT GAGGGGCAGGAGCTACGGGTCATTTCCTGCCICCATGAGTTCCATCGTAACTGTGTGGACCCCTGGTTACATCAGCATCGGACTTGCCCCCTCTGCGTGTTCAACATCACAG AGGGAGATTCATTTTCCCAGTCCCTGGGACCCTCTCGATCTTACCAAGAACCAGGTCGAAGACTCCACCRCATTCGCCAGCATCCCGGCCATGCCCACTACCACCTCCCTGC TGCCTACCTGTTGGGCCCTTCCCGGAGTGCAGTGGCTCGGCCCCCACGACCTGGTCCCTTCCTGCCATCCCAGGAGCCAGGCATGGGCCCTCGGCATCACCGCTTCCCCAGA GCTGCACATCCCCGGGCTCCAGGAGAGCAGCAGCGCCTGGCAGGAGCCCAGCACCCCTATGCACAAGGCTGGGGAATGAGCCACCTCCAATCCACCTCACAGCACCCTGCTG CTTGCCCAGTGCCCCTACGCCGGGCCAGGCCCCCTGACAGCAGTGGATCTGGAGAAAGCTATTGCACAGAACGCAGTGGGTACCTGGCAGATGGGCCAGCCAGTGACTCCAG CTCAGGGCCCTGTCATGGCTCTTCCAGTGACICTGTGGTCAACTGCACGGACATCAGCCTACAGGGGGTCCATGGCAGCAGTTCTACTTTCTGCAGCTCCCTAAGCAGTGAC TTTGACCCCCTAGTGTACTGCAGCCCTAAAGGGGATCCCCAGCGAGTGGACATGCAGCCTAGTGTGACCTCTCGGCCTCGTTCCTTGGACTCGGTGGTGCCCACAGGGGAAA CCCAGGTTTCCAGCCATGTCCACTACCACCGCCACCGGCACCACCACTACAAAAAGCGGTTCCAGTGGCATGGCAGGAAGCCTGGCCCAGAAACCGGAGTCCCCCAGTCCAG GCCTCCTATTCCTCGGACACAGCCCCAGCCAGAGCCACCTTCTCCTGATCAGCAAGTCACCGGATCCAACTCAGCAGCCCCTTCGGGGCGGCTCTCTAACCCACAGTGCCCC AGGGCCCTCCCTGAGCCAGCCCCTGGCCCAGTTGACGCCTCCAGCATCTGCCCCAGTACCAGCAGTCTGTTCAACTTGCAAAAATCCAGCCTCTCTGCCCGACACCCACAGA GGAAAAGGCGGGGGGGTCCCTCCGAGCCCACCCCTGGCICTCGGCCCCAGGATGCAACTGTGCACCCAGCTTGCCAGATTTTTCCCCATTACACCCCCAGTGTGGCATATCC TTGGTCCCCAGAGGCACACCCCTTGATCTGTGGACCTCCAGGCCTGGACAAGAGGCTGCTACCAGAAACCCCAGGCCCCTGTTACTCAAATTCACAGCCAGTGTGGTTGTGC CTGACTCCTCGCCAGCCCCTGGAACCACATCCACCTGGGGAGGGGCCTTCTGAATGGAGTTCTGACACCGCAGAGGGCAGGCCATGCCCTTATCCGCACTGCCAGGTGCTGT CGGCCCAGCCTGGCTCAGAGGAGGAACTCGAGGAGCTGTGTGAACAGGCTGTGTGAGATGTTCAGGCCTAGCTCCAACCAAGAGTGTGCTCCAGATGTGTTTGGGCCCTACC TGGCACAGAGTCCTGCTCCTGGGAAAGGAAAGGACCACAGCAAACACCATTCTTTTTGCCGTACTTCCTAGAAGCACTGGAAGAGGACTGGTGATGGTGGAGGGTGAGAGGG TGCCGTTTCCTGCTCCAGCTCCAGACCTTGTCTGCAGAAAACATCTGCAGTGCAGCAAATCCATGTCCAGCCAGGCAACCAGCTGCTGCCTGTGGCGTGTGTGGGCTGGATC CCTTGAAGGCTGAGTTTTTGAGGGCAGAAAGCTAGCTATGGGTAGCCAGGTGTTACAAAGGTGCTGCTCCTTCTCCAACCCCTACTTGGTTTCCCTCACCCCAAGCCTCATG TTCATACCAGCCAGTGGGTTCAGCAGAACGCATGACACCTTATCACCTCCCTCCTTGGGTGAGCTCTGAACACCAGCTTTGGCCCCTCCACAGTAAGGCTGCTACATCAGGG GCAACCCTGGCTCTA'ICATTTTCCTTTTTTGCCAAAAGGACCAGTAGCATAGGTGAGCCCTGAGCACTAAAAGGAGGGGTCCCTGAAGCTTTCCCACTATAGTGTGGAGTTC TGTCCCTGAGGTGGGTACAGCAGCCTTGGTTCCTCTGGGGGTTGAGAATAAGAATAGTGGGGAGGGAAAAACTCCTCCTTGAAGATTTCCTGTCTCAGAGTCCCAGAGAGGT AGAAAGGAGGAATTTCTGCTGGACTTTATCTGGGCAGAGGAAGGATGGAATGAAGGTAGAAAAGGCAGAATTACAGCTGAGCGGGGACAACAAAGAGTTCTTCTCTGGGAAA AGTTTTGTCTTAGAGCAAGGATGGAAAATGGGGACAACAAAGGAAAAGCAAAGTGTGACCCTTGGGTTTGGACAGCCCAGAGGCCCAGCTCCCCAGTATAAGCCATACAGGC CAGGGACCCACAGGAGAGTGGATTAGAGCACAAGTCTGGCCTCACTGAGTGGACAAGAGCTGATGGGCCTCATCAGGGTGACATTCACCCCAGGGCAGCCTGACCACTCTTG GCCCCTCAGGCATTATCCCATTTGGAATGTGAATGTGGTGGCAAAGTGGGCAGAGGACCCCACCTGGGAACCTTTTTCCCTCAGTTAGTGGGGAGACTAGCACCTAGGTACC CACATGGGTATTTATATCTGAACCAGACAGACGCTTGAATCAGGCACTATGTTAAGAAATATATTTATTTGCTAATATATTTATCCACAAAAAAAAAAAAAAAAAA
253
MLMAWCRGPVL CLRQGLGTNSFLHGLGQEPFEGARS CCRSSPRDLRDGEREHEAAQRKAPGAESCPELP EISDIGTGCLSS ENLRLPT REESSPRELEDSSGDQGRC
GPTHQGSEDPSMLSQAQSAIEVEERHVSPSCSTSRERPFQAGELILAETGEGETKFKKLFRLNNFGLLNSNWGAVPFGKIVGKFPGQI RS8FGKQYMLRRPA EDYW MK
RGTAITFPKDIM^ILSMMDINPGDTVLEAGSGSGGMSLFL8KAVGSQGRVISFEVRKDHHDLAKKNYKHWRDSWKLSHVEEWPDNVDFIHKDISGATEDIKS TFDAVA DM NPHVTLPVFYPHLKHGGVCAVYVVNITQVIELLDGIRTCE ALSCEKISEVIVRDWLVCLAKQKNGILAQKVE8KINTDVQLDSQEKIGVKGELFQEDDHEESH8DFPYGS
FPYVARPVH QPGHTAFLVKLRKVKPQLN
254
GGGGGCGAAACACTATGCTAATGGCATGGTGCCGCGGTCCTGTCTTGCTGTGCCTGCGGCAGGGGCTCGGAACCAATTCATTCCTGCACGGCCTGGGGCAGGAGCCCTTCGA GGGAGCTCGGTCACTGTGTTGCAGGTCCTCGCCTAGAGACCTGCGAGATGGAGAAAGAGAGCACGAGGCGGCACAAAGGAAAGCCCCAGGAGCAGAGTCITGCCCATCTCTC CCTCTGAGCATCTCGGACATTGGGACTGGATGTCTTTCGTCACTGGAAAACCTCAGACTGCCGACGCTGCGGGAAGAGTCATCACCTCGAGAGCTCGAGGACTCGAGCGGAG ACCAGGGCCGGTGCGGTCCCACACACCAGGGATCCGAGGATCCTTCGATGCTCTCGCAGGCCCAGTCCGCTACCGAGGTCGAAGAGCGTCACGTCTCCCCTTCTTGTTCAAC TTCCAGAGAGAGACCCTTTCAGGCTGGGGAGCTGATTTTAGCTGAGACTGGGGAGGGAGAAACAAAATTTAAGAAATTATTTAGGTTGAACAACT'ICGGACTCTTAAATAGT AACTGGGGGGCAGTCCCGTTCGGCAAGATCGTGGGGAAGTTCCCCGGCCAGATACTGAGGAGTTCCTTCGGTAAGCAGTACATGCTGAGGAGGCCAGCCTTGGAAGACTATG TAGTATTGATGAAAAGAGGGACTGCCATAACATTCCCAAAGGATATTAATATGATTCTCTCAATGATGGATATCAACCCAGGTGATACTGTTTTGGAAGCTGGCTCAGGCTC TGGTGGAATGAGCTTATTTTTATCCAAAGCAG'rTGGATCACAAGGACGAGTCATAAGTTTTGAGGTACGAAAAGACCACCATGATCTGGCTAAGAAGAATTACAAACACTGG CGTGATTCATGGAAATTAAGTCATGTAGAAGAGTGGCCAGACAATGTGGATTTTATTCATAAGGACATTTCAGGAGCAACCGAAGACATAAAATCTTTAACATTTGACGCAG TAGCTTTGGATATGTTAAATCCTCATGTTACTTTGCCTGTTTTTTACCCACATCTTAAGCATGGTGGTGTATGTGCTGTATATGTAGTAAACATCACACAGGTTATTGAACT TTTAGATGGAATTCGCACCTGTGAACTTGCTCTTTCATGTGAAAAGATAAGCGAGGTCATTGTCAGAGATTGGTTGGTTTGCCTTGCAAAACAGAAAAATGGAATTTTAGCT CAAAAAGTAGAATCIAAAATCAACACAGATGTACAACTAGATTCTCAAGAGAAAATTGGAGTTAAAGGTGAGCTGTTTCAAGAGGATGACCATGAAGAATCGCATTCTGATT TTCCATATGGATCATTTCCCTATGTTGCTAGACCAGTACACTGGCAACCTGGTCATACAGCTTTTCTTGTCAAGTTGAGGAAGGTCAAACCACAACTTAACTGAGTACTCCA GATGACAGTAACTGACTTGAAGATGGAAAAATATCAAAATAGAACTTTATATTGAAAATCACTGCTTCCATAGATTGGCATTTTTAGCTATTACTATGACTTATATAACTTA TACATATAATTTTGAAAATAACAACTAAAAGATG'IATAACATAGCAAAACTGCTTAAACATCCCATTTTGACACTTGTCTTGCAGTTAGTTTGACATTTTGTAGTTAATGAΓ TCCAAATTGGTTTAGTTGGGCCATCTCATTCTTCACTTCCTGTAAACCACTCCATAGATTTGTCTTTCTTCAAGAAATTAGTTTTCTTTCCTTTATTTGATTGATGGTCATR GACTACTGAAATAAAATATGCATTTTAAGATGAAAAAAAAAAAAAAAAAAAAAAAAA
255
MSVGLDLPQMLPGSPSPSLKEAFAEDGEAGEGGGRPSLE RLQQL PQHPLSLSWLLTSPQGTGPF PSWICHLLDQVLSLLHSPVPTPVHSSGPGSKQAVNS PE SLWL VAHAPFLWC
256
TGACATTTCATCTGGGTGGTCTGAATATTAAAGCTCTTCATTTCTGGAGATGGGGCAGCAGGTGGCTCTTCTGCTGGGGCTGACTTGTCCAGAAGGGGACAAAGTGCAATAC AGAGCCTTCCCTACCCTGACGCCTCCCAGTCATCA'ICTCCAGAACTCCCAGCGGGGCTCCCTGAGCTCTCAAGGAGATGCTGCCATCACTGGGAGGCTCAGAGGACCCTTCC TGCCCACCTTCGGAGACGGCTTCTGGAGGAACGGCITGGCCAGAAGACAGGGTGTGAGTGAGACAGTGGGGCACAGGTTGGGTTTGCCAAACGCCTAATTACCAGGCCAGGA AGCATGCCAACAAAGCCACACGGGTGTCCTAGCCAGCTTCCCTTCACCTGGTGTCTTGAGTAGGGCGTCTCCTGTAATTACTGCCTTGCCATTCTGCCCCTGGACCCTTCTC TCCGGACCAGGGAGGCGTCCCTCCCTATGAGCCACACATTATACTCCAAGTCCCTGCCGGGCTCCGCCTTTCCCCCACCCTGGCTCTCAGGGTGACGCCACCCACAGAGATT TAATGAGCGTGGGCCTGGACCTTCCCCAGATGCTGCCAGGCAGCCCCTCCCCAAGCCICAAAGAAGCATTTGCTGAGGATGGAGAGGCAGGGGAGGGAGGCGGGAGGCCGTC ACTGGAGTGGCGTCTGCTAGCAGCTGCTGCCCCAGCACCCGCTCAGCCTGTCCTGGCTGCTCACCTCCCCGCAGGGCACCGGGCCTTTCCTGCCCTCTGTGGTCATCTGCCAC CTGCTGGATCAAGTGCTTTCTCTTTTACACTCCCCTGTCCCCACCCCAGTGCACTCTTCTGGCCCAGGCAGCAAGCAAGCTGTGAACAGCTGGCCTGAGCTGTCGCTGTGGC TTGTGGCTCATGCGCCATTCCTGGTTGTCTGTTGAATCTTTCTGGCTGCTGGAATTGGAGATAGGATGTTTTGCTTCCCACTGCAGGAGAGCTGCCCCCTTTCACGGGGTTG GGGAAGGGTCCCCCTGGCCTCCAGCAGGAGCACAGCICAGCAGGGTCCCTGCTGCCCACCCCTCTGAGCCTTTTCTCCCCAGGGTATGGCTCCTGCTGAGTTTCTTGTCCAG CAGGGCCTTGACAGGAATCCAGGGAGTAGCTCCTGGCCAGAACCAGCCTCTGCGGGGCTTGTGCTCTGCAAAGACTCTGCTGCTGGGGATTCAGCTCTAGAGGTCACAGTAT CCTCGTTTGAAAGATAATTAAGATCCCCCGTGGAGAAAGCAGTGACACATTCACACAGCTGTTCCCTCGCATGTTATTTCATGAACATGACCTGTTTTCGTGCACTAGACAC ACAGAGTGGAACAGCCGTATGCTTAAAGTACATGGGCCAGTGGGACTGGAAGTGACCTGTACAAGTGATGCAGAAAGGAGGGTTTCAAAGAAAAAGGATTTTGTTTAAAATA
TGGGAGCTATTTTCTTTTTTGTGCATATAGATATTTCTTAAATGAAAAAAAAAAAAAAAA
AAAAAAAAAAAAAAAAAAAAAAAAAAAA
257
MGITPWPKGHTEPKGΞYSLRKKPCYGTVAALDCAGCQEG>mEAASVGLAQSESTTIMGHVCAERHTHDRYVTSMCPYLPLPMDGNAMDFSFLSSARAKQFFTVFSRSSSH S APQTGLLQWITNLAGRFWPALTAASGAGMKQKQ
258
GTCGCCTACTGTCACGGTGTTAACCTCCCTCTCTGTCTCTCTGAGTGCGTTCTCTCGCCCGTCACCCCTCTTCCTTTCTCGGTCTCCTCCTCTCCCTTCGTCCGAGCCGCTC CTTAGCGCCCAGTTGCGCAAATCAAATTCTTTCCCGTTCTATTTACTCCTGATCAAGAGGGGCTGTCAGTCCAACCCTCCAGCTGTAGGCTCGTGCATCTGCCAGTCTCTTG GCGCGTGGGGACCGCGTGGAAGTGCCCTCGCGTGTGCGTGCCAGCTGAGATGAGACGTGGAAGCTGGAGGGGTCCGGCATCCCAGAGAGGCGTGAGGCTCCCAAACCACCAC CTGCTCAGGTCCACCCTAATAACATCAGCCAAGGCCTCTACAGCAGCCCCCAAGCTGCCTCTGGATAGTTCAGACAAGGCCTCTGTGCTGTGATGGAACCAGGTGACCCGCA GCCTCCGGGCCAGCTACTCTGGCTTGGCTGAGGTCTTCCTAGATAATCAACATCCCTCAACAGCCTTGGCGGTGAGAAGGCACGTGAAAGCTGCCAGCACATCCCAGGAGCC TTGGCTGTGGCGGCTTCTCCTTGGAAAGCTCCACGCACCCTTCTGCCAGGGATCCTGTCCTGCAGGGATGACAGACCCAGCAGCCTCGGCAGAGGGAATGAGGCTCCAGCAG CTTCATCAGCAAGTGGCCAGGCCCAGCCCTAAGTCACAGACTGTCAGAAGGGGACAATGGTAGGAGAGAGCTGGGCTCAGGGTCTGGAGCCTGCCACATGCCACCTGCACGG CTΓTGGATACACTCCCTCCTTCATCTGTGGAACGGGGAATGGGGATAACACCCTGGCCCAAGGGTCACACAGAACCAAAAGGAAGCTACAGCCTAAGGAAGAAACCCTGCΓA TGGGACTGTGGCTGCTCTGGACTGCGCAGGCTGCCAGGAAGGAATGGCGGAGGCAGCCTCCGTGGGCCTTGCACAGAGTGAGAGCACCACAATTATGGGCCATGTGTGCGCA GAGAGACACACCCATGACCGATACGTAACAAGCATGTGCCCCTACCTGCCGCTGCCGATGGATGGAAATGCAATGGATTTCAGCTTCTTATCATCAGCCAGGGCCAAGCAGT TTΓTCACTGTCTTTTCCAGAAGTTCTTCACACTTGTCTGCACCCCAAACTGGACTATTACAGTGGATCACAAACTTGGCAGGCAGGCCATGGCCTGCGCTGACAGCAGCTAG TGGTGCGGGGATGAAACAGAAACAGTGAGCTCTGGTTCACTGOIAAGCACAAGATGCCAAACACAGACCCACTCCCCTGCCACGGTATATCTTCCTGGGCCCTCCAATGCCC TGRGTCTGAGGAGTTCCACAGCTGTCTGCTGCGTTGTGATTCCAACGTGAGCTGGAGCCAAGCCACACCCTTGGAAAGTTGGCATTATGATGTGTCACCACCAGGAATTTTG ACCAAGTTCGTAGTAAGCCTCTCTCCACTCTCAGAAAGCATACACGGTTCTCCCAGAGGCAGAGCCTTATCCATCAAAACTCAACTGAACGCAAACTCAACGTGTCAGAACA TTΓGCAGCCTCAAAATAATTGTTTTGGGTTTCCAACCCTTCTTCTTCAAGTCGACTGGTGTGCTAATTATCGACTTGCACACCAATATGATATATTTGTCTCTACTATGATG TAΓΓCTCTAAATCTCCCΔAACCCAATTCAGGACAAAGCTACTAGGAAAGCAACTGCTTTAAATGATCTGCTAAGCAACCTGACCAGCATCTCCACTCTGCCATTGTCTTCTC CCRGCTGAGGATGGCCTCACTGTGTGAATAACGGATCCTGTTTATTTGTGGCAGAATTAGATTAGTTTTTAAGGAACIGTGTTTTTCTTTTCCTAGAAGAGGGGCCCCTTTC TAGCTATACATCTCCACCAAAGACTTGCCTTTCCCTTGCCAGATCTAAGGACACAGGCCTGGGGTCTGCCACAAACTGCAAAGTACCATGTCTCCCAGAGCATGTTCCAGAA CCCCRGTCCACAGATGCTCTGCAAAGAAGGTTTCCAGGGCACTGGGTTTAGCTGCATGCTACGCTTCTATACAAGAGCACACCAGAGTCTCCACACCACTGCTAAAGTAAAA
AGCGATTTGTGGGTAGTGTCTCATGGTACAGTGGAAACAGCTCAGTCACAGGGTGTGAATTTGAGTCCTGGCTCTGCTTTGTGACTGGGCTTGAGAACTCTGGGCTGACCTA TAAAAACCTGACATTGGGGGTTGAATTAAACCAGTGGGTTTGTCCCCATGAGAAGTCATGGCTAAACTATGCATAGAAAACGACTGGAAAGAAACATTAACAGTGACTATCT TTGCACAGTGAAAAAAAAAAAAAAAA
259
MIOjGCVLMAWALYLSIi3VLVWAQ LIjAASFETLQCEGPVCTEESSCHTEDDLTDAREAGFQVKAYTFSEPFHLIVSYD LILQGPAKPVFEGDLLVLRCQA QDWP TQVTF YRDGSALGPPGPNREFSITWQKADSGHYHCSGIFQSPGPGIPETASWAITVQELFPAPILRAVPSAEPQAG8PMTLECQTKLPLQREAARLLFEFYKDGRIVQSRGLSSE FQIPTASEDHSG8YWCEAATEDNQVWKQSPQLEIRVQGASSSAAPPTLNPAPQKSAΔPGTAPEEAPGPLPPPPTPSSEDPGFSSPLGMPDPHLYHQMGLLLKHMQDVRVLLG HLLMELRELSGHQKPGTTKATAE
260
GGCACGAGGGATGCAAGGAGATGAGACAGTTAGATTTACTTCCTCTTTTCTAATCTGAGAGGTTTCATGTTGAAGAAAATCAGTGTTGGGGTTGCAGGAGACCTAAACACAG TCACCATGAAGCTGGGCTGTGTCCTCATGGCCTGGGCCCTCTACCTTTCCCTTGGTGTGCTCTGGGTGGCCCAGATGCTACTGGCTGCCAGTTTTGAGACGCTGCAGTGTGA GGGACCTGTCTGCACTGAGGAGAGCAGCTGCCACACGGAGGATGACTTGACTGATGCAAGGGAAGCTGGCTTCCAGGTCAAGGCCTACACTTTCAGTGAACCCTTCCACCTG AΓΓGΓGTCCTATGACTGGCTGATCCTCCAAGGTCCAGCCAAGCCAGTTTTTGAAGGGGACCTGCTGGTTCTGCGCTGCCAGGCCTGGCAAGACTGGCCACTGACTCAGGTGA CCTTCΓACCGAGATGGCTCAGCTCTGGGTCCCCCCGGGCCTAACAGGGAATTCTCCATCACCGTGGTACAAAAGGCAGACAGCGGGCACTACCACTGCAGTGGCATCTTCCA GAGCCCTGGTCCTGGGATCCCAGAAACAGCATCTGTTGTGGCTATCACAGTCCAAGAACTGTTTCCAGCGCCAATTCTCAGAGCTGTACCCTCAGCTGAACCCCAAGCAGGA AGCCCCATGACCCTGAGTTGTCAGACAAAGTTGCCCCTGCAGAGGTCAGCTGCCCGCCTCCTCTTCTCCTTCTACAAGGATGGAAGGATAGTGCAAAGCAGGGGGCTCTCCT CAGAATTCCAGATCCCCACAGCTTCAGAAGATCACTCCGGGTCATACTGGTGTGAGGCAGCCACTGAGGACAACCAAGTTTGGAAACAGAGCCCCCAGCTAGAGATCAGAGT GCAGGGTGCTTCCAGCTCTGCTGCACCTCCCACATTGAATCCAGCTCCTCAGAAATCAGCTGCTCCAGGAACTGCTCCTGAGGAGGCCCCTGGGCCTCTGCCTCCGCCGCCA ACCCCATCTTCTGAGGATCCAGGCTTTTCTTCTCCTCTGGGGATGCCAGATCCTCATCTGTATCACCAGATGGGCCTTCTTCTCAAACACATGCAGGATGTGAGAGTCCTCC TCGGΓCACCTGCTCATGGAGTTGAGGGAATTATCTGGCCACCAGAAGCCTGGGACCACAAAGGCTACTGCTGAATAGAAGTAAACAGTTCATCCATGATCTCACTTAACCAC CCCAATAAATCTGATTCTTTATTTTCTCT'ICCTGTCCTGCACATATGCATAAGTACTTTTACAAGTTGTCCCAGTGTTTTGTTAGAATAATGTAG'ITAGGTGAGTGTAAATA AATTTATATAAAGTGAGAATTAGAGTTTAGCTATAATTGTGTATTCTCTCTTAACACAACAGAATTCTGCTGTCTAGATCAGGAATTTCTATCTGTTATATCGACCAGAATG TTGTGATTTAAAGAGAACTAATGGAAGTGGATTGAATACAGCAGTCTCAACTGGGGGCAATTTTGCCCCCCAGAGGACATTGGGCAATGTTTGGAGACATTTTGGTCATTAT ACRTGGGGGGTTGGGGGATGGTGGGATGTGTGTGCTACTGGCATCCAGTAAATAGAAGCCAGGGGTGCCGCIAAACATCCTATAATGCACAGGGCAGTACCCCACAACGAAA AATAATCTGGCCCAAAAΓGTCAGTTGTACTGAGTTTGAGAAACCCCAGCCTAATGAAACCCTAGGTGTTGGGCTCTGGAATGGGACTTTGTCCCTTCTAATTATTATCTCTT TCCAGCCTCATTCAGCTATTCTTACTGACATACCAGTCTTTAGCTGG GCTATGGTCTGTTCTTTAGTTCTAGTTTGTATCCCCTCAAAAGCCATTATGTTGAAATCCTAAT CCCCAAGGTGATGGCAΓTAAGAAGTGGGCCTTTGGGAAGTGATTAGATCAGGAGTGCAGAGCCCTCATGATTAGGATTAGTGCCCTTATTTAAAAAGGCCCCAGAGAGCTAA CTCACCCTTCCACCATATGAGGACGTGGCAAGAAGATGACATGTATGAGAACCAAAAAACAGCTGTCGCCAAACACCGACTCTGTCGTTGCCTTGATCTTGAACTTCCAGCC TCCAGAACTATGAGAAATAAAATTCTGTTGTTTGTAAAAAAAAAAAAAAAAAA
261
MGTPASVVSEPPPWQAPIEARGRKQASANIFQDAELI^IQGLFQRSGDQIiAEERAQII ECAGDHRVAEALKRLRRKRPPRQKP GHSLHHCεRLRILEPHSAIANPQSATE TASSEQYLHSRKKSARIRRNWRKSGPTSYLHQIRH
262
TTCCGGGQCTAGGGAGCGCTTTCTCCCGGGAACCGCGGCTGTGACCCAAGTGGCCCGGACCAGTTTGGGGCTGCGTGCGGCCTGCCTCAAGCAACCAGGTACGTAGGTCGGC GGCCCAGCTCGGCGCΓGCGGTGGGAGCCGGAGGGCGACAGTCAGAGCCGGGGTGCCAGCGGGACGCGACCGCCAGATCCACTTAGGACCCCGTCG'ITCTGCGAAGCGGCCAC GTCRGAGTCCCGGGGCCRCCTCGTGCTGCAGATGTCGCCTTAGGACCTCGGCCAGGATACCCTCTGCCATGCTCTTGTGCTGCCCGTGATCACCGACTGGCCCTTGTAAGCA CCTTCGCAGCAGGAAGCCCAGAGCTGCGCCTGCCCTTTCTGAAGGCTGTGGAAGAGGTTGGAGTGGGCGCATCTTAGCTTGCCCCATCCCCATTTGAGGTCTGTCGGAGCTG CCCTTCAGTGTGAGCATCCACAATGGGTACCCCAGCCTCGGTGGTCAGTGAGCCACCCCCTTGGCAGGCCCCGATTGAGGCCCGGGGCCGCAAGCAGGCCTCGGCCAACATC TTCCAGGACGCCGAGCTGCTGCAGATCCAAGGCCTGTTTCAACGCAGCGGGGACCAGCTGGCCGAGGAACGGGCACAGATCATCTGGGAATGTGCAGGGGACCACCGTGTGG CTGAGGCCCTCAAGAGGCTGCGCAGGAAGAGGCCCCCAAGGCAGAAACCCCTGGGCCACTCGCTACACCACTGCAGCCGCCTCAGAATCCIGGAGCCCCACTCTGCACTGGC CAACCCACAGAGTGCCACAGAGACAGCCTCCAGTGAGCAGTATCTGCACTCTAGGAAGAAAAGTGCCAGGATCCGCCGGAACTGGAGGAAGTCAGGCCCCACAAGCTACCTC CACCAGATCAGACACΓGATCCAGGGAAAGAGCCAGGAATGGCAGTGTCTTCCCTCTTGCCAAAAGGCCTGGGGAGGTGAAGGAAGAGAGACTTTAGGCAAGCAGCCCAAAGG GGTAAATGAAAGCAAGAGGCTGCTGCCACTGACCTGCTCCATTCAGAACAAGACTGGATGCTTCTGTTGAGCTCTCCATTATGTGGGACCCATTCCTCACCAAAATGAGGAG AGACAGTGACTGTTCCTGCCACAGTCCTTCCCAGTCTAACACTATTCCTGGGCTGCATGATATTCCCCTGGGAGCAAAGTGACAGGCACTTAGATGCAGCATTTCACCACTC ATGCTACTAATCATCΓACCTGCTACTACTGTAAACCATGGTTCCAGCAGCCTGTTCCACACCCCCACACCATCAGGATAGCACAGGGAAACTGTAGTTTAAGTGGCAAATAA AAACATTTGCATCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
263
MGAAVFFGCTFVAFGPAFALF ITVAGDPLRVIILVAGAFF LVSLLLASVVWFI VHVTDRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGI-AEL8EDGRSPI SIRQl^YVSGLSFGIISGVFεVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFDACERRRYWALG VVGSHL TSGLTFLNPWYEASLLPIYAVTVSM GLHAFITAGGSLRSIQRSSCVRTDYLD
264
GGGGGGTTTCCGCGGΓGGCCATGACTGCGGCCGTGTTCTTCGGCTGCGCCTTCATTGCCTTCGGGCCTGCGCTCGCCCTTTATGTCTTCACCATCGCCACCGAGCCGTTGCG TATCATCTTCCTCATCGCCGGAGCTTTCTTCTGGTTGGTGΓCTCTACTGATTTCGTCCCTTGTTTGGTTCATGGCAAGAGTCATTATTGACAACAAAGATGGACCAACACAG AAATATCTGCTGATCΓTΓGGAGCGTTTGTCTCTGTCTATAΓCCGAGAAATGTTCCGATTTGCATATTATAAACTCTTAAAAAAAGCCAGTGAAGGTTTGAAGAGTATAAACC CAGGTGAGACAGCACCCΓCTATGCGACTGCTGGCCTATGTΓTCTGGCTTGGGCTTTGGAATCATGAGTGGAGTATTTTCCTTTGTGAATACCCTATCTGACTCCTTGGGGCC AGGCACAGTGGGCATΓCATGGAGATTCTCCTCAATTCTTCCTTTATTCAGCTTTCATGACGCTGGTCATTATCTTGCTGCATGTATTCTGGGGCATTGTATTTTTTGATGGC TGTGAGAAGAAAAAGΓGGGGCATCCTCCTTATCGTTCTCCΓGACCCACCTGCTGGTGTCAGCCCAGACCTTCATAAGTTCTTATTATGGAATAAACCTGGCGTCAGCATTTA TAATCCTGGTGCTCAΓGGGCACCTGGGCATTCTTAGCTGCGGGAGGCAGCTGCCGAAGCCTGAAACTCTGCCTGCTCTGCCAAGACAAGAACTTTCTTCTTTACAACCAGCG CTCCAGATAACCTCAGGGAACCAGCACTTCCCAAACCGCAGACTACATCTTTAGAGGAAGCACAACTGTGCCTTTTTCTGAAAATCCCTTTTTCTGGTGGAAAAAAAAAAAA AAAAAAAAC
265
MLQNVNCFKLKLPLKRPRYIYLIVYIMFNICQSILQVCSFISIKYGYYVAQLLKWYCIVYICTPNNIVCTFCFLYCICAGFFRLYQCN CLLRYVQKMSI
266
ΓΓTAAGACATGAATTACATTTAAAATTAGAATATGGTTAAΓATTAAATAATAGGCCTTTTTCTAGGAAGGCGAAGGTAGTTAATAATTTGAATAGATAACAGATGTGCAAGA AAGTCACATTTGTTARGRATGTAGGAGTAAACGTTCGGTGGATCCCCTGTCTTTGTAACTGAGGTTAGAGCTAGTGTGGTTTTGAGGTCTCACTACACTTTGAGGAAGGCAG CRTTTAATTCAGTGTRTCCTTATGTGTGCGTACATTGCAACTGCTTACATGTAATTTATGTAATGCATTCAGTGCACCCTTGTTACTTGGGAGAGGTGGTAGCTAAAGAACA GTTGAGTATAGGTTTΓTCTCCATTTACAGATGTCTTTGGΓCAAATATTGAAAGCAAACTTGTCATGGTCTTCTTACATTAAGTTGAAACTAGCTTATAATAACTGGTTTTTA CTTCCAATGCTATGAAGΓCTCTGCAGGGCTTTTACAGTTΓTCGAAGTCCTTTTATCACTGTGATCTTATTCTGAGGGGAGAAAAAACTATCATAGCTCTGAGGCAAGACTTC GACTTTATAGTGCTATCAGTTCCCCGATACAGGGTCAGAGTAACCCATACAGTATTTTGGTCAGGAAGAGAAAGTGGCCATTTACACTGAATGAGTTGCATTCTGATAATGT CTTATCTCTTATACGΓAGAATAAATTTGAAAGACTATTTGATCTTAAAACCAAAGTAATTTTAGAATGAGTGACATATTACATAGGAATTTAGTGTCAATTTCATGTGTTTA AAAACATCATGGGAAAAAΓGCTTAGAGGTTACTATTTTGACTACAAAGTTGAGTTTTTTTCTGTAGTTACCATAAT TCATTGAAGCAAATGAATGAGTTTGAGAGGTTTGT TTTTATAGTTGTGTTGRARTACTTGTTTAATAATAATCTCTAATTCTGTGATCAGGTACTTTTTTTGTGGGGGTTTTTTTTTTGTTTTTGTTTTTTGTTGTTGTTTTTTTTG GGCCATTTCTAAGCCTACCAGATCTGCTTTATGAAATCCAGGGGACCAATGCATTTTATCACTAAAACTATTTTTATATAATTTTAAGAATATACCAAAAGTTGTCTGATTT AAAGTTGTAATACATGATRTCTCACTTTCATGTAAGGTTATCCACTTTTGCTGAAGATATTTTTTATTGAATCAAAGATTGAGTTACAATTATACTTTTCTTACCTAAGTGG
AAACCACAATTGGCTGATATTGAAAATGAAAGAAACTTAAAAGGTGGGATGGATCATGATTACTGTCGATAACTGCAGATAAATTTGATTAGAGTAATAATTTTGTCATTTA AAAACACAGTTGTTTATACTGCCCATCCTAGGATGCTCACCTTCCAAGATTCAACGTGGCTAAAACATCTTCTGGTAAATTGTGCGTCCATATTCATTTTGTCAGTAGCCAG GAGAAATGGGGATGGGGGAAATACGACTTAGTGAGGCATAGACATCCCTGGTCCATCCTTTCTGTCTCCAGCTGTTTCTTGGAACCTGCTCTCCTGCTTGCTGGTCCCTGAC GCAGAGACCATTGCCTCCCCCACAGCCGTTTGACTGAAGGCTGCTCTGGAGACCTAGAGTAAAACGGCTGATGGAAGTTGTGGGACCCACTTCCATTTCCTTCAGTCATTAG AGGTGGAAGGGAGGGGTCΓCCAAGTTTGGAGATTGAGCAGATGAGGCTTGGGATGCCCCTGCTTTGACTTCAGCCATGGATGAGGAGTGGGATGGCAGCAAGGTGGCTCCTG TGGCAGTGGAGTTGΓGCCAGAAACAGTGGCCAGTTGTAΓCGCCTATAAGACAGGGTAAGGTCTGAAGAGCTGAGCCTGTAATTCTGCTGTAATAATGATAGTGCTCAAGAAG TGCCTTGAGTTGGTGTACAGTGCCATGGCCATCAAGAARCCCAGATTTCAGGTTTTATTACAAAATGTAAGTGGTCACTTGGCGATTTTGTAGTACATACATGAGTTACCTT TTTTCTCTATGTCTGAGAACTGTCAGATTAAAACAAGAΓGGCAAAGAGATCGTTAGAGTGCACAACAAAATCACTATCCCATTAGACACATCATCAAAAGCTTATTTTTATT CTTGCACTGGAAGAATCGTAAGTCAACTGTTTCTTGACCATGGCAGTGTTCTGGCTCCAAARGGTAGTGATTCCAAATAATGGTTCTGTTAACACTTTGGCAGAAAATGCCA GCTCAGATATTTTGAGATACTAAGGATTATCTTTGGACATGΓACΓGCAGCTTCTTGTCTCTGΓTTTGGATTACTGGAATACCCATGGGCCCTCTCAAGAGTGCTGGACTTCT AGGACATTAAGATGAΓTGTCAGTACATTAAACTTTTCAATCCCAΓTATGCAATCTTGTTTGΓAAATGTAAACTTCTAAAAATATGGTTAATAACATTCAACCTGTTTATTAC AACTTAAAAGGAACΓΓCAGΓGAAΓTTGTTTTTATTTTTΓAACAAGATTTGTGAACTGAATAΓCATGAACCATGTTTTGATACCCCTTTTTCACGTTGTGCCAACGGAATAGG GTGTTTGATATTTCΓΓCATATGTΓAAGGAGATGCTTCAAAAΓGTCAATTGCTTTAAACTTAAATTACCTCTCAAGAGACCAAGGTACATTTACCTCATTGTGTATATAATGT TTAATATTTGTCAGAGCATTCΓCCAGGTTTGCAGTTTTATΓΓCTATAAAGTATGGGTATTAΓGTTGCTCAGTTACTCAAATGGTACTGTATTGTTTATATTTGTACCCCAAA TAACATCGTCTGTACΓTΓCTGTΓTTCTGTATTGTATTTGTGCAGGATTCTTTAGGCTΓΓAΓCAGTGTAATCTCTGCCTTTTAAGATATGTACAGAAAATGTCCATATAAATT TCCATTGAAGTCGWIRGATACTGAGAAGCCTGTAAAGAGGAGAAAAAAACATAAGCTGRGRRRCCCCATAAGTTTTTTTAAATTGTATATTGTATTTGCAGTAATATTCCAA AAGAATGTAAATAGGAAATAGAAGAGTGATGCTTATGTTAAGTCCTAACACTACAGTAGAAGAATGGAAGCAGTGCAAATAAATTACATTTTTCCC
267
M E LSYRPSGHPAVSIHV IFVGLFLAGHTRFCPAQGL.WR PAWACMHAGRATQHSCEGRSQP SVPQGRHSSQEETGKGPMEDIALPIPLVEVNFGDRKITAF
263
AAATGCTTTTGCTTRGTGRTCAGCCAAGATTTGCAGCCTRRTTTCAGAGGTTTTAAAARRRTCAGAAAAAACATTTCTAATGTGTCTAATGTGTCAGTGGTAACACTGACTT AATGGTAAATGGTAAATGATTTAAGTTTCCTTGTCAGAGΓCAGTATTATTTGAAGGAGΓΓAGGAAGGCAGTCTGAGGCTGTGATGAGTCTCCTTACCTCCCAAATGATCAAG ATGGCAACCCCAGCRCGCAAGCCATTCAAGGCGGGCARAACGTACCATGGGTTTTCTCCCTTTGATCCACATACCCTTCTCCCGGGAGCTGGAAGAACTGTGAGGAGAAAGG GAGCTCTTGAAGTTGAAGCATCAGTGAGGAGAAAAACCAΓΓCACCCCTTCCCCCCACTAΓGGCTGAGGACTGGCTTCTGAGACAGTTTAGGAAACTGACAAAGCCATGAAGG AATGGCTCAGCTATCGACCATCTGGACATCCAGCAGTATCRATCCATGTCCTTATCTTRGRGGGGCTCTTTCTAGCTGGACACACTAGATTCTGCCCGGCCCAAGGCCTCTG GAGAAATCCAGCTTGGGCARGCATGCATGCAGGGAGAGCCACACAGCACAGCTGTGAGGGCAGGAGCCAGCCCTGGAGTGTGCCCCAGGGAAGACACAGCTCTCAGGAGGAG ACTGGAAAGGGTCCRATGGAAGACATTGCCCTTCCCATRCCCCTCGTTGAAGTGAACTTRGGGGACAGGAAAATAACTGCATTTTAGGTGGTCAGCCAGGCTTCCTTCCTTA TCTGTTATGAGAAAAΓGAGAGACACCAAAATCTGACAGTΓACAGGCTAGATTTAACATACTACTCAGGCACTATCTTTAACAGCCACTTTCATTAACTAAAATTGGGTTTCT AATCATATTTTTTTAAAAGAACCAAGAAGGAATGTACTATTTCCTGTAGCCAAGTAGGTCAGGTCAGGCAGTCTGCATGTCCATCCAGACACTCCTTCCCTGTCATCATCGA CAGACCGCCTCCTGCCCTGCCCTAAATGGTGGGGGCCAGCCTCCCATCCAGGCGAGGACAGCTTGGCTCTGAGCCACCTCAGATACAAGCCAGGCCCAGGGCTCAATTTCTG
AGCTCTGGCATTTCCATTAACAATGCCTTAAAGGAAAGCAAGCAGGGGCAGTCATTTTATGAGTTATATCTAAGGATGT'ITGATGTTCAGTTCTAACTCTACATGCCCAGGG GAACCCCAGCACTGGCTTAGGCACTGTGCAGCACTCAGGGTTAGGGGGCCACACCCACTCCTGCCTTCAAAGAGATTATACTCTGATGAGCATATACCATGAGTAAAGAACA AGGGTTTCCACGGACATCCTCACCACAGGGAAGACTCGGGTACTGCTTGTATCAGAAGCTGGCCCAGCAGAGCCAGTGAGGTTAGGATTATCGGATCCCAGTGCTGGAAGGG ATCTTGAAGGTCCCTTGGCTACGACCCTTTCTGCCAACTGTGCAGCCACGCGGGGACCCCCTTCTGCTCTATAACTGGCAGTGCCCTATGATTACTT'TCCTCAGTGGCTAAC
AGTCTTCATAGCTGCTTΓAAATTCCTCATGCTGTGGTTTAAAACTTAGTTTTCCATCTTTCCTAACGACGGTACAAAGAAGCAGTCACCTTATTCAAATTCTGAAACCATTA ATGATCCTTATTCCTCCCAGAAAATCAGACTAATTTTGGGAATTTTTACAGTCCCCAGAAATCTGATTTCCTAACCCACAAGGACCACTTCTCTGCCATGTACTTCAGATGG ACACACACCCCTCTGGCRGATAAACCCCACTGGATCTGACCCTGGCTGGTGGGAGGGGACCCTGGGGCCTCCTAGGACTGGACCTCTGTCTTGGCTCTATCTCGCTTATTCA TΓΓGTGACTGGACAGTGGGAGCCTGTCCAGACACATGTGTACCTGGTCCATTTGCACGCTATGCTCATGGGCTTTCTTCTGTATAGTGGAGCTACTGTCTTCGTTCATGATC ARCTCACTGTCAGCTTCRGCCCACTGGCCCACCTGCCAAGCTGATTACCCATTTGTCCTTCCAAAGTACTTGAATTAATTTGTCTTCTCCCCTTCCCATTCTCTTCCCCRGA TGCACACATCCΑ^GCACACACTTTCTAGTCAAGATTCTTTAAAAATACATATTTGTACACATTTTACAGCAAAAAAACTTTTGTGGCTCAGCTGCATACCCTGAGGACTTC TGCTGAGCCCCAGTGCARAGCAGAGCATAGTTGGAAAATCACAGCTCTAGCCTCATCCACAGATGTGAAGAGTGAAACAGCACTTGGTTGGCAGGAAATCCTCAATGCTGAG TAGTAGTGGCTCCCTGAGGTACTGTAGTCTGCACTTCCAAGAGTGGGGATGCCTCTGGTCAGAAGGGAAGGTAGTGAGTCCAAAGGAAGCTGAGAATTCTCCATGAGCTTGA GΓΓCTGTTCGCAACTGCΓCCCTTCCTTCAGCAAATCCAAGTTTCCCCCAGAGAATCCCATTCCCCTAGACAGAGCAGGTGGTTCTCCCGCGAAGAGAGTCAGATACAGGCCA CΓGAGGGGGTCTTCCTGGCTAGCTGAAGCAGAGCCCGCCAAAATAGCTTCTTTTCCAATGAAACATTTCTGAATATAACACCAGAAGCATCTATACAATTGGAAAAAATTGC GTGAATTTTAAGGATTGAACATGTATTGTTTTAAACATAGGAATTTATAGGTGCCTTAAAAGCATACACATCCACATTACACTGAGTAGATCGAGTCTTTTTCTCCTTTGCC TGCCTRCCTCACCAACCRCCTGCCTCTTCACACTGTGTGGGGTGTGTTTTGGTGGTGTGTGGTGGGGAGTATTGGCTTAATTTGAGTTTTTGTAAATAGCATTTGCTTGGAG CCAAATGCAGAACTAAARAATAGAGTAAAATCCTTTGCCTTGTTCTAAATCCTGAGAGTTCACTTGCCTTACCCTAAGGCCCCCGACTCTGTGCCCACCCACACCCCTACTC CCCAGTGGCAGCAGTCAGGCCCCAGCCCCCATGCCGTCTCTTTTCTGTGCCTCTGTCCTGGTGCCAGGGCTCTGAGCTGCTGAGAGCTTCGCTTTGTGAGATCACCCCCATG GCTTCCTTCAGCTTCAAGGGTGTGGGTGGCCTCTAAATCACTCTATAGTGCGAGGAGCAATAACCCAGAAAGTCCATATGAATAATACTTGGTCCTCTTCTCTGAGTCTTTA ACCAAAAATGAAGTCCACTGCCCTGGCCAGAATTCTTCCTTGGCTGTTTGACAAAACTTAATTCCACAACTGTTTCCTCCCAGAGGATGACTCTTAGTGTAAGCACATCCCT CTTTGAGAATCTGACTGΓTTCTGGGAATCAAAAATGTGGGTTTATATTTCCGATACTTCTGGAGTGCCAGGTTGTTTGGTTTTGTTTTCAACAAAATGTTTGGCCCTAGAAA ΓGCAGCAACTTGCTCTGΓTGCCAGGAGCTTCCCTGCCAAGTGTCTTGTGCACAGCCCTCTCCTGGGTGAGCTCCTGGACAAAGCCTCATGCCCTGGTAAACCCTGCAGACTG CAGCCACTATTCTGGCCΓAGGTCATAGTCTTGAGCACCAGCTCTGCTAGGGCTACTCAGGCATTGCACTTGTCTGCAGGTGCTAGGAATTTATGTTACTGAAGAGTGAGCAA ΓGTCATTGTGAGAGCATGTGCAAGAGCAAGCTTTCCTGCAATACCTAAAGAAAAGCAAGGGGAATAGTAGGACCTGGGACAGCAGTCCTAGGCCCATTAATTCCCCTTGCCC CTCTGACAGAATTTCGAACTCAGTATTCTTCGAATACTCAGATGCCAGGGTTGCCATTGTAACAGAATAACAGTGGCTGGGGGACACCCATTCAGTGGCTCTTCAGAAAGAA CAAATTCACTGGGTGGATATAACACTTAAGGAAAATGCTCAATAAGCCACCCATTGAGTCTCAGAGCAACCTGACCAACAAGGTGAAAACCATTTAAAAGACACATTGTCTT GCTGGAGAACCTTCCTCCCCTGGGTTTCACCATGGAACTTCAGCATTACATGACTAATGGGCACGTAAATTAAATGTTACTAAGCAAGAGACTATTCTCACTTCTTGCCACC CTGAGCAGGGCAGGGAAGCCAGCCAGCAGTCACAGTGATGGGGACAGCCTTAAAGGCCCATAGTCACTTGGAAGACAATGGCAGTGCCCTTAGGGGTTTGCCCAAGCCAGGT AGGATGTTΔGCAGCAGCCTAGTGCTCAAGGATGAGGACAGTCACATCCACCAGCCCCCAACCCTCAGCAATGAGTACTCATTCTAGGTCCTGATAGCTGCCTTACTTTGGCC
CCCAGATCACAAGTCCCTTTAAAGGAAAGCTGATCTCCTCGTCCACTGTGGCTTGTGCTTCCTTTTGTCCCAGGTGCCACCCACGGGCTCTGAACA'ITCATCCTAGTTTGCT
TGCTCCCGCATCCCGAGCAGCATTTGAGTCTTATGTTTGAAATGGGTTCATTTGAGCCAGCAACTCCCTGCTTCCCTTTTGTGCCTCGTGCACTTGGAGTGTCCACTGTCCT TTACCTGTATCCCAAGGCTCCTTCTCTGAGACTTCCCAGCTCTCCTGTTATTTCCCACCTCATGCTTTTCTTTGCAGCTGAACCTTATTCACAGTGAAATCAGTAATTTAGC CGGCTTTGAGGTGGAGGCCATAATCAATCCTACCAATGCTGACATTGACCTTAAAGATGACCTAGGTAATTGGGGACGGGGTTCGGCACCACCAGCTGTCAGATGAAAAGTT TGGAACCCAGAATTTAGGCATTTCATCTTCCCAGACTTTACAGTGGTCAAGCCAAATTTCCAAATCCAAGATTGATATTTGAGTGTAGACGCTGAATATCAACTTACTCCA GGCCATTCCAAGTGTAAACGGTCTGTTTCATTAAGTGTGATTGGCTACTCTCTCCTCAATTGCAAATACATTGCCATCTGAATTCTCTTCCATAATGATCAAACTGACTGCT
CTTAATTAGAAATGACAAAGCTTGAAAGAGAAGACAGGCCACATCAGTATGCTATTAAGCTGTCTTTAGTCCACAATTTACTACCATCACTTCAACTTTTCTTTAGAACTGA AAACAGTATATGACTGAATGCCACCTTCTTGAATTATTTGGCTAGAGGATGGTATTAAACAGAΔGGGCAATATCTCCAAGTGAGTTCTTATGGAGGAAAACTGCCCCAGAGC CATGGTGTCTCCCTGTΓCAAGATGGCAGATGGTTCAGGGCAGACTGAGAGGTGCCCCTCAAGTGTCCTGCCTCTATGGCTTTATCTTTGCATATGTGGCACTGTCAGCTCAA TGGCACGACAGGGCTGCΓCTGCTGCTCTTCGATGTAGAGGCTTGCCAGGGGAAATAGGCACACAGATGCAGCCTCCTTCCTAACCCTCAACTGCAATCTATTTTGTATCCCT TGAGCTCTCAGCTTCTGCTGTTTTTGTCAGATAGCAGACTTCCTTACTGGGAGATACACTCATTCCATGGGCCCAGGCCTGACCCACACGAACTGGGTGCAACAGTGGGCTG AAAACATGAGGACTGGACTCAAGAGTGTCCAGCTTGAACTTGTTTTCCAACTGCCTTATACAGATACTTAAAAAAAAAAAGGCCACAAGCTAGAAAAAGCAATGATTCTATC CAAAGCACATTTTATACΓAAAATACAAAGGCCAGGTGCAGTGGCTCACACCTGTAACTCCAGCGTTTTGGGAGGCTGAGGCAGGAGGATTGAGTGAGGCCAGGAGTTGGAGA CCAACCTGGGCAAGATAGTGAGACCTCATCTCTACAAAAAATAAAAAACTTAGCTGGGCTTGGTGACACGTGCCTGTAGTCTCAGCTACTCAGGAGGCTGAGGCAGGAGGAT TGCTTGAGCCCAGGAGTTCGAAGCTGCAGTGAGCTATGATTGTGCCACTGCACTCCAGCCTAGGCAACAGCAAGATCCTATCTGT
270
GTTGTTGGGGCCGTCGAGGCGGCGGCGACTCTGCGTCCCCGGCTCCTGATGGAGGCGGGGCCGCATCCCCGGCCGGGGCACTGCTGCAAGCCTGGGGGGCGGCTGGACATAA CCACGGCTTCGTGCACCATATCCGACGGAACCAGATCGCTCGGTACCGCCCCGCCCTGCGCCGCCGCCGCCACCACTCCTGGCCTGGCCTGGCCCGGCCCGACAGTCCCTG ACTCCCGCTCGGCTCCCCGCAGGGACGACTATGACΔΔGΔΔGGTGAAGCAGGCGGCCAAGGAGAΔGGTGAGGAGGCGGCACACGCCCGCGCCGACGCGGCCCCGCAAGCCAGA CTGCAGGTGTACCTGCCGCGACACCGAGGTGAGGCCGCCCGCCCCGCCTGCCTCCAGCCCGCGCGCTCTTCCTGCAACGCACTCCCCTTCTCTATAGGGAAAAACCACTTC TTACTCCTAAGGTTCAGCTCATCTCGTCTCTTTCCGGAACCTCCACCTCAGCGCTCCCAAATCTCCGCTGAATGATTCTCACCAAGAACTGGGACGACTCATAAGCCCCCAG ΓTAAGCATCGCTGTCAGAGTATCGGGGAGCCAGCAAGAAGTTTATCTGCCGGTTTGCCCCACCGTGCTGTATTTTAGTAAGGTGCTCCGCTACCIAGCAAAGAGAAAGTCTG
GCACAGCGATGAGCGACCAGCACATAATTGCGGAATGAACCCAGTAAATGGCCTTTCCCCAGCTTCTCTGCTACCTAGAGATCACACTGGTTAA'IATATGACGGTCAATTTT
ΓGTTAAGCATTATTACΓΓTΓTTTAAAATGTTTTTATTTTATTTTTGAGACTAGGTCTCTGTCGCCCAGGCTGGAGTGCAGTGGTGCGATCTGGGCTTACTGCAGCCTTAGCC ΓCCCGAGTACCTGGGACCGCAGGCGTGTGCCACCACACCGGTTAATTTTGGTATTTCTTGTAGAGAAGGGGTTTCCCCGGCTGGGCGCGGTGGCTCTCGCCTGTAATCCCAG CACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAAATTAGCCGGGCGTGG RGGTGGGCGCCTGTAGRCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGTGAACCCGGGAGGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGG GCAACACAGCAAGACTCGGTCRCAAAAAAAAAAAAAAAAAAGAGAGAGAGAGAAGGGGTTTCTCCACGTTGTCCAGGCTGATCTCGAACTCCTGAGCTCAGGTGATCTGCCC GCATCGGCCTCCCAAAGRΣCRGGGATTATAGGTGTGTGCCACTACCTTTGTTAGGCATTAGTGAAAGTGCTTTTAGATCTTACGTATATTAATTCATTGAGTCTTTATACAA CCTCATAAGAAAGCTΓCΓGTCΓGTTTCACAGTCAGGAAACAGGCACAGAGAGGTTAAACAACTTGCCCAAGATCTCAGCTAGTAAATGGCAGAGCCTGGATTTGAACCCAGG CAGAGCTCTATCCACCCΓTCΓGCΓTTCCAGTACTTTTTGCΓAGACAAATGTGCATTGTGTACCTACTGTGTGACAGGATTGTGCTGGCCTCAGAGCAGGGATGCAAAGGTAA ATAAGTCCTTGATTGGCAGCACACCAAATGCTTACACTGGRCCGGGCGCGGTGATTCATGCCTGTGATCCTAGCAGTTTGGGAGGCCGAGGTGGGCGGATCCCTTGAGGCCA GGAGTTCGAAATTAACCTGGACAACATGGTGAAACCCCATCRCTACTAAAAATACAAAAATTAGCCAGGCATGATGGCAGGCGGCTGTAATCCCAGCTACTTGGGAGGCTGA EGAAGGGGAATTGCTTGAACCTGGGAGGCAGAGGTTGCGGTGAGCCGAGATTTAGCCACTGCACTCCAGCCTGGGCAACAGAGCAAGACTCCGTCTC
272
TAGCGTCTAGGCTCTCAGCAGGGACACTGGTAATCAAGCRRGTGTTCCCAGTCAGAAATCCAAAGAAACTCTTTTTCATCAGGGTGTTCAACCTGGGAAGCAAGGAGTGGGT GCAGGATCCCTCTGTTTCRGTTTGAACAGTGGCACTCCCRCRGGCCTCTGGAATGGTAAATCTGCACCATTGCTAGCTTGGCTGTTTGCGTTTGGGGGCTGACTAGAATCCA CTGTCATACACTACTTGTRCAGTTCAATATTTCTTGTGCRTRAAACAACATTTAAACCTAGATGGTAGGGATAAGATGATTCCTGCACTTAAAGAGCCTGTGACGTTTAGGA AAOAAGGGAATGCAAGGCΓCACCATGGAGGGTAGAAGAAΓGTΓACAGATAAGGTTGTTTGGTGTTGTAACAAACACACAAGATGGAAAATCTATGTTGCTGCTATTAGCTAC TATTGATTGAACACCTTCΓTAGTTTCTATGTATATATAGATAΓATATATATAGΔGΔGAGAGAGACAGGGTCTCGCTATGTTGCCTAGACTGGTCTCAAACTCCTGACCTCGA GCAGACTTCCCACCΓCAGCATCCCAAAGTGTTGGGATTACAGGTGAGCCACCACGCCGAGCCCTATGCAGTCTCAAAAAAAAAA
274
GAAGGAACCTTCAGACAGCΓGGCΓCATAGCCAGCTTGGATTTGCAAAACAGTTCCAAGAAATTCAAGATTTTAATAGAAGGTGTACTAGGACAGGGAAACACAGCCAGCATC GCACTATTTGAAATCAAGARGACAACCGGCTACTGTATRGAATGTGACTTTGAAGAAAATCATCTCTGTGGCTTTGTGAACCGCTGGAATCCCAATGTGAACTGGTTTGTTG GAGGAGGAAGTATTCGGAARGTCCACTCCATTCTCCCACAGGATCACACCTTCAAGAGTGAACTGGGCCACTACATGTACGTGGACTCAGTTTATGTGAAGCACTTCCAGGA GGTGGCACAGCTCATCRCCCCGRTGACCACGGCCCCCARGGCTGGCTGCCTGTCATTTTATTACCAGATCCAGCAGGGGAATGACAATGTCTTTTCCCTTTACACTCGGGAT GTGGCTGGCCTTTACGAGGAAATCTGGAAAGCAGACAGGCCAGGAATGCTGCCTGGAACCTTGCGGAGGTCGAGTTCAATGCTCCTTACCCCATGGAGGTTATTTTTGAAGT TGCTTTCAATGGΓCCCAAGGGAGGTTATGTGCCCTGGAΓGATATTTCATTCTCTCCTGGTTCACTGCCCGAATCAGACCGAACTTCTGTTCACGTGCCGTGGAAGCCGTTGC AATTTGAGCCAGArCTCTGGCATTTTTCCCAGCATrAAGCAAGGGCCGGCTGGGCCCGGTGGAATTAAACCACTGTTrCGCGTGGGACCCCTTACGGTAGGGTTCCTTGCCC CAGGTGCTTCCCCCGGGTCTGGGGGCTGGCCCCCACGGAAGGTGGGGCCCA
276
GAATACCTTGGACCTTAGGGCTACTCTAGTTGTAARGTATRAGTGAGTTATCACTAGAGAAGTTCCACAGTTTAATARRATCTATACCTATATCTATATATCTACCTATATA GATAGATATATGTΓAGATGCTTCAACAACTAGGGTCTACACΓTAATATACTGACATCΓAAGGATGCGGCCAAGAAAAGCTGTAATTAGGCTGAATTTTATTGCCAAAGTTGT TCTTTTTTCATΓΓAGΓCCTTTAATAAAAGATGATCΓTCAΓAAATTACAGAAAGTTTGCΓΓACCCTGTTTGACCTTTTGCAGAAAAGAACAAGAGGGAAGACAGACCTTCAGG CTGGGATTACAGGTGRCAGCCACCGCACCCGGCCTCAAARACATTTTTTTAATGGCCTRGTCTTTCCTGGTTTTAGGCCCTTTTCCACAATTTCTGATGGAAATACAGAAAC CTTGCCATCATΓCTTACTGCTGGTTTGCATCTCATTΓAΓGGΓGTATCTGGGATTTCTΓCTCATGAACAGAAAGATTCAGTGGCTGTTATATGCCTTGTCAATTTAATGTATT GCCCTATCCTCΓΓTTΓGATCAAAGATAGAGACTAAGACΓGGGAATTATGACAGAAAAAGTCATATTTTTCTTTAAATGATTTTGAAATGTTAAΆATAGGCCAATATGAGTCA AAGTGCAAATTTΓTTGGTGAGTAGGTTQACAAAAAAAAAAAAAAAAAATCCAGGAAAAAAAGTGCAAATTTTTATAGGΓCCTAATTCTTTTGTTTGCCTAATGAAGTGTTCC CTCTATTTTATTGTTΓΓTATATGCTACAAAGTCCCAΓCΓΓCΓGCAGTTATGGAAACAGTGTGGCTGTATGTTTTAGTAAΓTATTTCATAATCTGTAGCACTTTTCACT TAA GTGCAATGAATAGTCCAGCACTTTGGGAGGCCAAGGΓAGGAGGATCGCTTGAGCCCAGGGATTCGGGACCGGCTTGGGΓAACATGGTAAAACCCCATCTCTACAAAAAACAG AAAAAATTACCTGGGCATGGTGΓGTGTGCCTTGTGGAΓCCAGCTACTTGGGAGGCΓGAAGΓGGGAGGATCGCCACTGCACTCCAGAAACTAAAAAAAAAAAAAAAAAAACCT TCAAAAATATATCTAAGCCAGATGTGATGGCATGGGRCRECAGTCCCAGCTACTCAGAGGGCTGGGGCAGGAAGATCGCRTGAGCCCAAGAGTTTGAGGCTGTAGTATGCTG TGCAGTGGCGCGATCΓCAGCTTACTGGAATCTCTGCAΓΓCCCAGTTCAAGTGATTCΓCCΓGCCTCGGCCTCCCTAGTAGΓGGGGATTGCAGGCGCCCGTCACCACATCTAGC TAATTTTTGTATTTTTAGTGGAGATGGGGTTTCACCAΓGTTGGCCAGTCTGGTGTCGAACΓCCTGAGCTCAGGTGATTCACTTGCCTTGGCCTCCCAAAGTCCTGGGATTAC AGGCGTGAGCCACCGΓGCCCAGGTGCCCCCACCTΓTTΓTTTTTTTTGAGGCAGAGΓCΓCACTCCATCGCCATTGCACTCCAGCCTGGACAACAAGAGCAAAACTCCATTTCA AAAAAAAAAAAAAAAATCTGTTAAAATTTGATATAΑRAGGCACRGACAAAAGAGGRCAAATGCAGGACTGATTTCTAAGCRTGCAATCTATCTAAATGCAGATGCTAATTTA GAGTGCATAATTATRACACAAGTACAGACCTAGGRRAGGGCTTAAATTTCATTATGRGCAATAAAAAGGTTAAGTGARGGRTAAGCAAGGTGTAGATTATCCTTACCTCTCC TAATGACATGGGCTCACATTGGCATTCCTTTCATACTTTTACGTATAAAGTGGGCAGΓΓGTTTCTGAATGACTGTTGCTGGAGCCTCAGGCCTGCTTTGTGCTTGGTGCTTT CCAGACTTTCTCCTTTATTCCTATCACCATATACGΓACTCACAAAAGAGCAGTGTAAACCAGGTATTACATTTCCACAAGGGAAAGTAGAACCAGGAATAGCCACACGATAC TTACCGAAAGCTTCACTTTCCCTATAGAGAAAGCAAGCAACATGAATCTTCTGATTTGGGGCCCAGCCTGCTGCTGΓAΓACAGAGGTTGGCATTATTGGTGATAGAAATGTC TGATAGGAGTCTTTTAATTATACTCTGGAGTGTGGAGGTGGAGTGCAAGGCTGCTTCCTTTATTACTGCAAGTGTTAΓΓTΓCTATTATCTCAGGTTTCGTTTTGTGTAATAA ACTGCTTCTTGTAAAAAAAAAAA
278
GGTAGCGCTAGTTCTCTTCAAGATTTGCTTAGTGΓCATTTCATTTCGGTTTCTTTTCΓCGCCATGTTTTTCTGTCGGAATΓACGGTTCGTTTTGGTTCTATGTACTCTCTAA AATGTTATCGTTTTΓCATTTGTCTACTAATTTTCGΓGCATTTGΓΓACTACTGAGTΓTCTTAATATCTGACTGGCCTCCGCCCACGGGCTCTGCAGAGCATAAATACTCAGGC TGATGGTAGTGCAGAGACTCTCCCTCCTTGATCAGCGCAAACGΓTGGTCTGAGGCΓTGAGGGATGGAGCAACATTTΓCΓTGGCTGTGTGAAGCGGGCTTGGGATTCCGCAGA GGTGGCGCCAGAGCCCCAGCCTCCACCTATTGTGAGTTCAGAAGATCGTGGGCCGTGGCCTCTTCCTTTGTATCCAGΓACΓAGGAGAGTACTCACTGGACAGCTGTGATTTG GGACTGCTTTCCAGCCCTTGCTGGCGGCTGCCCGGAGTCTACTGGCAAAACGGACTCTCTCCTGGAGTCCAGAGCACCΓTGGAACCAAGTACAGCGAAQCCCACTGAGTTCA GTTGGCCGGGGACACAGAAGCAGCAAGAGGCACCCGTAGAACGAGGTGGGGCAGGCAGAGGAACCCGACAGACTCAGGCTCCGGCAGCTTTCCCTGGAGCAGRCCTCTCCAT CCCTGGGACAGACAGCAGGACACCGAGGTCTGTGAACAAGCGGGTGCCCTTTTGGGAACGCCGCCAATCCTACTGCCCΓCCAGCCGTGGCGCCAACTACCGGGTTTCTCAAA CTGCCTTAGGAATGGAATTCCTCGCAATTAGGTTΓAGCGCGAGATCATCTTGTACΓCATGGGCCGTGTCTGGTCACCGAAΓCTGAΓCGGGAGCTAAGCAAGCCTTATGATTA GCACGCACCAAAGGCTTATAGGATATAGACCTCCCΓTGTACAAGATTCTCAGTTΓACCCAACGTTTCCCCCTATCAAΓCTCCACAΓTCCCTCTAGAATGTCΓΓCACATGGAC GGATGTACAAGTGTAAGATCT
280
AAGCTTGAGGGTGΓATGTGAAGTCACAGAGCCCAGΓAGCCAGGATGTAGACCCAGΓCTTCCCAAATTCAAACCTCTGCΓCCTACCTTCACACAACATCCACCΓCCATGGTGT CTTGACAGGGAACGGGAGACGTGTGTTGATTAGGΓCAATGTAGTAGGAGATTCAΓΓTTATTTCTGTTCAGAAGTTCAGAGAAAGΓCAGATTTGTTTTΓGAΓCAAATAATGAA AGAGAAAGGGTCTΓAAAGAAAAAGTTGGCTAGGTACAGGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCTGTGGCCAAGAGGATTGCTTGAGACCAACCTGAGCAACAT ATGGGAGACACCGCCTCTGCCAAAAATTANAAAACCTTGCTGGGCGTTGATGGCCAΓGCACCTGTTAGTCCCCAGCTACΓTΓN
282
ATTTTTTCACCTCAGCCTGAACTAACACTAGCTGACAGACGTTTTGATTTCTTTGACCATCACGGAATCGTNGCCAAGCGCGGTGGCTCACATCTGTAARCCCAACACTTTG GGAGGTCAAGATGGGCGGATTGCTTGGATCCAGGΓGTTTGAGATCAGCCTGGGCAACATGACAAAACCCTGTTTCTAGTAAAAATACAAAAATTAACCGGGCTCAAGCCATG ACCATGCACCATTGCACTCCAGCCTAGGCGACAGAGCAGGACCCTGTCTC
284
GTGGTGCTGCAAGΓCTGTAGTCCCAGCTAGTAGGGATGCTGAGGCGGGAAGATCGCΓTGAACACAGGAGGTGGAGGCTTCAGΓTAGCAGTGATGGTGCCACTGTACTCGTCC AGGNAACAGAGTGAGACTTTGTCCATAAAACCCAAAACCAAATGTTGTGTGCTGRRRGGRATTAACAGCAAGGAATCAGATAATTAAAGCAGAAGTACAGACAAAAAGAAAA TTTTATGGGAATTAGTTATTGGCTTATTTTGAGGGAAGAATGGATCAGANCAGCAAGGNCACGGGATAAAATCTAATACCCTGAAATGGGATCTTCCCACCAGGGAAACTCC GGAGGGATTTTCAAACCAATGGCCTAGGAGTCTTΓGΓTTTTCAGAGGTTAANGAAGGCCΔTCCACATTATTCCAGTΓGCCCCAACCCCGGANTCGG
286
GTGGTCATTTTGTTCAGTTATTTGAAACCAATTAAACTGTATTTATTTCAAGCTCAGTCCAAACTTGCCACACTCTΓGAAACACAGATGTCATTATAACTTCATTTAAAAGA GGGAAACACAACAAAΓGCCACCCTTCACCTGCCTCCTACCCCCACCTCTCTGCCAAΓCCΓGTGTCCTGCTTGTTAGΓGAAAGTTTCTATAAAAACATCCTGAAACATTTCCC CTGTGGTTAAGACATGATCCACCATCTTCTAATACCTGCAATCCTTCCATGGAAAΓGΓGATGCGTACACTGTGAAGGΓTGAGGCTTAAGTTAAATTGΓΓATAΓAAACAGAAA CAGAGATTCCTGATAAATGTACCTGATGAAACACRGTGGCRTCATCCTGGGAACAAGGGACAAGAAAAAATGGATRRGCAGCTGAGGCTGAAGAAGTGCTCRAAGCCCCAAG GCCTCCTGGTCTGTCCAGAAGTTGCCAGACAGGGCACTAAGGAATACTCTCTTCGΓAGGGT
288
TTNTTGNTTTTAGTAGAGACAGGGTTTTGCCATGΓTGNGACGGNTNTTCTGGAACACCNΓGTCCATCATGTGATCΓGCCCACCTΓGGNTNCCAAAGΓACΓGGGATTACAGGT NTGAGCATCGCACCTGGCCΓTATATGAGATTTCTΓΓATΓΓCAGTCTAAGTTTAAGΓΓAGΓTTAGTCTAACTTTAAΓTTTAAAAAΓΓAAAAAAAATAΓATCGATCΓGATTGNC CTGGATATGAGTACTGACTTGAATTAGAACTTTCTTGGCΓΓAAAGTACTCTTCAGTAΓCATGCAGAAGTCAAAACCTTGTΓΓAΓCACCAACTCAGAAGCCAAATATCCTTAT ATGAAAGTTAAGACAGGATTTAATTCTGATTAATRTATAGGACTTAATATGGGGGAAATRTTTACAGAAACAGCATACAANGCAAANTAACCCGAAAATAGANAAGTAAACC ATGATTAANTGTATTCCCAATATATTGCNGTCTGΓCACAΓAGAGGCTTTGANGGGANAAΓGTCTTATACNGGGCATAGG
290
EAGACTGCATAGGGCTCGGCGTGGTGGTGGGTGCRATGGRCCCCGCTACACAGGAGGCTGAGGCAGGGGAATCGCTTCAACCCEGGAGGCAGAGGTRACAGRGAGCCAAGAT CGCCCGACAGAGCAAGGCTCTATCTCAAAAAATAAAAAAATAAATAAATAAAAAGAACAAGGAGTATATAAAAGTATCΓGΓCACAGAAAATATCTTGAAΓGΓGATGGTGGAT ACATAAACCTACACAΓGTGGCACAACTGTACAGAACΓACATACACACACACGAGAACAAGCAGAACTGGGGAAATCTG
292
TGAGACGGAGΓCTCGCTCTGΓCGCCCAGGCCGGACΓGCGGACΓGGCAATGCTTTTTATTTTGAAAGGAGAAGCTAAATACTΓTCGGATATTTTTAAAGAAAGAGCTAAAAAT AACTACCATTTCTGCCTTTACAATGTGATCCCCAAAAGCCTRRCTAAACAAACAGTAGCTGGAAAATGCTGAAAARGAARAAATΒGAATCCCTGTCCRTAAAGACATCCCAG CCTGGCAGAAAGATGGATAAGTAAACAΔCAGTGGGGΓGCAGGAACTGATACTGACCATTGATGGGCACAAAGTATΓATGGGAACACAGACAGCAGGCACTAACCTGCTTTAG GAATGCCTGGGATGATTTACTAAGAGAACTGACGTGAAGGATGGCAACTTGGATCGGCCCAGAAGCCTTCCCTGGRACTCACCCAGGGCCTGATGTAGATGRCACTCGGTGG
TCCC
294
AGAGATATGTGTATTTATTTAAGGTATGTAAATTArGrCACATGACTCTGCAAGTACATTTCTGGGGTCCCTCCCAGGGCCCTGAGAAAGGGGTGAAGGTCAGGGTCCCTGA
CTCTCAAACCΓCACCAGCCTCACGGCCCTACATGGCΓGGCCTCCGGGACCTCGGCCCCΓGGTCTACTCCCTGACCCCTGCCΓGCACCTCTAAATGAGΓΓCGAAGGAGAGAGC TCCAGTTTCTGCAGGCCCCACCCAGGGCGTTCTCGCGCAGGCCTGCCACCCTGCCΓGCCTCCTTACTAGTTTGGTGCCTGCTGCTCTCATGGGCTCCCACATTCGGAAATAC CCAAGGTGGTGGGCATCGTCTCCACGTTCATCTGGACAGCCCACCTTCGGGGACAATAAGCCCAGCCCCAAGGATCGCTCTGCTCCCAGGGAGACAGCAGGACTGTCTGCAG GGAATGTA
296
TTΓAAGTCTTCAATATCATTTTATTACGATTCTCACCCCATATTTACAAGCCTAGTCCAAGGATTAAGATGGGGCCAAGGGTACCCTCCAGGAGCGCATCCTGAAACACACA TAACAATTTCGATCCTACTGAGGGGTGATAATGATAGCTAAAATGCACTGAGTGGTAGGATACAGTGGCTCACACCTG'RAATCTCAGCACTTTGGGAGGCCAAGGCNGGTAG ATCCCTTGAGTCCAGGAGTTCAAGACCAGCCTGACCAACATGGCAAAACCCCATCTCTACAAATAATATAAAAATTAAGGCTGAGCGCGCGGGCTCACACCTCTAATCCCAG CACTTTAGGAGGCTTAGGGGGGGGTGGATCATCTAAGGTCAGGAGTTCAAGACCAGCCTGGCCAACATGGCAAAACCTCGTCTCTACT
298
CTGCATAGGGCTCGGCGTGGTGGGTTCTGAAGCCGGCACCGCAGAGCCACCCGGTGAGGTTCCAGCCACCAGCGAGGAGGGCACTAGGTCACCGACACTGGGCTGGGGCTCG TCTAATCTTAGGTTGTGAGTCTCTTTGAGAAGGGTACAGAGGTGAACGCACTCCAGAGGGGAGGGAGGGAGACCCTGACCGCCAAGGTGACACACACCAGGGAGGGAAATGG ATGGTGCCTGTCAAGGTGACACACACCAGGGCGTGGAGGGGGGCTCTGCTGCTGACTGACGGTGACCTCAGACATGTGGCCCCGTAGACACCAGCCTCCTGGGTGTTGGGAC TGGCGCTAGACCTGGGAATCACTCAGCACCGGCCCGGCACACAGCAGATGCTCCGTGAACTCAGCCTCGCTCCCAGGGACACGCCCCCACACCACGGTGCTTGCTGAGCCTC GTGC
300
RGGGCGTGNGTGATGTGCGCCTGTAGGCCAGCTACTTGGGAGGCTGAAGCAGGAGGTTGCAGTGAGCTGAGATCACACCACTGCACTCCAGCCTGGGCGANCAGAGCGAGAC RCCATTTCAAAAAAAAAAAAAAAAAAAAAGTATTTTTTGCCAAGCTTCATTATTTACCTATTACGTGTGGGAAAAGAAATGCACCTTTGAAGATGGTGTGTATGTGTAGATT ΓGGGANTATTAAGCTACACTTTCTGGGAACTTGGGANCCAGAATATTCTTGCCAGTGTTGGGAGTGGGACCAGCTTGGGGAATTGCCCAGGGGGTGGGTTAAACCATTTTTT ΓGGCCTTCTCCTTTAAGGTAA
302 rTACCAACCCTTTAAGAATGTAAAACTCATAGCTCACAGGCCATACAAAAACAGGCAATGGGACAGATTTAACCCATCAGCCACCGTTTGCCAACCCCTCATATAAGGTAAT CAGGGTGGTTTCATTTCCTTTGCCAAAGATTGGTTTTAGCATGGACGTATAGT'IAAGTCCTGACAGATGTGATCTGCAGATGTTCCTTAGTTCAAAAAAGAGGCCTATGAGG AAGGGAACAGTCCTTTTATTGGCCTTGGGATATGGGCTGTGTTAATGCATTAATGCCCGGGAGANTGCTGGCAGGCCATTCCTGGAGGGACATGGCGGGTTTTCTTCACCTT rTAGGNCAGGAGGATTAGGCCAGGAAAAGGAGGAAGGGGATTCTGGACTGGAATTNTCCCATGGAACNTTAACTGGAACCNGTTTGGATTTAGGCCN'rGCCAGNCTTACTTG
GG
304
RTTTACCATCACCATATATATATTTGCTTTAAAAAAATTATGACAAGCTTCAGGTAAAAATAATTTTTAAAGGGTCCATTTTTCATTTACGTACAATCAGTACATCTTATTT ACATATATGACTGGATCTTTATTCTATTTTCTTCATATAAGATATTTTAACTGGTAGGTAACTGCTCTATTCTGTTTTTATAGAAAGACTAAACACCTTATTTACAGGCAGT ΓTTGATGATGCTAGTTTGTCTCCAAATTACGTACTGAATATAGTTAAAATCTTAATGAATAACATAAAAATTAAGATCCGGTATTAACAGACTATTTTATGTGTCAATTACA GCTGCAACAAAACAGAΆATCAAGTGTGGTTCTGAAGACCTTGAAAAAGAAGTCTGACTTCTAAGACATTAACCACTGCTTAATACTGCTACTGATGGCAAATTCTTAAACTG GGTTCATTTCTTCCCTTGTAATAACACTGATTTTTCTAGTGATATTTAACTTTAAAAAGGTATTTTACTTCTTTAACCCTCAGAGAACTAGTGT
306
GAGACTGCATAGGGCTCGGGATATGTCAGTGAAGGAGATTTCTGCCCTCAGGGAGCTAATGTTCTCAAAGACAT'IAGGGAGGCAGATAGCAAACACGTGACCACAGAGTATG
RTAGCCGGTGAGAGGTGCTCTGTGGGCTGAGGGAGT GCAAGTTTCCTTATGGTGGACAGGACAGGCCTAACAGAGGAAATGGCTATTGTGCGAAGATCTGGAGTTGGTGAG AGTTGGCTGTGAGGATGCCCGGCGGAGGAGCCTAGCAGTCAGAGGGACTGGCCAGGGCAGAGCTCCTGAGGCTGGGCGTCTTCAGCCTGCTCAAAGGACAGCAAGGAGGGCT GGATGGCTGGAGCAGAGTGAGCTGTGGGGACAAATGTGAGATGAGGTTAGAGAGGAAATGAGCAACCAAGGTCACATGGGGACCTGCAGGCTGGCGTGAGGACTTTACCTTT ACTCTGTGGGAAAGGGAGAGCAGGCTTTCCAGCA
308
AACTTCCATATAATGCAGGAGGAGACATGACCACAAACGTCTGGTGAGAGATAAAAGTCAGGCAGAAAGTAGCGCCCTCTGCCCTGCAATCAGGAACCACCCTGTGTTATGT GCTTTGCTGCATGTCACTGTTGATCTGTCAGGCTCCAAAGTCTACCTATTGAGGCCAATAATATCTACCTGACCCTCICACATTGGCATCTTTTAAAAAATAGTTTTATTTC TACTGTTTATAAAATACATGCTCATTGCAAAATAGAAATAAAATGCTAGTGAATAATACAAAAGAAAAAAAGGATCGCCTCCAAAACACACCCAGTGATAGCCACTGTTACC
ATGCTGGATATATGTCCATCAGAATGTTTTCTCTATACAAACAACTTGTACGCTT'ITAATATAAAAAAGAGAAATCACGATATATACTCTTTTTCAGCTNTTAAAATTGCAT ATATTTCAGATGTACAATGTGArGTTTTGATACACATGTGAACATGGTCCAGCATATGAACATATCTATGCCCTAACGTAGTCAGCTGTCGTTTTCTACTTAACATCATGGA CATCTCTCCTTTCAATAAATAGATACTT
310
TTTATCTTAAATATTAAATTTATGAAAATTTCAAAGTAACAGACTTCCTTATAGATGAGATACACAATAACAATTTTGATATTCCTTTAAGCTGTTTAAAAGTGATGCTAAC TATATCTTTAAAAAAGTCTATΓΓAACGTAAAAGATTTTGGATAAAAACCAGTAAGTTTCTTAATGATCCTGAACCAGGTAATAAAATGTTGAGGAIGCTGAAGAAGGTTAAA TCCAGGTAAGCTTCAAGAACAGAAGTCATCCATCTTTAAATATTAGACATTTGCTGGCCAGΔAGGCGAAAGTAAGACTTCAGGATATATTGTGGGTCCTTGCAGTTCACATT CTAGTATGTTGGCACAAAATAAAGATAGGTCCCAAAACCTA
312
ATTTTTCATGTCATAGAAATTATATAGCATTGATTTTTAGCTATGATTTTGATTCAGTTTTTAAAGTATTTAATTTTTATTATATCAGCCCACACTGAACATTGGTTTTTCA GCAGATAATGCATCTTCCAAGRGCTCCAAGGCGAAGAGCCGCAGAGAAGAATACTGCATCTTGAGTCATACCCTGAAATTACTGAATGAATTACCTGTGGCCATGTAAACAC TCTGCTTCAGTAGGTAGAGTGCAACAGACAATCCAATCATTCAGAACTAAGTTTTTAGTTAGCTTCTGTTATTCACTGAAGTAGTTTGCAATTACAGTTGTCTCTAGGTATC CATGGGGGATTGGTTCCAGAACTCCCTGCTGATAACAAAATTCATGGATGCTCAAGCGCCTTACATAACTTGGTGIAGTATTTGCGAATAACCTATGCACATCCTCAAGTAT ACTTTATATCATCTCTAAACATATAATACTTAATATGTAAATGCTATGTAATTAGTTGTTATTACTGTATTTAGTGAATAATGACAAGAAAAAAAAGTGTGTACCTGTTTAG TACAGACACTACTCTGTACTGATTΓTTTTTTCTGAGTATTTTCCATCCAGGTTGGTTGAATCCACAGATGTGTAACTCACAAATATGAAGGGCTGACGGTACCTAGTAGTTC ATTCAGATTTATCGCAGTGATCTACAGTAATTTTGCAGTTTAACAAGCATTTTCTTTTGGTTCTAACCACACACAAA
314
CTTAATGAGTGAGCAGTAAGTCTGΓGTAAGAGGCTGAATGCATGCCCCTCAGATAAGCCAGTACACTCCTTGCTTAGCAACAGAACATCAGGGTGATGTGGAGAGGGGCAGG ATGRGGACGCCACATTGGAAATCGGCAACATCTGAGGGCAACAACAAACAAGTGTGTTGGGAAATAAGAAATAACTCAGTTTTGACAACTGGCTTTGTCAGCTTTTGTGATG TTTCTTTAGCAGTTTATTGGAAAGATGGTATGAGATGACGTGCTGCTTCATTGAA'ITGCTCTTTCCCCCATCTTTGCCAAATCTCAATGTATCGTTCTTAACCCCACCTCCT GTAAGGGGCTTTGCTATGCTΓCAGCΓGGTTGTCTCAGCAGCTGAAGTGCTGCCCACCTGTGTGAGTTGGGTCCAGGAAACCATGTCTGCCCTTCTGATAAGGGAAGATGAAT CTAGAGCTGGGTGAAGATCTAAATTTTAACCAAACCCCTGGGCCCAGGAAAATAACAATTGAAAATGTACAAGGCAG'IGTTTTCAATATTAAACTTCCCCAAGGAAAGCACA AACTAGTCTTTTTGGAAAGGGAGAAAGGATTAAGCCACACAGTATTAGTCTTTGAAGCAGTACTGGTCTCTAGGGGCTGGTGCCAAAATGGAGTCCCATAGTAGTTACACTC GATGGCCTCATGTACTATATACTGTGCCGAATTGTATTAAACAGTGGTGGGGAGTTACTGGGATAAGAACTTGTCTAAAAGTTTACAAACCAAAACAGATCTGTTAGGTTGG TGCAAAAGTAAGTTTTTGCCATACTTAATGTATTGCCATTAAGTATGGCAAAAACCACAATTACTTTTACACCAACCTATGTATTTAAGAATGTTTGGTTTGCCAGATTCCA AATGAGGTCTTCAGTGCAGCAAAGCCCAAAAGGTGTAGACTCAGTTATGCAATTATAAGGTTAAGGCGTAGAAGAAAGCTGCTGCTAGGTTTTTGTTGCATTTTACTTGACT GCTCTGCTGTTTTTCTTGTCTCRCATGTTTGGTTAGCTATGACTTGAGCATCTTGGTAACTGACAAAGGTCTTCCTTGGGGGACTTGAACATCTTGGTAAATGACAGGTCTT CTTGGAGGACTCCAGCAGTATCTTGTTTAAACGACTGAAAGGACTATTAAGGTTGTTGAATTGTGTTAATTGGAACTCATTGAGGAAATGCGACATTGATCCTCCTCTTATT CCACAGTGTGTTTTCTGATCATATAAAGAAGGTTCCGAACCATCCATCCCCCTCAGAGTTTATTCCCCTGGTAAGCTGTAATTGCATATCCAGTTTAAACTGGACTGGGACT GCATGTTGGTGAGGATCGGCAGGGGTTTTCCCCCTTTTCGAAAGATGAAATAGATTCTTGAGCACTGGTTGCAGAAGCCAAAATAGTTCAAATAGCTTTGCATAACCATTGG GTTCTGCTTCTGATTCAGGTGCTGGGCATCATGTCCTCCCTATTCTTCTCTTCTTGGAAACCCAGCCTATCTCATAAATACCTACTTCCGGCCACCCATCCAACCTCCCTGC TCCRTTCAACACAAATCTTGEATATTGCCAAAGGAAGCCATTCAGCAGCTGCTGGGGTTTTTCATCCCCCTGACATGCATACATTTGCTCTGGGAGAAGTGTCTTCCCTCTG ACCCTGGTCCCCAGCTCCGTCTΒTGCTTAATTGCTCTTACCTΒTTGCACTAATGAATATGACTAGGTTTTAAAGGGGGAATGTGAAGCAATAGGCACATGGGGCTTGGATGA ATTGGTCCCACAGATATACCCTGCCTTAAGCCGCTGAGGTGATGAGTCCACTGCTCATGTGACCCTCCACCTTTGTGGATCCCTCTTGGTTTGTGACCAGTGTGTCTGTTTG
GTCTTTGATGTCTACATΓTΓTΓCCTTTAATGTTTTTTATTTGGAAGGTTACCTGCTGTTGGATTTAATAAATTTGTTTACTTGAAAAAAAAAAAAAAAAAAA 316
AGACTGCATAGGGCTCGGTGGGTTGTGTTTAAAAGCTCCCAGGGCTGATTGTAATGTGCAGCCAGGCTGAGAGCCCCTGCATAAACCAACAACAGCAAACAGGGGACTATCT GCCGAACCAGGGGCAAAGTGCGCTGAGTCA'IAGAAAACTGGCCACTATTCAGCTGTGTTAAAAGAAACAAAAGTCTGTTTCCTACTGTTCGACCCAATACCGCAGGCTΓACT GAGAAGAGGCAGTTATCCAGTTGAGCTGAGTTCTGTGATTTTCCCACTGTCACTGCATTAGTGGAAAAGGTGAGACTTGAAGGACAGTTAGAATCTGGATTGGGATCTGGAT
CATAATATTATATGCAGTATGTCAAAAGGA'IGGAAGGCTTACTAGCTGCACGACATTATTTCACCAGCCTAACACCAGCACACACACATAAGGTGCAGGC 318
GCTGAGCATAGGGGACTTTATTGATGGTAGATGACAAGGTGGGGCTTCCAAGGCCCT'ICCCTTTTCAGGGGGTCTGCATGGAAATTGCGGGGAGGGGAGATTCTCAGTGTGG
CAGGGAACTGGACACGTCAGGGACTCACCAGCAGCTGAGGGCCTCTCTCTTCCTCTTGTGTTTTTGCTGGGGCTAGTGGTCTGGGGGTCTTATTCCTTAAAGGCCGTGTGGG
CCATGAGGTCCACCATCCTGTTGTCGATCTCCATGTCAATCTTCTAGTAGATTCACGTTTGCCAACTCTATCGGGCTGCATGCTGCTCCCAGTACTCTGAAGGACCCGCCTG
GTGATGATGCCATCCAGAATCCACAGAAGCAGGGCTGCTTGCTCTGAGGGCTCTTCTGCTTGGGCTTGACACCAGCCCCCCGAGCCAGTCAACAAGACCCCCTGAAGTGACT
GCAGAGTCTCATGATCACATGAGTTCCTGGAAACTTCATCTTATAGCAGGTAGTTGTCGAGAGAACTAAACGTAAAGAGTTCCTTTGTACCAAAAGGTTTGGAGCTAGGGCA
TATTTCACAGAATTCAGGGCCAACTTAATGAAAAGTGGATTGAGAATATTGCTAAAGCTGGATTCAAAGAATTGTACCCATTTGGG
320
TCAGTATAAGCACCTTCCCCCATCATTACCTACAGCATTCACACACAGATGTGAAATTGTTTCATTTCTGACCCAGATTCTGGCTTTGAGTATTAAGTCTTTCCAAACTCCA TATTTCTTCATATTTCACTAGGAAGATTATAAACTTATCTGAAATGGCAGAAATTCATTTTGCTTTCAATTTCTCATTCTGCTGTATACTGCCGGAAAGGGGTACATAATGA GAAGTGAGAGCAGCAGCCTGGCCTGCTCGCCAGCTGGAAGCAGGAAGTTCACCTGATAAGGACTTGATGCTTCAAATTCTAAAAACTGGAAAGGGAGCTAGAAGTGGGGGAA
GGAAGATCTGGAAACATGCCCAGGGGTAGTAATGAAGAAAGTGAATTCAGCCTGAGGGTGGGACCTTCTGCCCAGCCTCTGTCAACTTGATGCCTCG'ITATCTTCTCCATCT
322
AGGGAACTCTCTTTTTCGGGAATTAAGGTGTCATATA'ITGCTCTAGCTGGCTTGGGACAGAGGAGAGAGGAGTGCATGTAAATCTTCTAGTCTCTCTGCTTCTCTTGAAATG
ΓGGCAGTCTGAGCTCCACGTTTATATTCCCCTATTTCTTCTCCCTAATTTCTTACCCAGTGAGTGCTGAGTGGGTGCCCGCAAGCATTGCTGTATAGCACCCAGGCCTCCAG ΓGAGCAATCCTTAAAGCCCAGTTTTCCTGGGGTCCCAGCCTGCTGTGAGTCCCAGCCTACACCTACCTTTTGCATATGCTTTTCTTGGCCTTAGGATAGTACTGGACTTTGT RGTCCTCTGCTGTTTCCAAAATAAGAGGGCTATGTGTGCGATTATCTTTGGTAATTAAAAAAAAAAAAAAAAAAAAACTCGAGGGGΑGGCCCGGTACCCAATTCGCCCTATA GTGAGTCGTATTACAATTCACTGGCCGTCGTTTTACAACGTCGTGACTGGGGCTGGCGTAATAGCGAAGAGGCCCGCACCGATCGCCCTTCCCACAT
324
GGGGCGGCGGCGTGAGGGCTCCGGGTCGCTGGCGGCGTGGACACCTGAGTCCCGGGGTAGGGGTCTCCCGCGAGGAGTGAGCTGTTGCCGCAGAATGGGCTGCTGGCTCCTG CCCTGCTTCCTGTGATCGAGCCGGCCCTGAGGACTCTGTGGAGATGCCTGTAACCCACCGGAAATCAGACGCATCTGACATGAACTCAGACACGTCCCCCAGCTGCAGGCTC CGAGCCTTCAGCAGAGGCGGCAGCCTGGAGAGTCGAAGCAGCAGCTCTCGCTCCAGAAGCTTCACTTTGGATGATGAGAGCCTGAAGTACCTCACCCATGAGGAAAAGGATG RGCTCCTGTTTTTTGAAGAGACGATTGACTCCCTAGACGAGGACTTTGAGGAGCCAGTGCTGTGCGATGGAGGAGTGTGCTGCCTCTGCTCCCCGTCTCTGGAGGAGAGCAC CTCCAGTCCCTCCGAGCCTGAAGATGTCATCGACTTAGTGCAGCCAGCACCTGGCGCCGGGGAAGCCGAGGGCCTTCCAGAGGGGACCCAGGCAGCAGGGCCTGCACCTGCT GGGAAGGAGCACAGGAAACAAGGATGCTGAGACTCCTCCACCTTCCAGACCCCCGGTCCCGAGACCCTTCTTGGGCCACA
326
GGAGACAAGGTCTTGCTCTGTCACCCAGGCTGGAGTACAGAATTGTATGGGACA'TTTATTAAAGTCTCATTTATGGTTAACCTTTCAGAAAAAGAATAAAGCATGTATCTGC CRATGCATTTGAATTTTTCCTGTGAACACTGTGATGAGATTTGTTTAGAGAAAAAAAAGGAAAAATTTTCACTGTAA'ICACCTTATTTAAGCATCTTTACCTACTTATCCAG TΓATCTCAGAATAAATCTATAAATGTGAAATG
328
CAGGATTCCCAGGTTTACTGTGTTTTTTTTT'IT'ITTTTTAAAGAAAGCTAAATATTACATTATGTAAATACTTCT'ITTCACCAACTTCTGTAGTTTCACCATTGCATGGTGT CATTTCAGGTTATTTAACAGTTATATCCCTCTATGCCAATAATTAAAAGTGTACACTAAACATGAAGTTTGGCATATGTTGCAAAATGTCATTTTATCTTTTCTAAAGGCTT TAAGAAGAATATACTAGAATCTATATATTGATGTTAATTTTGATTCAGAAAAAAAATACAACCCAGTATCTAAAAAGTGTTAACTAGTCCAAGATAGTAATGCATATGCCAA AGAAATATTACACCTAATCTCATGTTTAGAATTTAAAATAGAATTGGTCAGCTACTTATTCTTACCACCCTACTTCCAGTATTTTAGCTCTGTCATTATTAAATTCAGATCT TCCTGATTATTTTTTCTGTTGAAAGTTAAACTACTGCTTTCAAGTAATTTAAAGTTATCCTACCTTTTATTCATGGGTAGTTTTGCAAAATTAACATGGTAGCCATTGTTTG AATTTAATCGGGCATCATAACTTTTCATTTATTGAGGAACTAATCATTATTACTATAAAGCATACAAATTAGCCAGTCAGCACACTTTGGTCTTCTTTACCTAAGGGTTAAA CATCAGAACATCAAATTTAATTATTTGCATAGAAATGTGTGGGCTCTTTAAAAAATGTTACAGTATATAAGTTGACTATCACTAACAGGTAATATTTTTCTGTTTGAAGTTG
TRACTCTTGTTTACAGCAAAGTTTGATGTAGTGTGCAGTAGTGAGCTCTAGACTGATCTTTTTCTAAATCAGAAAGTGATTAAAGTATGCACAACCAAAGGCAGGTTTTTCT TΓTTCATTTATTCAGCAACTATTTATTAAGCATCAACTCTGTGCCAGGCACGTTACTAGCTGCTACATACTGTCTGAACATGACATACGGTTAAGTAACTTTACAATTATTA TCAAATACTTCAATGTAGATATTTCTTAAGTTGAAATAGCATTAACTAGGATAATGCTTTCATGTTATTTTATTGTCTTGTGATAGAAATTCAACT'IGTACCATCTAAAACT AGGTTGCTATAAAAATAGGAGGATGAAGTCAATAAAGTTTATGCCAGTTTAAAAACTGGAAGGAAAAGGTAAGAGCTCTCCATTATAAAATAGTTGCATTCGGTTAATTTTT ACACATTAGTGCATTGCGTATATCAACTGGCCCTCAATGAAGCATTTAAGTGCTTGGAATTTTACTAAACTGACTTTTTTGCAACTTTGGGAGATTTTTGAGGGGAGTGTTG AAAATTGCCAAACACTCACCTCTTACTCAAAACTTCAAATAAAATACACATTTTCAAGAGGGAGCACCTTTTATATTTGATAAGTTTTCATTATAAACCTTATAATACCAGT CACAAAGAGGTTGTCTGTCTATGGTTTAGCAAACATTTGCTTTTCTTTTTGGAAGTGTGATTGCAATTGCAGAACAGAAAGTGAGAAAACACTGCCAGCGGTGATTGCTACT TGAGGTAGTTTTTTACAACTACCATTTCCCCTCCATGAAATTATGTGAAATTTATTTTATCTTTGGGAAAAGTTGAGAAGATAGTAAAAGAATTAGGAATTTAAAATTACAG GGAAAAATATGTAAGTGAAAAGCAATAAATATTTTGTTCACTTTGCTATCAAGATGTTCACTATCAGATATTTA'ITATATGGCAGCAATTTATATTTTTAATCATTGCCCAT ΓAATAGACGCAGTAAAATATTTTTGAATCAGACATTTGGGGTTTGTATGTGCATTAAAATTGTCTTTTGTACTGTAAGTTACTGTTAATTTGAATATTTTATTGAACTGTCT CCCTGTGCCTTTATAATATAAAGTTGTTTCTACAACTTTTAATGATCTTAATAAAGAATACTTTAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAA
330
ΓTTTCTTCATAGAGGANCCTCTGAGATTCTCATTCGGAACTCTGGGCTCTTATGTTAGCCACAATTCTAACAAGCTTTGCAATCTGGTTTCTCAGTCACGGAAGAATAGAAG AACAACTCAGAGGAGGAAGAAGTCAGACATAGCCAGACACGGCTGCTAGCAGTTCCACCAATGAAAGAGGAGACCAGGATGTTTAAANCAGGCAAACACAAGGTGCGAAAAA CCAGAAGCGAAAACTTCTGAGGTCATTTAAGCAAGGACTATCGTTATCCCCGGANGCAGAGAGAAGTTCCCTTTGCCCAACATCACACTGCAAGCACGTGTTGGAGCTGAGA RTCAAACCCAGGGCATCCAGGGTCCAGGGCCCATGCTTTTGATATATTCCATA'ICTTTAGGGAGAATTTCCCCTGTT'RAAACAATAAAAGTTTCAAAAAATCTTGTGGGCTA GGCCAAATTTTTCAGTTGTTTNGGAAAACTTATTTTTTCCATTAAGTTGGAAAATTCATTGTGCTCCAACAATTNTGGGTNAATGGA
332
AATCACAGACTTCCAAGAGTAGGAGGAACTGTCTCCTCCCGAACCCTTCCTTGCTTTCCTGGGGAAGAGGGTTCTTCCTGCAGGGACCCTGGGCATCCTGCTGCTGGGCCTG GGCCTATAGACTGCCCTGCCCCTTCTTCCCAAACACTGAGAAGACCCCGCTGGAGATGACCCCAAAGCCACGCGTGCTCTACGGCCCTAAGCAATAGACGCCTGCCCTGGCT GCTGATGATGGTGATCCCTTTGTCCTTGGACTTGGCAGTCAAAAATGGAGTGACACCCCAGACTCAGTCAGGAAGAGAACCTGCAGCCTGCCTCAGCTCAGGCTACCACGCC GGCTCCACTCGCTGGTATTTCCAGGCTTGCTAAGTAGTAACCAACTCATCCCCAGTAACACTGCATGTTCATATCCTGAATTACAAATCCAAATGAGGCAACACGTGCATA GCAGATGAGACAACCACGCAGGCCACTATAAATGATG
334
TGATCTAGAGGATCCCAGGGGAACAGTACTTATGAAGACAAGACAGAGGCTGACAAACAAAAGCAATAGCCATTCTCCAGGAAGAAAATGGTGGCATGACCATGTGTTTGGA GCAAGGAAAAATGGCAAGGGGCTAGAGAGATTTGGAAGGACTTTCTAGAAGAGTTAGAATGGGAGCTGGGTCTCCGACATGGGTAGGATTAGGGTGGGTAGAGAGGACATTC CAGGCTAAACAATGATGCAAGTTAGAGTTCTAAGGCAGAACAGTGTGTGATTGGTTTAGCATGATTGGGTCATGGTTCTCTTGGGAGAGTCCCAAAGAACTGATTCTCCAGA GGGTGTTACTAAAACTCTTATTGAAGGGCGGGACTACAGAGATGAATCTCATCACTCTCCCAGAATGGCACAGAGCTTTTCATGGACCCCCGGGCCACCTATGTAGGAACCT CAGGGGGTCTGTGGACCACTAAAAGCCCAACATGCCTGAGACTCCACAGATACTGGCTTCCACCATGATAAAGGCAAAAAGTCCCTCTTTCCCAAAATCAATACTTTTATTC TCATAGGCCTCCTGCTGTGGTCTAGTCCCCATGTTGAACGCTGCTGTCCCAG
336 TGATCTAGAGGATCCCAGGGGAACAGTACTTATGAAGACAAGACAGAGGCTGACAAACAAAAGCAATAGCCATTCTCCAGGAAGAAAATGGTGGCATGACCATGTGTTTGGA GCAAGGAAAAATGGCAAGGGGCTAGAGAGATTTGGAAGGACTTTCTAGAAGAGTTAGAATGGGAGCTGGGTCTCCGACATGGGTAGGATTAGGGTGGGTAGAGAGGACATTC CAGGCTAAACAATGATGCAAGTTAGAGTTCTAAGGCAGAACAGTGTGTGATTGGTTTAGCATGATTGGGTCATGGTTCTCTTGGGAGAGTCCCAAAGAACTGATTCTCCAGA GGGTGTTACTAAAACTCTTATTGAAGGGCGGGACTACAGAGATGAATCTCATCACTCTCCCAGAATGGCACAGAGCTTTTCATGGACCCCCGGGCCACCTATGTAGGAACCT CAGGGGGTCTGTGGACCACTAAAAGCCCAACATGCCTGAGACTCCACAGATACTGGCTTCCACCATGATAAAGGCAAAAAGTCCCTCTTTCCCAAAATCAATACTTTTATTC TCATAGGCCTCCTGCTGTGGTCTAGTCCCCATGTTGAACGCTGCTGTCCCAG
338
GAGACTGCATAGGGCTCGGCGTGGGGGTGGGAGGGGAGCTCTGAAAGCATCTTTGCCAGTCCCCTCTGGACCAAGTCCCACCTGCAGAGTCCCCAGACTTTGGCTGCAGATG CCGTAGACAGTGTAGAATGAAAGCCAGACCTTGGGTTAGTTACTTCACCAGGTGCAAAGCCCTTCTTCACCTCTGACCTGGCAGCAGCACTGGGAGGTGGGCAGGGTGGGGT RTATTGTTCTCATTTTATAGGTGAGAAAACTGAGTCTCAGGAAGGGGCAGTGATTTGCTCAAGGTCACACATCCATTCAGGCAGAGCAGGACGAAGAGGTCAGATATTTGGG GGAGTCACACTGGGCACTGTTCTCTATCCAAGCCCAAGAGGCCGAGACAAAGCCCAAGTCTTTGAGGGGTGGCITGGGCCCACTCTCACCCTACTTGTACCCCCGGGTCCCC ΓGTACTCAGGAC
340
GAGACTGCATAGGGNTCGGAGTGGGGGGTGGCGGGAACACACATTTTAAAAA'ICATGCTTCTAATCCTTAAAAAGACTAAAATAGTTTCATCCTTTCATAACCTGTCATCAC GCATGTTTTTCTAAAATTAAACACATATGGCTCAAGCCAGAGTTACATTATGCACCATATTATGTAATTATCTTTTCAATTTATTACTCCTCAAAATAGAAAAAGATTAGCC
CATGTTTCTTAAGTCTGAGTAAACATATGGCCTGAGGATTGTAAATGACATCCTATCTTTAAAAGAAGTTCCAAGACTAAACAACATACAATACTCCCTTCGGAAAGGCCAT ATGTGGGTATCAGGGTTGTGAGATACAGAAGGACTGTGCGTGTGTGTGTGTGTGTGTATACATCTTTTTGCTTTCTGGCCATGTCTTTGATGCCGTGAAATATTCCCTG
342
GAGATAAAGAGTACCATGTGGGAGACATTTATAGGGCTCAGTGGCTGCTTTATTCCCATCTTCCTTACCTGCACCCACACCTGCAGGGCCTGTCCAAGCAATTACCCAGCAC CCACTTCACACCATCACCTGACCΔGAGCAAAGCTCTCATAGTGATGGTGCATAGGCTAGTGGTGGCCCCTAAGACACCAATGCCAGTGGTTCACATCTGCTAGCCAGCTCGT CΓCCAGAAAAAAGTACAGCACAGAAAATATCACAGTTCTAATTGTTCCATACIAGTAAAACCATACTAACTACACATATTCAGATGAAAACAGTATIAGAATACAGGTATTA GACTTCAGAGCTTTACTAAGCCCCATTCTAGAAGGTTGGACTAAAATACTAAAGATAAAAGGAGGACCAAAGTTAGGAAATTACAAGATATATAAGAAAAATTCTAGCATTA ΓAΓAGCTGTTAGAATTTGTCTAGCAGGTTTTCCAGTTTCTACCAGAAACCCCTACCCAAAAAAGAACG
344
GCCGTAGTACTTTCTACCTGAGGGAACCTAAATAGAGTCATTGTGTGGCCATTTATGGTTGCCACTGTTCACATAAATATGACACTGCACCCAGACAGAAAATTCCAGCCTC ΓCTGAGACACTTTCTCTAATATCTCACAGATATCAATAAAGGGCCCACTGAAGAAATGGAATGGCTGGGGAG
346
AGACTGCATAGGGCTCGGCGTGGGAAGAGCATTAAGAAAAAGAGCTAAGGCATGCTGGGCTTAATACCTAGGTGATGGGTTGCCAGGTGCAGCAAACCACCATGGCACATGC RRACCTATGTAACAAACCTGCAC^TCCTGCACATGTACTATGGAACTTAAAATAAAATAAAATAATTATATAAAAAGAAAACACTGCTAAAAAACCTAACCCTAGCCCATTG ΓAATGCCAGGGATGTCTTGACCTATGTATTTCCTTCATCCCAAGATGCTGAACATGTCAAGACATTCGGTGAGCCAGAGTCAAAAGGCATTGAGGAGTCGTTCTGTTTTTGC AGCAGTTGCAGGCTTGAGAGGCTCCAGGGTCAGATGCTCAAGACAAAGGAGGCCCTCCTTCGCATGTGTGAGAGN
348
GAΓATCTTGACTCTGACTCAGGTGATCGCTGTTCGGCTCCTATCACGGTGCTGGNCAAGAACTGTTTCTTGTAGGCTCTGGTGCTGGTGACTTAGAACCCGCAGCTCCTGGA GAAAGGGGCTGGGCGACCACCCTGTGTAGCTTTCCCAAAGACAGAGTCAAACGTCTCCTGGAGAACAGAGGCTTCCCTTCGTCTTTGGTCATNTGTCCTCTAGCTGGGGGTA CCCCCTGGTGGCAAGGCACAGGTCCTTTGCTCCCCAGGTGGCAACGGCAAGGCCAAGACACGGCCCTGGCACAGTTCICCTGGGTGTAGGCTCAGGACAGCCCTGTTTCCAA ACΓGTTTAGGCGGGTGAGGGGTGGTGGCCCTTTGGTTCCAAGGTTGAAACTGCCCATGTGGTGCTTGATTTAGCAAGACTGGGGAGGCTCTATTTGTAGGCAGGGTTCTTTT CΓΓTCCCCCAGCTGCTGGACCTGGGAGTTGGAAGAGAAGTTGCCCCATTTTAGGGTACCAGGATATTTCTGTGGCTCTTGGTTGGATGGAAGTGATTGAGGGAGGCCGTTCC AGGGTCTTGGGTTTCTGTCAGGATTTCTTC
350
GΓGGGTAAAAGCATCTCCTATAAGCTGTGGTCTGGGGTAAAAACAGCTCACTGGGGCAGGAGCTTTACTGAATAGTAATTCTGTCCATGCTGGGCTCCCCAGGCCTGGTCAG
AAGGCCTGTGTGTTTTGATTCCATCCTACCTCCAGTAAGGGAAAAAAGATGAATGCTCTCAAACTGAAACC'IC'IACTGGCTGGTATGTTTCTTTACTATCTGTACAAAACCA
AΓΓGCAAATATCAAACTATTACACAACAAAGGAACTCAACATTAAGGGGACACTGCCTAATGATAACAAAAACTTAAGTTATAATTAGAGTTTCAGAGATAGATTTAGATTG GGGTTTCTGTATTTTTCTTACATCAGCTGGAAACTTATGCACCAATTATGTGGGGGACACTGTGCTAAGAGCTGCATACACATTATCTCACTAGGTTTCACCTGAAAAGGCA GGGTACCGTCCCCTTTCACAGA
352
GAGCTGCATAGGNTTCGNCGTGGTCAGGANAGAAGGAGAGCAGCCACACAGATCACCTGGGCGGGCGGCATGAGNCTGCCTCATCAAGTCTGCTCACACATCAGCATGCTGC
TGAGAGCCTCAAATCCTGGAGAAGACCTACAGTTGGGGTGGAAAGATCGCAGACATGATCTCCATAGACTACAAACCAGGGACCAGATGAATGG'IAAGTTGCCATGGATACC AGTATGGCTACATGATGACAACCAAAGATATCCCCCACCCACTCCCATCCTCAGCTGACCCTAAGGTTTTATATAAACAATCTAAAACTTAGACGCACATCCAAGGAGGAGG GAGCCCTGGAAGTGACTGAGGGAAATCCTGATTTGACAGTGAGTACTTTCCCACCACTCTGGGAGAAAGTGAGCTNCAAAAAAGGTNTTCCAATTTAAGGGTTTGAAAGGAN AGCAAGGGTCCCCTTTT GGTGCCCCGATTNTTTTGGCCTTTGAGGGCCAAAATTTCCCTATTAGGTTAGGNCGGTT'ITTAAATTCCGGGAATCA
354
ACATTCCTTCTCCAAGCAACCTCCAGTTTCTGCAATGCAGAACCACACATAGAAGGGATTAGGGCTAATAGTGACAAACAAGACCCTTGAAAGCCACTTTAAGTTGAGCCTT
TATCCTGAGGACAATGGGAAGCATTACAAGTTTTCACCAGAACATGCTTGAATTTGCTGTTTAGAAAGGACAGGGAGATTGCTGTATGAGGGTGGCCGGAGGAAAACGCTGT CCATAGTGAAATAATCAAAGACATGCCTGCACGGAAGACAGATGATCTAGAAGCTGCATCCCCAAAAGGATTATCTATTTCCTTAGCTGTTTCCTCTCTGGGGGCCCTCTAC CCCTTTCACTTACTATCAGGGAAGCTCCCAGCAGTTCATCAGGGATGATACATTAAATGATGCTNTATGGTATNTAGCATCAGCCCAGCC
356
AAATGATTAACTTTACAGCTGCCTATGGTAATAGGTAACAGTTGTGGTGAACATTAAGCTAACCAAAAAGCTTAAAAGTAAATGCTGGGGAATGAGATGTCCATATGGAGCT TAGAAAACCTCCAACAAATACCTGGGAATCTAAAAGGCTATGCATATGCACAGGATGATAGGCATTCCCAAGGCTGTGCACATGCTCAGAAAACACCTAAGAAAGGCCAAAG TTCTCACCTATGGCTGAACTTCAAGCTCTGTACAAGTGAAGTGCTAAGGCAAAGTTGCCCCCAACATACACACAGAGCATCTTGGTAAAGACTGGGAG
358
TATAAGAGTGACCTATTAGCAATATATTTGCAAAACTAAACCAAAATCTGTACAGGATATTATCAAAGCCTTAGGAACAACAGAACATACATATTTTATGGAGTGGTTGGAG ACCATCTCCCCTTTAGTAGTTAACGTACTGATGAGTGTCCCCATTTTCATAAGCAAGGACATACTAACACTAAGCAGTTGAAAGGCCTGTCTCAGAAGCATCCTGCCCCAG GTAGCTGATCACGGTGGCCCCATACCACGACACAGCTTTTCTTTTGGTTGGTCTTGCTGAGTGCCTTCTCTAGATTTGGGCTGTCATTCAAGCCTCTTCATTTACAATGTTC ATTAAAAATTCAGTACCATACCTGTCCCACTCCCAACCATTTTTTAATTCCTGATTCTTTTGTTTGCCTTTGTGGGTAAAATGCANATGTGTCCAAGGTGAAAAAGCAAACC
360
TTTTTTTTTTTGTGCACAAAGGGGGACTGTTTAATTTTTAAGCAGTTTTATTCACAATAGTAAAAACATTATAAACAAATGCCAAAAAACAAATGAACAGAAAAACATATTT TGCCTAAATGCCAAAAAATAAATGAACAGAAAAACAAATTATGATCTATTTATCCAATGAAATACTACCAAGCAATGAAAAGGACTGAACTACTTATACACATAGCCACACG AATGAATTTCAAAAACATGCTAAGCAAGAAAAACTAGATACATAATGTATTATATGACCCCGATTATATAAAATTCTAGAACAGGTTAAGCTAATCTATAGTGAAACAAGGC TΓATTGGTTGCTTGCACAAGGAAGGAGGGTGGAGTGAGGAGGTGGGGATAGTATTGTCTGGAAGGAAGTATCAAGAAATTTTCTGGTGGTCATGGAAATGTTCTATATCTCG ATTAAAATGGTGGTTGTGTGGTTGTATACATTTG
362 GATTGTATAAATAATTTATTTCTGTTCACAGCATCATATATGCATTATAAAAGGCTATGGAAACAAAAGAGAAGGATGATGAGACAGAGAATTACAGCAGTAGAAAGGAAAA CAGAAACCAGGGCACACAGTTCCAACACCAGAACAGAGAATTTGGGAAGATAATTGCTCTGAAACAGAACT
364
GAGACTGCATAGGGCTCGGCGTGGTTTCATGCAGGGAAGTGTCCAGTCAAGGAATGATAGAAGACTTTTCAGGTCTATTGGCTTAGGTAGTGAACCATTCTGCTGGATTCCA
TCCTAACTCACAGTTTTCCTCCTCTGACTGCTATAA'ITCTCCAGATGTGCTGATGTAGTTTGATCCAGCTTTGCCTTCCTGGATTAATTTATTTAATAAATATGTATGGGGC CCTCTATGACATTGGACATGATTATAAGGCTTTTTGGAACCGTATCANGGAAGCAAGACAGCCTAAGGGNCCTATGCANGGTACAGATANACAATAAANGTAGACAACTGAT AAGTTAAGTTGCAGGGTTGTGGNAACAGNTAAGGANGGGGAAGAACCAGNGGTGATGTGATGGAATGG
366
CTGGAGAGTGCTCTATTCTAGGATTTAATTACACTTCAAACGTAATTGAAATTTACCTACCCTGCTTGTCCAAACAATCAAGAGCCACTTCCATAAAATCTAAACTACTTTA
GATATAAACCATTTTTACCAAAAGTCACATCATAG'ICACAACTGCAAACTGGCATTGCTATGCAAGGCTGGCAGTAAACATTAACATTAGCTTGCAAAATTAATACAGGCCT
ACAGTCTGATAACTCTTCTAGACCCAGCCTGATTCTTATCAGGCTATGGATGAAGAAGTTTAATTAAAACTCAATCCAGTCTAGACTGTGTGACCTGTTCTTTGTGCTAΓTA CTGTTCAGTGGCATCAAATGCAT
368
TTTTCAAGTTTAAAAGTCAGAATATATTTCACTGAAAATATGTGTATGTGTGTGCCTTCAAGAGTGAGTGCTCCTCAAGGGAGACTCACACAGTTCCTTACAACATAAAΓAA GAAATAGACGTAATGGCTTCACTCAGTAGAAAACTAGCAGCATCATTCTGGGCCATGGGGCATTCCCCAGGGGTCACCATCCAGCAGCCTCTCCCTGGGGGCAGAGGACGCC TGGTCAGAACAGCTATAACTCATCCATCATGGCGAGCAAATCGTCCCCTTTGCTGGTGCTCAGCCTTG
370
AAGACTGCATAGGGCTCGGCGGGGGAGAGGTATACAAATATACAAAATGCTACAAGCATTGTAGACCATATATATACAAATACACATATGCATATTTATATCACACATATAT GCATATATATATATATGTACACACATACATATGCATATTTATATCAAAACCAAGAGTTGGTTCTCTAAAAAAAGGATGCCCTCCAAAAAAAACAAATCCAATTGGGTGCCNG CTCAGGTCGCAATAGGGGTAAAGCNTCAGGGTAGGTTTCTAAGGGTTCCCAAGGTCCGGGNTCTGGGCTCTCAGGATGGGCATCTNTTGGGNGCTGCCNGGGGGCTTGGGGG GGAACTTGCTGTTCCTGAAGGGGGNGGGGCACAAGCCCGGGGTGGGNCTT
372
CCCCTGGTAAATAAAATATTGGTAAATTAGTTCCACRGATTATGATAGCAGAGGTTAATATAGCCCTATGGTCAAAGTCTTGGATATATTCATATCTGGAGCAGATTAAGGA ATTTTGCTAACTGACTTCAACTTCTTAGCAATCTTAAAATGTAAGCTTAAATATCTTGTAGGTGTCAGTGAAAGAGGAGTATGTTCATCTTGTGGCCACAATTCAGCAATTA GTGCAGATAAGANTGATCTTGTTTGAAGAGCAGTGGGGNAAAGCTNGGTA
374
GCGTAGGGGCCATCGTTTTCCCTGCAGGTCCCCACTGACCAGTGGGGCAGGTCGGTAGGACGGCAGGGTCATAGACITCAAGGAGTCCTTGGTGGAAGATTCGGAGAGCTGC CTGTCAGAAGACAGCCCACCTCCTTCAGCAGGCTCCTTCCAAGACCCAGCCGCCAGTTCTCTGTAGAAGAGAACAAATGCTTCTTTCTGAAGCCCTTGGGGAAGGAGAGGAG GACGGGCTGCTATCCTTGATCTCACCCTTGGCTTCTGGCTGCTCCAGGTAAACATGGTTCCCATTGATGCAGACATTAGAGCGGGAAAGGACATCATTCTTAGACCGAAGCC ACCAAGAAAGGAAAGTCCTTCCTTCTTGGGAAGGGTAAAGTTGACCTGGTTCAGTTGCTTAAGATCCGTACTCGCTGTTCTCTTGTGAGACATGACATCCGAGGCCGAGGAG GACTCATCCTCATTGTCATCTTCATCCCACTGGGACTGAAAGTCTCCGGGACGAAGCAGCACTTTTTCTGGCTTTGAAGTCGG
376
TATTGAAATACATTCACGTTCATTCATTTATATATTGTCAAGGGCTGCTTTTGCACTACATATGGTCAGAGTGGGTAGTTATGACAGATTGAATGGCCCACAAGGCTAAACT ATTTGCTATCTGATCCCTTACAGTAAGTAAAGTTAGCCAACTTGTGATTTAGACAGTAGAGGAATCAAATNGAAATAGCATCAAAAAGTTGTAGGATCATTGGGCCATTCTA ACCCTAAGTCANAGGAAGAAATGGAATGGGAAATAGAGGGTGAACAGAAAGAACACAATTACATCTGAGTTGGGACGCACACATGTTTGAGTAGTAANAATCTCTGAGGNCT TCTTGTNAGGGGATGCCAAAAANGTGGGGCCTACCAGGAAGATATAAAAANGGC
378
AGGCGGGGTCTCACTTTGTCACCCAGGCTGGAGTGCAGAGGTACAATCTCAGCTCAATGCAATCTCTGCCTTCCTGGCTCAAGCAATTCTCCCACTGCAGCCTCCTAAGTAG CTGGGAATACAGGTATACACGAGTACACCCAGCTAATTTTTGTATTTTTATGTGGAGACAGGGTCTTGCTGTATTCCCCAGGCTAGTCTCGAACTCCTGGACTCAAGCAGTC CGCCCGCCTCGGGTGCCCAAAATGTTGGTGTTATACGTGTGAGCCTCTGCACCCGGCGGCAAAACTGGCTTTTAATCAACCTTTTGGCTAAAGGATTTCTCTTTTTATTTAT TTTTAAAAGGATTTCCCATTTTTATC
380
GGACAAAGATAGCTGATAATGCAAATAACTTCAGGTNCCGGCAGTTGGAAGTTGGCCCAATGTGCAGAATGTTCTGTTCAGGGGCATGTGGGCTTGGCTAACAGATCTGTTA TAGCCCTAATATCATACTGTTGTTGGTTTTTCAATCAATGCACAAAGTTGGAAAGATATAGAGCTGACCCTGAACAACAGGGGTCTGAACCAGTGTGGGTCTACTTATATGC AAATTGTTTTCAATATATACAGTTGGCCCTCCATATCAGTGGGTTCCACAACTNGAGCC
382
TTATTGTGCTTGAAATTTGCTTTATTACGAAGAATTCCCAGAAATATTCTGATTTCCAATTATTTGTTTTTTTCT'IGCATTTACAAGTTGTTCTTAGTTGCATGTTATTATG TATTATTTGTGGTCTGAAAGAACTATATTATCTTTAGAAATCATTGGTAGTTTCCTATTTTATACTATGTCTAAAGTTTATATAATTCGGATGTTAGAAAATTTTACAGCTA CCTTTCCTCATTTTACAAATGAGATATGCAAAGCCTACAGACATTTGCCTTCCTCAAGGTAACAAACAGAAGGGTTCTTGCAGCAAAGGCAGGATTAGCATCCAGACTCTCA ACTCCACTCTTTGAACCACATCTCACAGCCTCTGTGAATTGATATTGCAAAGAAGCAATATGACTATCTGGGCAACA
383
NDYEEFAYCWENFWNEGQQFMPWYKFDENΥAFLHRTLKEILRYLMDPDTFTFNFNNDPLVL^
D VPSLQLDPAQIYRVT FISWSPCFS GCAGEVRAFLQENTHVR RIFAARIYDYDPLYKEA QMLRDAGAQVSIMTYDEFEYCWDTFVYRQGCPFQP DG EEHSQA SG
R RAILQNQGN
384
CAGGGACAAGCGTATCTAAGAGGCTGAACATGAATCCACAGATCAGAAATCCGATGGAGCGGATGTATCGAGACACATTCTACGACAACTTTGAAAACGAACCCATCCTCTA TGGTCGGAGCTACACTTGGCTGTGCTATGAAGTGAAAATAAAGAGGGGCCGCTCAAATCTCCTTTGGGACACAGGGGTCTTTCGAGGCCAGGTGTATTTCGAGCCAGGTGTA TTTCGAGCCTCAGTACCACGCAGAAATGTGCTTCCTCTCTTGGTTCTGTGGCAACCAGCTGCCTGCTTACAAGTGTTTCCAGATCACCTGGTTTGTATCCTGGACCCCCTGC CCGGACTGTGTGGCGAACGTGGCCGAATTCCTGTCTGAGCACCCCAATGTCACCCTCACCATCTCCGCCGCCCGCCTCTACTACTACTGGGAAAGAGATTACCGAAGGCGCT
CTGCAGGCTGAGTCAGGCAGGAGCCCGCGTGAAGATCATGGACTATGAAGAATTTGCATACTGCTGGGAAAACTTTGTGTACAATGAAGGTCAGCAATTCATGCCTTGGTAC AAATTCGATGAAAATTATGCATTCCTGCACCGCACGCTAAAGGAGATTCTCAGATACCTGATGGATCCAGACACATTCACTTTCAACTTTAATAATGACCCTTTGGTCCTTC GACGGCGCCAGACCTACTTGTGCTATGAGGTGGAGCGCCTGGACAATGGCACCTGGGTCCTGATGGACCAGCACATGGGCTTTCTATGCAACGAGGCTAAGAATCTTCTCTG TGGCTT TACGGCCGCCATGCGGAGCTGCGCTTCTTGGACCTGGTTCCTTCTTTGCAGTTGGACCCGGCCCAGATCIACAGGGTCACTTGGTTCATCTCCTGGAGCCCCTGC TTCTCCTGGGGCTGTGCCGGGGAAGTGCGTGCGTTCCTTCAGGAGAACACACACGTGAGACTGCGCATCTTCGCTGCCCGCATCTATGATTACGACCCCCTATATAAGGAGG CXSCTGCAAATGCTGCGGGATGCTGGGGCCCAAGTCTCCATCATGACCTACGATGAGTTTGAGTACTGCTGGGACACCTTTGTGTACCGCCAGGGATGTCCCTTCCAGCCCTG GGATGΒACTAΑAGGAΣCACAΣCCAAGCCCTGAGTGGGAGGCTGCGGGCCATTCTCCAGAATCAGGGAAACTGAAGGATGGGCCTCAGTCTCTAAGGAAGGCAGAGACCTGGG TTGAGCAGCAGAATAAAAGATCTTCTTCCAAGAAATGCAAACGAGCCGTTCACCACCATCTCCAGCTGCTCACAGACACCAGCAAAGCAATGTGCTCCTGATCAAGTAGATT TTTTAAAAATCAGAGTCAATTAATTTTAATTGAAAATTTCTCTTATGTTCCAAGTGTACAAGAGTAAGATTATGCTCAATATTCCCAGAATAGTTTTCAATGTATTAATGAA GTGATTAATTGGCTCCATATTTAGACTAATAAAACATTAAGAATCTTCCATAATTGTTTCCACAAACACT
385 OTRNRVV SGLGASPASRPTRDPQDPSGRQGELSPVEDQREGLEAAPKGPSRESVVHAGQRRTSAYTLIAPNINRRNEIQRIAEQELANLEKWKEQNRAKPVH VPRR GG
SQSETEVRQKQQLQLMQSKYKQKLKREE8VRIKKEAEEAELQKMKAIQREKSNKLEEKKRLQENLRREAFREHQQYKTAEFLSKLNTESPDR8ACQSAVCGPQSST ARS A
YRDS KAEENRKLQKMKDEQHQKSE LELKRQQQEQERAKIHQTEHRRVNNAFLDRLQGKSQPGGLEQSGGCWNMNEGNSWGI
386 CGCTAAGCGTCCCAGCCGCATCCCTCCCGCAGCGACGGCGGCCCGGGACCCGCGGGCTGTGAACCATGAACACCCGCAATAGAGTGGTGAACTCCGGGCTCGGCGCCTCCCC
TGCCTCCCGCCCGACCCGGGATCCCCAGGACCCTTCTGGGCGGCAAGGGGAGCTGAGCCCCGTGGAAGACCAGAGAGAGGGTTTGGAGGCAGCCCCTAAGGGCCCTTCGCGG
GAGAGCGTCGTGCACGCGGGCCAGAGGCGCACAAGTGCATACACCTTGATAGCACCAAATATAAACCGGAGAAATGAGATACAAAGAATTGCGGAGCAGGAGCTGGCCAACC
TGGAGAAGTGGAAGGAGCAGAACAGAGCTAAACCGGTTCACCTGGTGCCCAGACGGCTAGGTGGAAGCCAGTCAGAAACTGAAGTCAGACAGAAACAACAACTCCAGCTGAT
GCAATCTAAATACAAGCAAAAGCTAAAAAGAGAAGAATCTGTAAGAATCAAGAAGGAAGCTGAAGAAGCTGAACTCCAAAAAATGAAGGCAATTCAGAGAGAGAAGAGCAAT
AAACTGGAGGAGAAAAAAAGACTTCAAGAAAACCTTAGAAGAGAAGCATTTAGAGAGCA'rCAGCAATACAAAACCGCTGAGTTCTTGAGCAAACTGAACACAGAATCσCCAG
ACAGAAGTGCCTGTCAAAGTGCTGTTTGTGGCCCACAATCCTCAACATGGGCCAGAAGCTGGGCTTACAGAGATTCTCTΔAAGGCAGAAGAAAACAGAAAATTGCAAAAGAT
GΔAGGATGAACAACATCAAAAGAGTGAATTACTGGAACTGAAACGGCAGCAGCAAGAGCAAGAAAGAGCCAAAATCCACCAGACTGAACACAGGAGGGTAAATAATGCTTTT
CTGGACCGACTCCAAGGCAAAAGTCAACCAGGTGGCCTCGAGCAATCTGGAGGCTGTTGGAATATGAATAGCGGTAACAGCTGGGGTATATGAGAAAATATTGACTCCTATC
TGGCCTTCATCAACTGACCTCGAAAAGCCTCATGAGATGCTTTTTCTTAATGTGATTT'TG'ITCAGCCTCACTGTTTTTACC'IT'AATTTCAACTGCCCACACACTTGACCGTG
CAGTCAGGAGTGACTGGCTTCTCCTTGTCCTCATTTATGCATGTTTGGAGGAGCTGATTCCTGAACTCATATTTAAACTCTACTGCCAGGGAAATGCTACATTATTTTTCTA
ATTGGAAGTATAATTAGAGTGATGTTGGTAGGGTAGAAAAAGAGGGAGTCACTTGATGCTTTCAGGTTAATCAGAGCTATGGGTGCTACAGGCTTGTCTTTCTAAGTGACAT
ATTCTTATCTAATTCTCAGATCAGGTTTTGAAAGCTTTGGGGGTCTTTTTAGATTTTAATCCCTACTTTCTTTATGGTACAAATATGTACAAAAGAAAAAGGTCTTATATTC
TTTTACACAAATTTATAAATAAATTTTGAACTCCTTCTGTAAAAAAAAAAAA
387
MGNGESQLSSVPAQKLGWFIQEYLKPYEECQTLIDEMVNTICDVCRNPEQFP VQGVAIGGSYGRKTVLRGNSDGTLVLFFEDLKQFQDQKRSQRDILDKTGDKLKFCLFTK
W KNNFEIQKSLDGETIQVFTKNQRISFEVLAAPNALELNDNPSPWIYRELKRSLDKTNASPGEFAVCFTE QQKFFDNRPGKLKDLILLIKH HQQCQKKIKDLPSLSPYA
LELLT YAWEQGCRKDNFDIAEG RTV ELIKCQEK CIY^^VNYNFEDETIRNILLHQ QSARPVILDPVDPTHNVSGDKICWQ LKKEAQ LTS LDNELPAPS NV
PAPLFTTPGHL DKFIKEF QPNKCF EQIDSAVNIIRTPLKENCFRQSTAKIQIVRGGSTAKGTA KTGSDADLWFHNSLKSYTSQKNERHKIVKEIHEQLKAF REKEE
ELEVSFEPPKWKAPRVLSFS KSKVLNESVSFDVLPAFNALGQLSSGSTPSPEVYAGLIDLYKSSDIiPGGEFSTCFTV QRNFIRSRPTK KDLIRLVKH YKECERKLKPK
GS PPKYALE LTIYAWEQGSGVPDFDTAEGFRTVLELVTQYQQLGIFWKVKYNFEDETVRKFLLSQ QKTRPVILDPGEFTGDVGGGDRWC H LDKEAKVR SSPCFKDG
TGNPIPP KVPTMQTPGSCGARIHPIVNEMFSSRSHRILNNNSKRNFWRSSGNRF
388
CGGCAGCCAGCTGAGAGCAATGGGAAATGGGGAGTCCCAGCTGTCCTCGGTGCCTGCTCAGAAGCTGGGTTGGTTTATCCAGGAATACCTGAAGCCCTACGAAGAATGTCAG ACACTGATCGACGAGATGGTGAACACCATCTGTGACGTCTGCAGGAACCCCGAACAGT'rCCCCCTGGTGCAGGGAGTGGCCATAGGTGGCTCCTATGGACGGAAAACAGTCr TAAGAGGCAACTCCGATGGTACCCTTGTCCTTTTCTTCAGTGACTTAAAACAATTCCAGGATCAGAAGAGAAGCCAACGTGACATCCTCGATAAAACTGGGGATAAGCTGAA GTTCTGTCTGTTCACGAAGTGGTTGAAAAACAATTTCGAGATCCAGAAGTCCCTTGATGGGTCCACCATCCAGGTGTTCACAAAAAATCAGAGAATCTCTTTCGAGGTGCTG GCCeCCTTCAACGCTCTGAGCTTAAATGATAATCCCAGCCCCTGGATCTATCGAGAGCTCAAAAGATCCTTGGATAAGACAAATGCCAGTCCTGGTGAGTTTGCAGTCTGCT TCACTGΔΔCTCCAGCAGAAGTTTTTTGACAACCGTCCTGGAAAACTAAAGGATTTGATCCTCTTGATAAAGCACTGGCATCAACΔGTGCCAGAAAAAAATCAΔGGΔTTTΔCC CTCGCTGTCTCCGTATGCCCTGGAGCTGCTTACGGTGTATGCCTGGGAACAGGGGTGCAGAAAAGACAACTTTGACATTGCTGAAGGCGTCAGAACGGTTCTGGAGCTGATC AAATGCCAGGAGAAGCTGTGTATCTATTGGATGGTCAACTACAACTTTGAAGATGAGACCATCAGGAACATCCTGCTGCACCAGCTCCAATCAGCGAGGCCAGTAATCTTGG ATCCAGTTGACCCAACCAATAATGTGAGTGGAGATAAAATAIGCTGGCAATGGCTGAAAAAAGAAGCTCAAACCTGGTTGACTTCTCCCAACCTGGATAATGAGTTACCTGC ACCATCTTGGAATGTCCTGCCTGCACCACTCTTCACGACCCCAGGCCACCTTCTGGATAAGTTCATCAAGGAGTTTCTCCAGCCCAACAAATGCTTCCTAGAGCAGATTGAC AGTGCTGTTAACATCATCCGTACATTCCTTAAAGAAAACTGCTTCCGACAATCAACAGCCAAGATCCAGATTGTCCGGGGAGGATCAACCGCCAAAGGCACAGCTCTGAAGA CTGGCTCTGATGCCGATCTCGTCGTGTTCCATAACTCACTTAAAAGCTACACCTCCCAAAAAAACGAGCGGCACAAAATCGTCAAGGAAATCCATGAACAGCTGAAAGCCTT TTGGAGGGAGAAGGAGGAGGAGCTTGAAGTCAGCTTTGAGCCTCCCAAGTGGAAGGCTCCCAGGGTGCTGAGCTTCTCTCTGAAATCCAAAGTCCTCAACGAAAGTGTCAGC TTTGATGTGCTTCCTGCCTTTAATGCACTGGGTCAGCTGAGTTCTGGCTCCACACCCAGCCCCGAGGTTTATGCAGGGCTCATTGATCTGTATAAATCCTCGGACCTCCCGG GAGGAGAGTTTTCTACCTGTTTCACAGTCCTGCAGCGAAACTTCATTCGCTCCCGGCCCACCAAACTAAAGGATTTAATTCGCCTGGTGAAGCACTGGTACAAAGAGTGTGA AAGGAAACTGAΔGCCAAAGGGGTCTTTGCCCCCAAAGTATGCCTTGGAGCTGCTCACCATCTATGCCTGGGAGCAGGGGAGTGGAGTGCCGGATTTTGACACTGCAGAAGGT TTCCGGACAGTCCTGGAGCTGGTCACACAATATCAGCAGCTCGGCATCTTCTGGAAGGTCAATTACAACTTTGAAGATGAGACCGTGAGGAAGTTTCTACTGAGCCAGTTGC AGAAAACCAGGCCTGTGATCTTGGACCCAGGCGAACCCACAGGTGACGTGGGTGGAGGGGACCGTTGGTGTTGGCATCTTCTGGACAAAGAAGCAAAGGTTAGGTTATCCrC TCCCTGCTTCAAGGATGGGACTGGAAACCCAATACCACCTTGGAAAGTGCCGACAATGCAGACACCAGGAAGTTGTGGAGCTAGGATCCATCCTATTGTCAATGAGATGTTC TCATCCAGAAGCCATAGAATCCTGAATAATAATTCTAAAAGAAACTTCTGGAGATCATCTGGCAATCGCTTTTAAAGACTCGGCTCACCGTGAGAAAGAGTCACTCACATCC ATTCTTCCCTTGATGGTCCCTATTCCTCCTTCCCTTGCCTTCTTGGACTTCTTGAAATCAATCAAGACTGCAAACCCTTTCATAAAGCTGCCTTGCTGAACTCCTCTCTGCA GGAGCCCTGCTTAAAATAGTTGATGTCATCACTTTATGTGCATCTTATTTCTGTCAACTTGTATTTTTTTTTCTTGTATTTTTCCAATTAGCTCCTCCTTTTTCCTTCCAGT CTAAAAAAGGAATCCTCTGTGTCTTCAAAGCAAAGCTCTTTACTTTCCCCTTGGTTCTCATAACTCTGTGATCTTGCTCTCGGTGCTTCCAACTCATCCACGTCCTGTCTGT TTCCTCTGTATACAAAACCCTTTCTGCCCCTGCTGACACAGACATCCTCTATGCCAGCAGCCAGGCCAACCCTTTCATTAGAACTTCAAGCTCTCCAAAGGCTCAGATTATA ACTGTTGTCATATTTATATGAGGCTGTTGTCTTTTCCTTCTGAGCCTGCCTTTATCCCCCCACCCAGGAGTATCCTCTTGCeftAAGCAAAAGACTTTTTCCTTGGCTTTAGC CTTAAAGATACTTGAAGGTCTAGGTGCTTTAACCTCACATACCCTCACTTAAACTTTTATCACTGTTGCATATACCAGTTGTGATACAATAAAGAATGTATCTGG
389
MGNGESQLSSVPAQKLGWFIQEY KPYEECQT IDEMVNTICDVCRNPEQFPLVQGVAIGGSYGRKTV RGNSDGTLVLFFSDLKQFQDQKRSQRDILDKTGDKLKFC FTK LKNNFEIQKSLDGSTIQVFTKNQRISFEVLAAFNALS NDNPSPWIYRELKRSLDKTNASPGEFAVCFTELQQKFFDNRPGKLKDLI LIKHWHQQCQKKIKDLPSLSPYA
LELLTVYAWEQGCRKDNFDIAEGVRTVLELIKCQEKLCIYWMVNYNFEDETIRNI LHQLQSARPVILDPVDPTNNVSGDKIC QW KKEAQT TSPNLDNELPAPSWNVL
PAPLFTTPGHLLDKFIKEFLQPNKCFLEQIDSAVNIIRTFLKENCFRQSTAKIQIVRGGSTAKGTALKTGSDADLWFHNSLKSYTSQKNERHKIVKEIHEQLKAF REKEE
ELEVSFEPPKWKAPRVL8FSLK8KVLNESVSFDVLPAFNALGQLS8GSTPSPEVYAGLIDLYKSSDLPGGEFSTCFTVLQRNFIRSRPTK KDLIRLVKH YKECERKLKPK
GSLPPKYALE LTIYAWEOGSGVPDFDTAEGFRTVLELVTQYQQLGIF KVNYNFEDETVRKFLi SQLQKTRPVILDPGEPTGDVGGGDR CWHLLDKEAKVR SSPCFKDG
TGNPIPPWKVPTMQTPGSCGARIHPIVNEMFSSREHRILNN SKRNFWRSSGNRF
390
CGGCAGCCAGCTGAGAGCAATGGGAAATGGGGAGTCCCAGCTGTCCTCGGTGCCTGCTCAGAAGCTGGGTTGGTTTATCCAGGAATACCTGAAGCCCTACGAAGAATGTCAG ACACTGATCGACGAGATGGTGAACACCATCTGTGACGTCTGCAGGAACCCCGAACAGTTCCCCCTGGTGCAGGGAGTGGCCATAGGTGGCTCCTATGGACGGAAAACAGTCT TAAGAGGCAACTCCGATGGTACCCTTGTCCTTTTCTTCAGTGACTTAAAACAATTCCAGGATCAGAAGAGAAGCCAACGTGACATCCTCGATAAAACTGGGGATAAGCTGAA GTTCTGTCTGTTCACGAAGTGGTTGAAAAACAATTTCGAGATCCAGAAGTCCCTTGATGGGTCCACCATCCAGGTGTTCACAAAAAATCAGAGAATCTCTTTCGAGGTGCTG GCCGCCTTCAACGCTCTGAGCTTAAATGATAATCCCAGCCCCTGGATCTATCGAGAGCTCAAAAGATCCTTGGATAAGACAAATGCCAGTCCTGGTGAGTTTGCAGTCTGCT TCACTGAACTCCAGCAGAAGTTTTTTGACAACCGTCCTGGAAAACTAAAGGATTTGATCCTCTTGATAAAGCACTGGCATCAACAGTGCCAGAAAAAAATCAAGGATTTACC CTCGCTGTCTCCGTATGCCCTGGAGCTGCTTACGGTGTATGCCTGGGAACAGGGGTGCAGAAAAGACAACTTTGACATTGCTGAAGGCGTCAGAACGGTTCTGGAGCTGATC AAATGCCAGGAGAAGCTGTGTATCTATTGGATGGTCAACTACAACTTTGAAGATGAGACCATCAGGAACATCCTGCTGCACCAGCTCCAATCAGCGAGGCCAGTAATCTTGG ATCCAGTTGACCCAACCAATAATGTGAGTGGAGATAAAATATGCTGGCAATGGCTGAAAAAAGAAGCTCAAACCTGGTTGACTTCTCCCAACCTGGATAATGAGTTACCTGC ACCATCTTGGAATGTCCTGCCTGCACCACTCTTCACGACCCCAGGCCACCTTCTGGATAAGTTCATCAAGGAGTTTCTCCAGCCCAACAAATGCTTCCTAGAGCAGATTGAC AGTGCTGTTAACATCATCCGTACATTCCTTAAAGAAAACTGCTTCCGACAATCAACAGCCAAGATCCAGATTGTCCGGGGAGGATCAACCGCCAAAGGCACAGCTCTGAAGA CTGGCTCTGATGCCGATCTCGTCGTGTTCCATAACTCACTTAAAAGCTACACCTCCCAAAAAAACGAGCGGCACAAAATCGTCAAGGAAATCCATGAACAGCTGAAAGCCTT TTGGAGGGAGAAGGAGGAGGAGCTTGAAGTCAGCITTGAGCCTCCCAAGTGGAAGGCTCCCΔGGGTGCTGAGCTTCTCTCTGAAATCCAAAGTCCTCAACGAAAGTGTCAGC TTTGATGTGCTTCCTGCCTTTAATGCACTGGGTCAGCTGAGTTCTGGCTCCACACCCAGCCCCGAGGTTTATGCAGGGCTCATTGATCTGTATAAATCCTCGGACCTCCCGG GAGGAGAGTTTTCTACCTGTTTCACAGTCCTGCAGCGAAACTTCATTCGCTCCCGGCCCACCAAACTAAAGGATTTAATTCGCCTGGTGAAGCACTGGTACAAAGAGTGTGA AAGGAAACTGAAGCCAAAGGGGTCTTTGCCCCCAAAGTATΑCCTTGGAGCTGCTCACCATCTATGCCTGGGAGCAGGGGAGTGGAGTGCCGGATTTTGACACTGCAGAAGGR TTCCGGACAGTCCTGGAGCTGGTCACACAATATCAGCAGCTCGGCATCTTCTGGAAGGTCAATTACAACTTTGAAGATGAGACCGTGAGGAAGTTTCTACTGAGCCAGTΓGC AGAAAACCAGGCCTGTGATCTTGGACCCAGGCGAACCCACAGGTGACGTGGGTGGAGGGGACCGTTGGTGTTGGCATCTTCTGGACAAAGAAGCAAAGGTTAGGTTATCCTC TCCCTGCTTCAAGGATGGGACTGGAAACCCAATACCACCTTGGAAAGTGCCGACAATGCAGACACCAGGAAGTTGTGGAGCTAGGATCCATCCTATTGTCAATGAGATGTTC TCARCCAGAAGCCATAGAATCCTGAATAATAATTCTAAAAGAAACTTCTGGAGATCATCTGGCAATCGCTTTTAAAGACTCGGCTCACCGTGAGAAAGAGTCACTCACARCC ATTCRTCCCTTGATGGTCCCTATTCCTCCTTCCCT GCCTTCTTGGACTTCTTGAAATCAATCAAGACTGCAAACCCTTTCATAAAGCTGCCTTGCTGAACTCCTCTCTGCA
GGAGCCCTGCTTAAAATAGTTGATGTCATCACTTTATGTGCATCTTATTTCTGTCAACTTGTATTTTTTTTTCTTGTATTTTTCCAATTAGCTCCTCCTTTTTCCTTCCAGT CTAAAAAAGGAATCCTCTGTGTCTTCAAAGCAAAGCTCTRTACTTTCCCCTTGGTTCTCATAACTCTGTGATCTTGCTCTCGGTGCTTCCAACTCATCCACGTCCTGTCTGT TTCCTCTGTATACAAAACCCTTTCTGCCCCTGCTGACACAGACATCCTCTATGCCAGCAGCCAGGCCAACCCTTTCATTAGAACTTCAAGCTCTCCAAAGGCTCAGATTATA ACTGTTGTCATATTTATAΓGAGGCTGTTGTCTTTTCCTTCΓGAGCCTGCCTTTATCCCCCCACCCAGGAGTATCCTCTTGCCAAAGCAAAAGACTTTTTCCTTGGCTTTAGC CTTAAAGATACTTGAAGGΓCTAGGTGCTTTAACCTCACAΓACCCTCACTTAAACTTTTATCACTGTTGCATATACCAGTTGTGATACAATAAAGAATGTATCTGG
391
MKVE CSFSGYKIYPGHGRRYARTDGKVFQFLNAKCESAFLSKRNPRQINWTVLYRRKIIKKGQSEEIQKKBTRRAVKFQRAITGASLADIMAKRNQKPEVRKAQREQAIRAA KEAKKAKQASKKTAMAAAKAPTKAAPKQKIVKPVKVSAPRVGGKR
392
TTTTTTCGCCATCTTTTGΓCTTTCCGTGGAGCTGTCGCCATGAΔGGTCGAGCTG'IGCAGTTTTAGCGGGTACAAGATCTACCCCGGACACGGGAGGCGCTACGCCAGGACCG ACGGGAAGGTTTTCCAGTΓTCTTAATGCGAAATGCGAGTCGGCTTTCCTTTCCAAGAGGAATCCTCGGCAGATAAAC GGACTGTCCTCTACAGAAGGAAGCACAAAAAGGG ACAGTCGGAAGAAATTCAAAAGAAAAGAACCCGCCGAGCAGTCAAATTCCAGAGGGCCATTACTGGTGCATCTCTTGCTGATATAATGGCCAAGAGGAATCAGAAACCTGAA GTTAGAAAGGCTCAACGAGAACAAGCTATCAGGGCTGCTAAGGAAGCAAAAAAGGCTAAGCAAGCATCTAAAAAGACTGCAATGGCTGCTGCTAAGGCACCTACAAAGGCAG CACCTAAGCAAAAGATTGRGAAΒCCTGTGAAAGTTTCAGCTCCCCGAGTTGGTGGAAAACGCTAAACTGGCAGATTAGATTTTTAAATAAAGATTGGATTATAACTCT
393
MANCEFSPVSGDKPCCRLSRRAQLC GVSILVLILVVVLAW VPRWRQTWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMK GTQTVPCNKILL SRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKI TYQSCPD RKDCSNNPVSVFWKTVSRRFAEAACDVVHVM NGSRSKIFDKNSTFGS VEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI
394
CTAAAGCTCTCTTGCTGCCTAGCCRCCTGCCGGCCTCATCTTCGCCCAGCCAACCCCGCCTGGAGCCCTATGGCCAACTGCGAGTTCAGCCCGGTGTCCGGGGACAAACCCT GCTGCCGGCTCTCTAGGAGAGCCCAACTCTGTCTTGGCGTCAGTATCCTGGTCCTGATCCTCGTCGTGGTGCTCGCGGTGGTCGTCCCGAGGTGGCGCCAGACGTGGAGCGG TCCGGGCACCACCAAGCGCTTTCCCGAGACCGTCCTGGCGCGATGCGTCAAGTACACTGAAATTCATCCTGAGATGAGACATGTAGACTGCCAAAGTGTATGGGATGCTTTC AAGGGTGCATTTATTTCAAAACATCCTTGCAACATTACTGAAGAAGACTATCAGCCACTAATGAAGTTGGGAACTCAGACCGTACCTTGCAACAAGATTCTTCTTTGGAGCA GAATAAAAGATCTGGCCCATCAGTTCACACAGGTCCAGCGGGACATGTTCACCCTGGAGGACACGCTGCTAGGCTACCTTGCTGATGACCTCACATGGTGTGGTGAATTCAA CACTTCCAAAATAAACTATCAATCTTGCCCAGACTGGAGAAAGGACTGCAGCAACAACCCTGTTTCAGTATTCTGGAAAACGGTTTCCCGCAGGTTTGCAGAAGCTGCCTGT GATGTGGTCCATGTGATGCTCAATGGATCCCGCAGTAAAAΓCTTTGACAAAAACAGCACTTTTGGGAGTGTGGAAGTCCATAATTTGCAACCAGAGAAGGTTCAGACACTAG AGGCCTGGGTGATACATGGTGGAAGAGAAGATTCCAGAGACTTATGCCAGGATCCCACCATAAAAGAGCTGGAATCGATTATAAGCAAAAGGAATATTCAATTTTCCTGCAA GAATATCTACAGACCTGACAAGTTTCTTCAGTGTGTGAAAAATCCTGAGGATTCATCTTGCACATCTGAGATCTGAGCCAGTCGCTGTGGTTGTTTTAGCTCCTIGACTCCT TGTGGTTTATGTCATCATACATGACTCAGCATACCTGCTGGTGCAGAGCTGAAGATTTTGGAGGGTCCTCCACAATAAGGTCAATGCCAGAGACGGAAGCCTTTTTCCCCAA GTCTTAAAATAACTTATATCATCAGCATACCTTTATTGTGATCTATCAATAGTCAAGAAAAATTATTGTATAAGATTAGAATGAAAATTGTATGTTAAGTTACTTCCTTTA
G
395
MNPD DTGHNTSAPAHHGE KNANFTGPNQTSSNST PQ DITRAISVGLVLGAFILFAIVGNILVI SVACNRHLRTPTNYFIVN AMADLLLSFTVLPF8AALEVLGYWV LGRIFCDI AAVDVLCCTASILSLCAISIDRYIGVRYSLQYPTLVTRRKAILALLSVWVLSTVISIGP LGWKEPAPNDDKECGVTEEPFYALF8ELG8FYIPLAVILVMYC RVYIVAKRTTKNLEAGVMKEMSN8KELTLRIHSK FHEDTLSSTKAKGHNPRSSIAVKLFKFSREKKAAKTLGIVVGMFILCW PFFIALPLGSLFSTLKPPDAVFKVVF L GYFNSCLNPIIYPCSSKEFKRAFVRILGCQCRGRRRRRRRRRRLGGCAYTYRP TRGGSLER8QSRKDS DD8GSCLSGSQRTLPSA8PSPGYLGRGAPPPVELCAFPEWKA PGA LSLPAPEPPGRRGRHDSGPLFTFKLLTEPESPGTDGGASNGGCEAAADVANGQPGFKSN PLAPGQF
396
AGGCAGGAGACGTGCTGCGGGCTGGGCTGCCCGGGGGAGATGACTCCTGCCAGGAGGGCGCCTCTGGGAAGAAGACCACGGGGGAAGCAAAGTTTCAGGGCAGCTGAGGAGC CTTCGCCGCAGCCCTTCCGAGCCCAATCATCCCCCAGGCTATGGAGGGCGGACTCTAAGATGAATCCCGACCTGGACACCGGCCACAACACATCAGCACCTGCCCACTGGGG AGAGTTGAAAAAIGCCAACTTCACTGGCCCCAACCAGACCTCGAGCAACTCCACACTGCCCCAGCTGGACATCACCAGGGCCATCTCTGTGGGCCTGGTGCTGGGCGCCTTC ATCCTCTTTGCCATCGTGGGCAACATCCTAGTCATCTTGTCTGTGGCCTGCAACCGGCACCTGCGGACGCCCACCAACTACTTCATTGTCAACCTGGCCATGGCCGACCTGC TGTTGAGCTTCACCGTCCTGCCCTTCTCAGCGGCCCTAGAGGTGCTCGGCTACTGGGTGCTGGGGCGGATCTTCTGTGACATCTGGGCAGCCGTGGATGTCCTGTGCTGCAC AGCGTCCATTCTGAGCCTGTGCGCCATCTCCATCGATCGCTACATCGGGGTGCGCTACTCTCTGCAGTATCCCACGCTGGTCACCCGGAGGAAGGCCATCTTGGCGCTGCTC AGTGTCTGGGTCTTGTCCACCGTCATCTCCATCGGGCCTCTCCTTGGGTGGAAGGAGCCGGCACCCAACGATGACAAGGAGTGCGGGGTCACCGAAGAACCCTTCTATGCCC RCTTCTCCTCTCTGGGCTCCTTCTACATCCCTCTGGCGGTCATTCTAGTCATGTACTGCCGTGTCTATATAGTGGCCAAGAGAACCACCAAGAACCTAGAGGCAGGAGTCAT GAAGGAGATGTCCAACTCCAAGGAGCTGACCCTGAGGATCCATTCCAAGAACTTTCACGAGGACACCCTTAGCAGTACCAAGGCCAAGGGCCACAACCCCAGGAGTTCCATA GCTGTCAAACTTTTTAAGTTCTCCAGGGAAAAGAAAGCAGCTAAGA∞TTGGGCATTGTGGTCGGTATGTTCATCTTGTGCTGGCTACCCTTCTTCATCGCTCTACCGCTTG GCTCCTTGTTCTCCACCCΓGAAGCCCCCCGACGCCGTGTΓCAAGGTGGTGTTCTGGCTGGGCTACTTCAACAGCTGCCTCAACCCCATCATCTACCCATGCTCCAGCAAGGA GTTCAAGCGCGCTTTCGΓGCGCATCCTCGGGTGCCAGTGCCGCGGCCGCGGCCGCCGCCGACGCCGCCGCCGCCGTCGCCTGGGCGGCTGCGCCTACACCTACCGGCCGTGG ACGCGCGGCGGCTCGCTGGAGCGCTCGCAGTCGCGCAAGGACTCGCTGGACGACAGCGGCAGCTGCCTGAGCGGCAGCCAGCGGACCCTGCCCTCGGCCTCGCCGAGCCCGG GCTACCTGGGCCGCGGCGCGCCACCGCCAGTCGAGCTGTGCGCCTTCCCCGAGTGGAAGGCGCCCGGCGCCCTCCTGAGCCTGCCCGCGCCTGAGCCCCCCGGCCGCCGCGG CCGCCACGACTCGGGCCCGCTCTTCACCTTCAAGCTCCTGACCGAGCCCGAGAGCCCCGGGACCGACGGCGGCGCCAGCAACGGAGGCTGCGAGGCCGCGGCCGACGTGGCC AACGGGCAGCCGGGCTTCAAAAGCAACATGCCCCTGGCGCCCGGGCAGTTTTAGGGCCCCCGTGCGCAGCTTTCTTTCCCTGGGGAGGAAAACATCGTGGGGGGGA
397 DNQAERESEAGVGLQRDEDDAP CEDVE QDGDLSPEEKIFLREFPRLKEDLKGNIDK RALADDIDKTHKKFTKANMVATSTAVISGVMSLLGLALAPATGGG8L STA GQG ATA GVTSIVSG^ E SK KEAQARAEDILPT DQED EDEEEKADYVTA GKIIY π-RNTLKYAKKNVRAFWKLRA^lPR ANATKR GQVSS S VQVQKAFAG TTLAMTKNARVLGG\mSAFSLGYDIΛTLSKE KHLKEGARTKFAEELPΛKALELERKLTELTQLYKSLQ^KVRεPyrøVGKDLTGTCETEAY KELREHVWMWLWLCVCLCV CVYVQFT
398
GGAGCCCATGATTTCCΓGGAAGAGCCCTAGAGCTTTGCΓΓTTTCTCTCCTGCAGCACTTAACCGAAACCAGTTTTGCAATCAATTCCTGTTCAAAGGCSACCCTACTCTTCC
ΓATCCGTCTTTCTCCAGCCCAGACACTCACAGCCCCCTGCCAGACCAGGGGACCTCGGAGAGGCAAGGACAGAGGTTCAGGATCTTCCTCTCCCTCGGGACCCAAGGSCACA
AAGGAGAGCTCCGTGGAGAGAAGAAAATCATTTGACTCCRGGGGACACAGATTTGCTGCCACAGAGGCTGATGGACAACCAGGCGGAGAGAGAAAGTGAGGCTGGTGTTGGT
TTGCAAAGGGATGAGGATGACGCΓCCTCTGTGTGAAGACGΓGGAGCTACAAGACGGAGATCTGTCCCCCGAAGAAAAAATATTTTTGAGAGAATTTCCCAGATTGAAAGAAG
ATCTGAAAGGGAACATΓGACAAGCTCCGTGCCCTCGCAGACGATATTGACAAAACCCACAAGAAATTCACCAAGGCTAACATGGTGGCCACCTCTACTGCTGTCATCTCTGG
AGTGATGAGCCTCCTGGGTTTAGCCCTTGCCCCAGCAACAGGAGGAGGAAGCCTGCTGCTCTCCACCGCTGGTCAAGGTTTGGCAACAGCAGCTGGGGTCACCAGCATCGTG
AGTGGTACGTTGGAACGCTCCAAAAATAAAGAAGCCCAAGCACGGGCGGAAGACATACTGCCCACCTACGACCAAGAGGACAGGGAGGATGAGGAAGAGAAGGCAGACTATG
TCACAGCTGCTGGAAAGATTATCΓATAATCTTAGAAACACCTTGAAGTATGCCAAGAAAAACGTCCGTGCATTTTGGAAACTCAGAGCCAACCCACGCTTGGCCAATGCTAC .
CAAGCGTCTTCTGACCACTGGCCAAGTCTCCTCCCGGAGCCGCGTGCAGGTGCAAAAGGCCTTTGCGGGAACAACACTGGCGATGACCAAAAATGCTCGCGTGCTGGGAGGT
GTGATGTCCGCCTTCTCCCTTGGCRATGACTTGGCCACRCRCTCAAAGGAATGGAAGCACCTGAAGGAAGGAGCAAGGACAAAGTTTGCGGAAGAGTTGAGAGCCAAGGCCT
TGGAGCTGGAGAGGAAACTCACAGAACTCACCCAGCTCΓACAAGAGCTTGCAGCAGAAAGTGAGGTCAAGGGCCAGAGGGGTGGGGAAGGATTTAACTGGGACCTGCGAAAC
CGAGGCTTACTGGAAGGAGTTAAGGGAGCATGTGTGGARGRGGCTGTGGCTGTGTGTGTGTCTGTGTGTCTGTGTGTATGTACAGTTTACATGAATGTTCCTCAGGACATGG
CATACAATGGCCTTGGAGGTCCAAATAATATCAAGTACARCTTGGAGATGAGGGTGCCTGTCCTGGACAGACCTCGGCATGCCTTCTGTTTCTCCTTCAATGCTCCTTAAGG
CCTATGTGCTGGGAAAAGKSGTCTRCCCTGTTTGTTTGTRRGTTTGTTTGTTTGTTTGTTTTGAGACTCCAGTCTGGGTGTCAGAATGAGACCCCATCTCAAAAAAAAAAAAA
AAAAAAAAAAAGAAGAAGAATACAGTCATGTATCTCTΓGGΓGACAGGGACGCATTCTGATAAATGTGTCATTAGGCAATTGCATTGTAGTGTGATTATCACAGATTGTACTT
ATACAAAACTTAGATGGCATAGCCTACTGCATACCTAGGCΓATATGGGAGAGCCTATTGCTCCCAGGCTACXSCACCTGTACAGCATGTGACTACTGAATACTATAGGCAATT
GCAGCACAATGGGAAATATTTGTGTATCTAAACATATGΓAAACAGAGAAAAAGGAAAGTAAAAATATGGCATAAAAGATAAGAATTGGCTCTCCTGTACAGGGCACTTACTA
CGAATGGAGCTTGCAGGGCTGAGAGTTGCTCCAGATGAGRCAGTGAGTGGTGAATGAATGTGAAGGCCTAGGGCATTACTGTATACTACTGTAGGCTTTATAAACACAGCAC
ACTTAGGGTACACAAAATGCATATΓAAAACATTTTCTTCCΓTCAGTATATTAGGCAATAGGAATTTTTCAAGTCCACTATAAATCTTATCAAACCATGGTTGTATATGCAGT RGACCGAAACATTGTRARRGGACACATAACTATAGTTGAAAGAATAAGCAAAAAGTCTATCTAGGTGTGCTGTCTTGAGCAACTTTTAATTATTCTCCTGTCCTGCAATATG AGTTAATCTTCTCTGARCGATGTAGATTCCAGGAAGGGGTGTCCAGGACAATTACCTTCCTTCTGGAGAAACTTCCC'IIAATCAAATAAGAGAAC'RTCAAAGAAAATCCCTC CCTGTGCTTTGGAAGGGAAGGGAGGTGGGCAGCAGTGGGTCAGAGATAGACCTTTGTTCTCTTATTTCTGAGGCCCTTCAGTCTCCTTTATTCAAAGCACTCAGCATGCCAA AGCACCCTATTTTAGGGΓATCTΓΓTTCTGAGCCCTAAACACTGTGTTGGGGATGTCAACTGTGACAGGAAAA'IATCTTGGGGCCCCAGAATCACTAAGGAAAACTCAAGCTT AGGGAAACTTCTTAGGGCAAACCCACCTCCCACTCTAΓTCAAAGTTATCTCTCTGCTCACTGAGATAGATACATA'ICTGATTGCCTCCTTTGGAAAGGCTAATCAGAAACTC AAAAGAATGCAACTGTTΓGTGTCTCACCTATCTGTGACCTGGAAGCTCCCTCCCCACTGAACCAATGTTCTTCTTACATATATTGATTAATGTCTTATGTCTCCCTAAAATG RATAAAACCAAGGTATGCCCCAACCATCTTGGCCACARGTCATCAGGACTTCCTGAGTCTGTGTCACAGTGTGTCCTCAACCTTGGCAAAATAAACTTTCTAAATTAACTGA GACAAAAAAAAAAAAAAA
399
MSERAADDVRGEPRRAAAAAGGAAAAAARQQQQQQQQQQPPPPQPQRQQHPPPPPRRTRPEDGGPGAASTSAAAMATVGERRPLPSPEVM GQSWNLWVEASKLPGKDGTEL DESFKEFGKNREVMGLCREDMPIFGFCPAHDDFYLWCNDCMQWKPQAFQSHYERRHSSSSKPPLAVPPTεVFSFFPSLSKSKGGSASGSNRSSSGGVLSASSεSSKL KS PKEKLQLRGNTRPMHPIQQSRVPHGRIMTPSVKVEKIHPKMDGT KSAVGPTCPATVSSLVKPG NCP8IPKPTLP8PGQILNGKGLPAPPT EKKPEDNSNNRKF NKRL SEREFDPDIHCGVIDLDTKKPCTRSLTCKTHSLTQRRAVQGRRKRFDVLLAEHKNKTREKELIRHPDSQQPPQPLRDPHPAPPRTSQEPHQNPHGVIPSESKPFVASKPKPH rPSLPRPPGCPAQQGGSAPIDPPPVHESPHPPLPATEPASRLSSEEGEGDDKEESVEKLDCHYSGHHPQPASFCrFG8RQIGRGYYVFD8RWNRLRCALNLMVEKHLNAQ W KKIPPVP8TTSPISTRIPHRTN8VPTSQCGVSY AAATVSTSPVL SSTCISPNSKSVPAHGTTLNAQPAASGAMDPVCSMQSRQVSSSSSSP8TPSGLSSVPSSPMSRKPQ K KSSK8LRPKESSGNSTNCQNASSST8GGSGKKRKNSSPLLVHSSSSSSSSSSSSHSMESFRKNCVAHSGPPYPSTVTSSHSIGLNCV NKANAVNVRHDQ8GRGPPTGSP AESIKRMSVMVNSεDSTLSLGPFIHQSNE PV SHGSFSHSHrP DΪ IGKKRKCSPSSSSII^SSSKPTKrAKVPAVMSrVHMKHTGTIPGAGGLMNSSLLHQPKARP
400
CGRTGCTGTCGAAAGGGTGAAAGAGAAACTT(3GCGACCTCCCGGAGGAGTTCGCGAAGCGACCAGGAGCGTGTTGCCATCGTCCTCACCCGGCACCCAATTCCACCACAGAG TCGGGATTTCGTCGGΓGAΓCGTGAΓGGGGTGCTTTTATTTTTCTCTTTGATTTTCAAAAAATGTCTATGTGACTGTCCCTATCTTAAGGGGAAGTTGAAAGTGGGGGCGGGG GRGCTCAATGAGAAACGTRGCCTTGTGTGTAGTTGTTTGGAGCACACTGCAAATTATATTGGCATCTCTTTCCAAAAGTCACTTTGATTCAACTTCGATAGCTTTCTCGTAA ARGGCACGTTTAGGTGGRGAGAGGRGGATGAGGAAACAGGCACCAGTGCAGCTGATTTGACCTCCAGTGGGA'IAGATACGATTAGCACCAGGATCGTGTCTCATTTTGAACC CAGATCTGAACAGAATΓAAGACGAACGAGCTTTCACAATTGCAGCAGATGAAGATCCATTGGTAAATTGATCAGGATTTTTGGCCTACCCTCCAAAGAAAAGGAGCGGAAAG AATGTCGGAGCGGGCCGCGGATGACGTCAGGGGGGAGCCGCGCCGCGCGGCGGCGGCGGCGGGCGGAGCAGCGGCCGCGGCCGCCCGGCAGCAGCAGCAGCAGCAGCAGCAG CAGCAGCCGCCGCCTCCGCAGCCCCAGCGGCAGCAGCACCCGCCACCGCCGCCACGGCGCACACGGCCGGAGGACGGCGGGCCCGGCGCCGCCTCCACCTCGGCCΣCCGCAA TGGCGACGGTCGGGGAGCGCAGGCCRCTGCCCAGTCCTGAAGRGATGCTGGGACAGTCGTGGAATCTGTGGGTTGAGGCTTCCAAACTTCCTGGGAAGGACGGGACAGAATT GGACGAAAGTTTCAAGGAGTTTGGGAAAAACCGCGAAGTCAΓGGGGCTCTGTCGGGAAGACATGCCAATATTTGGTTTCTGTCCAGCCCATGATGATTTCTACTTGGTGGTG ΓGTAACGACTGTAATCAGGTTGTCAAACCGCAGGCATTTCAAΓCACATTATGAAAGAAGACATAGCTCATCCAGCAAGCCGCCTTTGGCCGTTCCTCCCACTTCAGTATTTT CCTTCTTCCCTTCTCTGΓCCAAAAGCAAAGGAGGCAGTGCAAGTGGAAGCAACCGTTCTTCCAGTGGAGGTGTTCTTAGCGCATCCTCATCAAGTTCCAAGTTGTTGAAATC ACCCAAAGAGAAACTGCAGCTCAGGGGGAACACCAGGCCAARGCATCCCATTCAGCAAAGTAGAGTTCCCCATGGTAGAATCATGACACCCTCTGTGAAAGTGGAAAAGATT
CATCCGAAAATGGATGGCACACTACTGAAATCTGCGGTGGGGCCAACCTGTCCTGCTACTGTGAGTTCCTTAG'ICAAGCCTGGCCTTAACTGCCCCTCAATACCAAAGCCAA
CCTTGCCTTCACCTGGACAGATTCTΒAATGGCAAAGGGCTTCCTΒCACCGCCCACTCTGGAAAAGAAACCTGAAGACAATTCCAATAATAGGAAATTTTTAAATAAGAGATT ARCAGAAAGAGAGTTTGARCCTGACATCCACTGTGGGGTTARRGATCTCGACACCAAGAAGCCCTGCACCCGGTCTTTGACATGCAAGACACATTCCTTAACCCAGCGCAGG GCTGTCCAGGGTAGAAGAAAACGATTTGATGTGTTATTAGCCGAGCACAAAAACAAAACCAGGGAAAAGGAATTGATTCGCCATCCGGACTCTCAGCAACCACCGCAGCCTC ΓCAGGGACCCGCATCCCGCCCCTCCTAGAACGTCACAGGAGCCGCACCAAAACCCTCACGGAGTGATTCCTTCCGAATCAAAGCCTTTTGTAGCTAGTAAACCTAAACCTCA CACCCCCAGTCTTCCAAGGCCTCCAGGCTGCCCTGCTCAGCAAGGTGGGAGTGCCCCCATTGACCCTCCTCCAGTCCATGAATCTCCACACCCTCCCCTGCCTGCCACTGAG CCAGCTTCTCGGTTATCCAGΓGAGGAGGGCGAAGGCGATGACAAAGAAGAGTCTGTTGAAAAACTGGACTGTCATTATTCAGGTCATCATCCTCAGCCAGCATCTTTTTGCA CATTTGGGAGCCGGCAGATAGGAAGAGGCTATTACGTGTTTGACTCCAGGTGGAATCGACTTCGCTGCGCCCTCAACCTCATGGTGGAGAAGCATCTGAATGCACAGCTATG
GAAGAAAATCCCACCAGTGCCCAGTACCACCTCACCCATCTCCACACGTATTCCTCACCGGACAAACTCTGTGCCGACATCACAATGTGGAGTCAGCTATCTGGCAGCAGCC
ACCGTCTCTACATCCCCAGΓCCTGCTCTCATCTACCTGCATCΓCCCCAAATAGCAAATCGGTACCAGCTCATGGAACCACACTAAATGCACAGCCIGCIGCTTCAGGGGCGA ΓGGATCCTGTGTGCAGTATGCAATCCAGACAAGTGTCCTCTΓCATCCTCATCCCCTTCCACGCCCTCTGGCCTTTCCTOGGTTCCTTCCTCCCCCATG'ICCAGGAAACCTCA GAAATTGAAATCCAGCAAAΓCTTTGAGGCCCAAGGAGTCTTCΓGGTAACAGCACTAACTGTCAAAATGCCAGTAGCAGTACCAGTGGCGGCTCAGGAAAGAAACGCAAAAAC AGTTCCCCACTGTTGGΓTCACTCTTCCTCCTCCTCTΓCCTCCΓCCTCCTCTTCTTCTCATTCCATGGAGTCTTTTAGGAAAAACTGTGTGGCTCACTCTGGGCCTCCCTACC CCTCAACGGTAACATCΓTCCCATAGCATCGGCCTCAACTGTGΓGACGAATAAAGCAAATGCGGTGAACGTCCGGCATGACCAGTCAGGGAGGGGCCCCCCCACCGGGAGCCC ΓGCTGAATCCATCAAGAGGAΓGAGTGTGATGGTGAACAGCAGΓGATTCTACTCTTTCTCTTGGGCCATTCATTCACCAGTCCAATGAACTGCCIGTCAACTCCCACGGCAGT ΓΓTTCCCACTCACACACTCCΓCTAGACAAACTCATAGGAAAGAAAAGAAAGTGCTCACCCAGCTCGAGCAGCATCAACAACAGCAGCAGCAAACCCACAAAGGTTGCCAAAG TGCCAGCCGTGAACAARGTCCACATGAAACACACAGGCACCARCCCAGGGGCACAAGGACTGATGAACAGTTCCCTCCTTCATCAGCCAAAGGCACGTCCCTGACAGCTGAA AATAGCACGGGGAGGAAΓAAΓGCGGACACTTTTGAGGACAAGΓTACACCTCCACTCAGCACTCTGGACTCCACGATGCCTTTGAGTCTGTTTTCCCAACCTCCTGTGGGCCT CAAGGGTAGAAACCTGCCGGGCTGTTGTTTTAACGAGGATTRCCCTGAAGCTATGTCTCTAGCAGTGAGTACTCATAAAGGACACTGGATCAAGTTCAGCCACCGAATTGCT
ΓGGCTGGGCAAAAGAAΓGTΓΓTGGCAAGAGCGTTACΓGTAGACCTTTCTCCCTCCTTCCTTTTACTACCATTTTITTTTAACACTGTCATCTGTAGGTCACTCTCCAGCAGT ΓAGGCACCTTAACTGGAGACCAGAAACCTTCCAGAGAACACAGGGCTGCATCCCGAGCAACCCTCTGAAGAAGGGAATTAGGCTTTAGATTTTGATAGCAATGTTCCAGGAA RGAAATATAGATGTTAGCCCAAGACACCATGACAAAATAGCCCAGCCTTTTGAGAGTAATTTGGGAAAAGAAGCTGTCAGAAGTTTCTAACTTACAAACTGGTTTGAAATTT ΓΓGATGCCCAGACAGCAAGTAΓCGACAGCAACGGAAΓTCGAGCTCCGTC
401
MEGQQVILHLPLSQKGPF THEPSAPRTLLQVLQDPA KDLV TCPTLPWHSLILRPQYEIQAIMHMRRTIVKIPSTLEVDVEDVTASSRHVHFIKPLLLSEVLAWEGPFP SMEI EVPEGRPIFLSPWVGS QKGQRLCVYGLASPPWRVLASSKGRKVPRHFLVSGGYQGK RRRPREFPTAYDLLGAFQPGRPLRVVATKDCEGEREENPEFTS AVGDR LEVLGPGQAHGAQGSDVDV VCQR SDQAGEDEEEECEG-EAErQSGECCPSTSLAVSWRR
402
GACCACGCGTATCGAΓGΓCGACCCACAGGATTGTCACAGAGGGCAGGGTGGTGACTΞAGGACCAGCTCCTCATGCTTGAGGCTGTGGTGATGCACCTCGGGATCCGCTCTGC CCGCTGTGTCCTGGGCATGGAGGGTCAGCAGGTCATCCTGCACCTGCCCCTATCCCAGAAGGGGCCCTTCTGGACATGGGAGCCTAGTGCCCCTCGAACTCTGCTCCAGGTC CTACAGGAICCAGCCCΓGAAAGACCTCGTCCTCACCΓGCCCCACCCTGCCCTGGCATΓCCCTGATCCTGCGGCCCCAGTATGAGATCCAAGCCATCATGCACATGCGCAGGA CCATTGTCAAGATCCCΓTCTACCCTGGAGGTCGACGΓGGAGGACGTCACCGCCTCCTCCCGGCACGTCCACTTTATCAAACCGCTGCTGCTGAGCGAGGTCCTGGCCTGGGA AΒGCCCTTTCCCCCRGRCCATGGAGATCCTGGAGΣTRCCTGAΒGGCCGCCCCATCTTCCTCAGCCCGTGGGTGGGCTCCTTGCAAAAAGGCCAGAGGCTTTGCGTCTATGGC CTAGCCTCACCACCCΓGGCGGGTCCTGGCCTCAAGCAAGGGCCGCAAGGTGCCCAGGCACTTCCTGGTGTCAGGGGGCTACCAAGGCAAGCTGCGGCGGCGGCCAAGGGAGT TCCCCACGGCCTATGACCΓCCTAGGTGCTTTCCAGCCAGGCCGGCCACTCCGGGTGGΓGGCCACAAAGGACTGTGAGGGCGAGAGGGAGGAGAATCCCGAGTTCACGTCCCT GGCTGTGGGTGACCGGCRGGAGGTGCTGGGGCCTGGCCAGGCCCATGGGGCCCAGGGCAΑTGACG GGATGTCTTGGTTTGTCAGCGGCTGAGTGACCAGGCTGGGGAAGAT GAGGAGGAAGAGTGCAAAGAGGAGGCAGAGACCCAGAGCGGGTCCTGCTGCCCTTCCACTTCCCTGGCAGTTTCGTGGAGGAGATGAGTGACAGCCGGCGCTACAGCCTGGC AGATCTGACTGCCCAGTΓΓTCAATGCCTTGTGAGGTCAAGGTCSGTGGCCAAGGACACCAGCCACCCCAATGACCCTCAGAACCTCCTTCCTGGGCCTGCGGCTGGAGGAGAA GATCACAGAGCCATΓCTΓGGTGGTGAGCCTGGACTCΓGAGCTGGGATGTGCTTTGAGAΓCCCTCCCCGGAGGCTGGACCTGACTGTCGTGGAGGCCAAGGGGCAGCCAGACT TGCCAGAGGGGTCTCΓCCCCATAGCCACAGTGGAGGAAGCΓGGAACAGACACCTTTTAΓTATTGTCTTCGGAAGTTACCAGCCTGTGAGATCCAAGCCCCCCCACCCAGGCC CCCRAAAAATCAGGGCCTCAGCAAGCAGAGGAGACACAGCAGTGAGGGAGGCGTCAAGRCTTCTCAAGTCTTAGGATTGCAGCAACACGTTCGGCTGCCCAAACCCAAGGCG AAGACCTTGCCAGAGΓTCATCAAGGATGGCTCCAGTACGTACAGCAAGATTCCTGCCCACAGGAAGGGCCACAGGCCCGCTAAGCCCCAAAGGCAGGATCTAGATGATGATG AACATGATTATGAAGAAARACTTGAGCAATTTCAGAAAACCATCTAAGTGCTGGAGGAACCACGCTTCCTAACTGCTGCTTCTCAGGGAATCCGACACCAGCCAACCATTTT AAGCCTCTAAAAGACCTCGGGCAAGTCTCACAGAAACTGAGCTGCAGACGGGGAGTAGCTTTGTGGAAACTGATTTGATGGACACTGCACCAGCTTCCTTCAGGTTCTAGAT TCTTGCTACTTAGGGCGGGCTGGTTTGGACCTAACAΓCTCGCACGTGACTCCCTCAGCCTCAGAGCCTTGGGATGCAGAGCAGCTGGCAGGGTTCCTCTCAATCCTGCAACC CCAGCTGTCCCACCGGTGGATGCAGAGGGGAATCCGAGGCCATCAACCTTGGTGACAGCAGCGCAGTGCCAATGCTGATCACACTGCATGGGAGATTTTGTTAACGTCTGCC ACCCCCACTCTCACCCCCAAGCTCTAAGCCCCCGGGAGGCCΓGGACTGTCTTCCTCATCTCTGTAGCACCAAGCCTGATAGATCTGTATATGGTAAACAGGGGTTTAACCAC ATGTGGTTAACATGΒATTAATΒTGGGAATTTGGCTTCAAGAACACAACCTTAGGACCTRGGGCCCCAAAAGCTGGTGGTGAAATGAGAGGAGCCAATTTAAGAAGACCCTTA TGGAGACCTGAGGCTGCAGAAACTGGTAGGTTTCATCAGGTGGTTAAAGTCGTCAAAGTTGTAAGTGACTAACCAAGATTATTTCATTTTAAAACCACAGAATAAAAATGAC ACCTGAGCTTCTCC
403
MVWRPLWSLLLWEAIiPITVTGAQVLSKVGGSVLLVAARPPGFQVREAIWRεLWPSEELIΛTFFRGε ET YHSRF GRAQLHSNLSLELGPLESGDSGNFSVLMVDTRGQP WTQTLQLKVYDAVPRPWQVFIAVERDAQPSKTCQVFLSC APNISEITYSWRRETTMDFGMEPHSLFTDGQVL81SLGPGDRDVAYSCIVSNPVSWDLATV PWDSCHHEA APGKASYKDVLLV PVSLLLMLVTLFSAWHWCPCSGKKKKDVHADRVGPETENP VQD P
404
GGACCACAGCTCCTCCCGTGCATCCACTCGGCCTGGGAGGTTCTGGATTTTGGCTGTCGAGGGAGTTTGCCTGCCTCTCCAGAGAAAGATGGTCATGAGGCCCCTGTGGAGT CTGCTTCTCTGGGAAGCCCTACTTCCCATTACAGTTACTGGTGCCCAAGTGCTGAGCAAAGTCGGGGGCTCGGTGCTGCIGGTGGCAGCGCGTCCCCCTGGCTTCCAAGTCC GTGAGGCTATCTGGCGATCTCTCTGGCCTTCAGAAGAGCTCCTGGCCACGTTTTTCCGAGGCTCCCTGGAGACTCTGTACCATTCCCGCTTCCTGGGCCGAGCCCAGCTACA CAGCAACCTCAGCCTGGAGCTCGGGCCGCTGGAGTCTGGAGACAGCGGCAACTTCTCCGTGTTGATGGTGGACACAAGGGGCCAGCCCTGGACCCAGACCCTCCAGCTCAAG GTGTACGATGCAGTGCCCAGGCCCGTGGTACAAGTGTTCATTGCTGTAGAAAGGGATGCTCAGCCCTCCAAGACCTGCCAGGTTTTCTTGTCCTGTTGGGCCCCCAACATCA GCGAAATAACCTATAGCTGGCGACGGGAGACAACCATGGACTTTGGTATGGAACCACACAGCCTCTTCACAGACGGACAGGTGCTGAGCATTTCCCTGGGACCAGGAGACAG AGATGTGGCCTATTCCTGCATTGTCTCCAACCCTGTCAGCTGGGACTTGGCCACAGTCACGCCCTGGGATAGCTGTCATCATGAGGCAGCACCAGGGAAGGCCTCCTACAAA GATGTGCTGCTGGTGGTGGTGCCTGTCTCGCTGCTCCTGATGCTGGTTACTCTCTTCTCTGCCTGGCACTGGTGCCCCIGCTCAGGGAAAAAGAAAAAGGATGTCCATGCTG ACAGAGTGGGTCCAGAGACAGAGAACCCCCTTGTGCAGGATCTGCCATAAAGGACAATATGAACTGATGCCTGGACTATCAGTAACCCCACTGCACAGGCACACGATGCTCT GGGACATAACTGGTGCCTGGAAATCACCATGGTCCTCATATCTCCCATGGGAATCCIGTCCTGCCTCGAAGGAGCAGCCTGGGCAGCCATCACACCACGAGGACAGGAAGCA CCAGCACGTTTCACACCTCCCCCTTCCCTCTCCCATCTTCTCATATCCTGGCTCTTCTCTGGGCAAGATGAGCCAAGCAGAACATTCCATCCAGGACACTGGAAGTTCTCCA GGATCCAGATCCATGGGGACATTAATAGTCCAAGGCATTCCCTCCCCCACCACTATTCATAAAGTATTAACCAACTGGCACCAAGGAATTGCCTCCAGCCTGAGTCCTAGGC TCTAAAAGATATTACATATTTGAACTAATAGAGGAACTCTGAGTCACCCATGCCAGCATCAGCTTCAGCCCCAGACCCTGCAGTTTGAGATCTGATGCTTCCTGAGGGCCAA GGCATTGCTGTAAGAAAAGGTCTAGAAATAGGTGAAAGTGAGAGGTGGGGGACAGGGGTTTCTCTTTCTGGCCTAAGGACTTTCAGGTAATCAGAGTTCATGGGCCCTCAAA GGTAAATTGCAGTTGTAGACACCGAGGATGGTTGACAACCCATGGTTGAGATGGGCACCGTTTTGCAGGAAACACCATATTAATAGACATCCTCACCATCTCCATCCαCTCT CACGCCTCCTGCAGGATCTGGGAGTGAGGGTGGAGAGTCTTTCCTCACGCTCCAGCACAGTGGCCAGGAAAAGAAATACTGAATTTGCCCCAGCCAACAGGACGTTCTTGCA CAACTTCAAGAAAAGCAGCTCAGCTCAGGATGAGTCTTCCTGCCTGAAACTGAGAGAGTGAAGAACCATAAAACGCTATGCAGAAGGAACATTATGGAGAGAAAGGGTACTG AGGCACTCTAGAATCTGCCACATTCATTTTCAAATGCAAATGCAGAAGACTTACCTTAGTTCAAGGGGAGGGGACAAAGACCCCACAGCCCAACAGCAGGACTGTAGAGGTC ACTCTGACTCCATCAAACTTTTTATTGTGGCCATCTTAGGAAAATACATTCTGCCCCTGAATGATTCTGTCTAGAAAAGCTCTGGAGTATTGATCACTACTGGAAAAACACT TAAGGAGCTAAACTTACCTTCGGGGATTATTAGCTGATAAGGTTCACAGTTTCTCTCACCCAGGTGTAACTGGATTTTTTCTGGGGCCTCAATCCAGTCTTGATAACAGCGA GGAAAGAGGTATTGAAGAAACAGGGGTGGGTTTGAAGTACTATTTTCCCCAGGGTGGCTTCAATCTCCCCACCTAGGATGTCAGCCCTGTCCAAGGACCTTCCCTCTTCTCC CCCAGTTCCCTGGGCAATCACTTCACCTTGGACAAAGGATCAGCACAGCTGGCCTCCAGATCCACATCACCACTCTTCCACTCGATTGTTCCCAGATCCTCCCTGCCTGGCC TGCTCAGAGGTTCCCTGTTGGTAACCTGGCTTTATCAAATTCTCATCCCTTTCCCACACCCACTTCTCTCCTA'TCACCTTCCCCCAAGATTACCTGAACAGGGTCCATGGCC ACTCAACCTGTCAGCTTGCACCATCCCCACCTGCCACCTACAGTCAGGCCACATGCCTGGTCACTGAATCATGCAAAACTGGCCTCAGTCCCTAAAAATGATGTGGAAAGGA AAGCCCAGGATCTGACAATGAGCCCTGGTGGATT1GTGGGGAAAAAATACACAGCACTCCCCACCTTTCTTTCGTTCATCTCCAGGGCCCCACCTCAGATCAAAGCAGCTCT GGATGAGATGGGACCTGCAGCTCTCCCTCCACAAGGTGACTCTTAGCAACCTCATTTCGACAGTGGTTTGTAGCGTGGTGCACCAGGGCCTTGTTGAACAGATCCACACTGC TCTAATAAAGTTCCCATCCTTAATGACTCACTTGTCAACTAGTGGACTAA'ITAACCCTCCACCAAAAAAACACAAAGTGCTTCTGTGAGACCAATTTTGTGCTAATGAGCAT TGAGACTGATGCTTTGTAAGTCACACCACAACAAATATTGATTGAGGGCGCTGCATGTGCTGGGTACATTTCTTGGCACTTGGGAATCAGTAGTCAAGCGAAACCCTTGCCT TTGAGAGTTTATGGTCTGGATAATATAAATAAACAAGTAAGCATAAAAAAAAAAAAAAAAA
405
MSVGRRRIKL LGI M A VPIYFIMEVSKSSSQEKNGKGEVIIPKEKF KISTPEEAYIMREQEKLNRQYNPILSMLTNQTGEAGR SNISH NYCEPD RVTSVVTGF N PDRFKDFLLYLRCRNYSLLIIXΪPDKCAKKPFLLLAIKSLTPHFARRQAIRESWGQESNAGNQTVVRVFLLGQTPPEDNHPDLSDMLKFESEKΗQDILMWNYRDTFFNLSLK
EVLFLR VSTSCPDTEFVFKGDDDVFVNTHHILNYLNSLSKTKAKD FIGDVIHNAGPHRDKKLKYYIPEVVYSGLYPPYAGGGGF YSGH A RLYHITDQVHLYPIDDVY
TGMCLQKLGLVPEKHKGFRTFDIEEKNKNNICSYVDLMLVHSRKPQEMIDI SQLQSAHLKC
406
GGCGCCGGCAGCGTCAGCAGCGGCAACAAGTGCCGGAGTAGCAGAGCCAAGCCGGAGCAGTCCCTGCCGCCGACACCGCCGGGCCGCCCGTCCGGGGCGCCGCGCATGGAGC GTGAGCTGCGGCGGTCGCCGGGCTGAGCCGCGCGGAGCGCCGGGACGTGGATGTGGCCGCGATCTCCCGCCCTTGCCCCCGCCCCGCCGAGCTGGAGCTGCTCCCGGACAAG ATATGAGAAATGAGTGTTGGACGTCGAAGAATAAAGTTGTTGGGTATCCTGATGATGGCAAATGTCTTCATTTAT'ITTATTATGGAAGTCTCCAAAAGCAGTAGCCAAGAAA AAAATGGAAAAGGGGAAGTAATAATACCCAAAGAGAAGTTCTGGAAGATATCTACCCCTCCCGAGGCATACTGGAACCGAGAGCAAGAGAAGCTGAACCGGCAGTACAACCC CATCCTGAGCATGCTGACCAACCAGACGGGGGAGGCGGGCAGGCTCTCCAATATAAGCCATCTGAACTACTGCGAACCTGACCTGAGGGTCACGTCGGTGGTTACGGGTTTT AACAACTTGCCGGACAGATTTAAAGACTTTCTGCTGTATTTGAGATGCCGCAATTATTCACTGCTTATAGATCAGCCGGATAAGTGTGCAAAGAAACCTTTCTTGTTGCTGG CGATTAAGTCCCTCACTCCACATTTTGCCAGAAGGCAAGCAATCCGGGAATCCTGGGGCCAAGAAAGCAACGCAGGGAACCAAACGGTGGTGCGAGTCTTCCTGCTGGGCCA GACACCCCCAGAGGACAACCACCCCGACCTTTCAGATATGCTGAAATTTGAGAGTGAGAAGCACCAAGACA'ITCT'IATGTGGAACTACAGAGACAC'ITTCTTCAACTTGTCT CTGAAGGAAGTGCTGTTTCTCAGGTGGGTAAGTACTTCCTGCCCAGACACTGAGTTTGTTTTCAAGGGCGATGACGATGTTTTTGTGAACACCCATCACATCCTGAATTACT TGAATAGTTTATCCAAGACCAAAGCCAAAGATCTCTTCATAGGTGATGTGATCCACAATGCTGGACCTCATCGGGATAAGAAGCTGAAGTACTACATCCCAGAAGTTGTTTA CTCTGGCCTCTACCCACCCTATGCAGGGGGAGGGGGGTTCCTCTACTCCGGCCACCTGGCCCTGAGGCTGTACCATATCACTGACCAGGTCCATCTCTACCCCATTGATGAC GTTTATACTGGAATGTGCCTTCAGAAACTCGGCCTCGTTCCAGAGAAACACAAAGGCTTCAGGACATTTGATATCGAGGAGAAAAACAAAAATAACATCTGCTCCTATGTAG ATCTGATGTTAGTACATAGTAGAAAACCTCAAGAGATGATTGATATTTGGTCTCAGTTGCAGAGTGCTCATTTAAAATGCTAAAATAGATACAAACTCAATTTTGCATAGAA AGGTGTATTTTGAATAGTTCCCATGTTGTGTTCTCACATTAGAGTAATTTCTATATTAAACCATGAAAATTGCCTTTATGAGTGATACCCATTTGAGGGCCTCTAAACCCTT CAATTTGGTACTCACGTGAAGAGGGAAAGCGGAAGATGGTAATTTTTTTTTATGGATGATATGGCAGGATGATTGGTTCTGATCTTACCGGCTAGTGGTCATTTTTAAAAAA CTTGTACCCTCTTATCTGAAATCCTGTTTCTGGAATTTGGCCATTTTAAGTGATTTTGTTTGCCCTCTTCTATAATATTCCTACTTCCCATAATAATGACTGATTTATTTGT TATTCAGGTATTTATAAACCTATTGGCTACAAAGACTTTGTTAAACTTTATCCAGTGGTTTTCGTGAAATGGAATTATGTTTATTTTTATGGGATTTGGGTAAATTTTAAAT TGTCTAGAAAACTGAAATTTCAGTTGTCAGTTGTGGAATTCAGTTTTTCAATTGTGGAAATTTCCTGCCACCCCAACAGTATTTTTGTGTGTTAATTAATTTTGCAAAATGA GAATCATGGTGTGACACTCATCTAATTTATCTTGTTGTGATGTTATGGTCATAAIAAGGAGAAAGAGGGTTTAATTTTTCTTGTATTTGGTTTCCTGGTGGTATCATAGTGT AATTTTAGTATTTGAAAATCAGTGTGATTCCTTAATGGCCAACTGAAGATTGAATTGCCGCTAACAACCATATCGTGTTAGTGAATTTTCAATATGGACCAGGAAGGCATAT GTATTTTGAACTTGAGTGAAAAGGTTGAAGTTACAGACTTTTGCATAGATGGTTTGTCAGTTTAAAATTCCAGAATTTGTTATTGCCATATTTTCACATGCTGCTTATACAA GATTATTATTGAGTAGTAACTGCTTCCCTGTCTATGTAGAAGTGCCTGTGTTTTTATTTATTGTTCAGATCAAAGACCAAAACATTTTCTTAAATATATTTTATGTAATATT TTATTTGTATACAGTGTTGTTGATGAAATATTTAACTAGAGCATGATATTTTAAATGTTAAGGTGTAACATATGTTAAATAAAACTGTTATTTTTGAATTTTAAAATTTGTT TTTTGGGGGTATGAACTACTAGAGTTTAAAATTCTGCCAAACTATTACTTATATGTACTATTGTGTAACATACTTTCTTGAGATATTTTTGTTTATAGAATTGAAGGTTCTT ATCAGATGGGATACTGGGGACTATAAACAATGGAAATAAAGCCACTGTATTTTT
407 ENQVLTPHVY AQRHRE Y RVELSDVQNPAISITENVLHFKAQGHGAKGDNVYEFHLKFLDLVKPEPVYKLTQRQVNITVQKKV8Q WERLTKQEKRPLFLAPDFDR LD ESDAEMELPAKEEERLHKLRLESEGSPETLTNLRKGYLFMYNLVQFLGFSWIFVNLTVRFCILGKESFYDTFHTVAD MYFCQMLAVVETINAAIGVTTSPVLPSLIQLLGR NFILFIIFGT EEMQNKAVVFFVFYL SAIEIFRYSFYMLTCIDMDWKVLTW RYTL IPLYPLGCLAEAVSVIQSIPIFNETGRFSFTLPYPVKIKVRFSFFLQIY IMIF LGLYINFRHLYKQRRRRYGQKKKKIH
408
AGGCGCTCAGGAGCGCTAGGGΓTTGAGGCCTGCTTTCTGCTCGCGCCAGCAGAGCACTACCTGAGGCAGCGAGGCGCAGCGAGCCTAGCCTCCCCGCGCCCTGGGCAGTGTG GCCATGGAGAATCAGGTGTΓGACGCCGCATGTCTACTGGGCTCAGCGACACCGCGAGCTATATCTGCGCGTGGAGCTGAGTGACGTACAGAACCCTGCCATCAGCATCACTG AAAACGTGCTGCATTRCAAAGCTCAAGGACATGGTGCCAAAGGAGACAATGTCTATGAATTTCACCTGAAGTTCTTAGACCTTGTGAAACCAGAGCCTGTTTACAAACTGAC CCAGAGGCAGGTAAACAΓΓACAGTACAGAAGAAAGTGAGTCAGTGGTGGGAGAGACTCACAAAGCAGGAAAAGCGACCACTGTTTTTGGCTCCTGACTTTGATCGTTGGCTG GATGAATCTGATGCGGAAARGGAGCTCAGAGCTAAGGAAGAAGAGXSCCTAAATAAACTCCGACTGGAAAGCGAAGGCTCTCCTGAAACTCTTACAAACTTAAGGAAAGGAT ACCTGTTTATGTATAAΓCΓΓGTGCAATTCTTGGGATTCTCCTGGATCTTTGTCAACCTGACTGTGCGATTCTGTATCTTGGGAAAAGAGTCCTTTTATGACACATTCCATAC TGTGGCTGACATGATGTATTTCTGCCAGATGCTGGCAGTTGTGGAAACTATCAATGCAGCAATTGGAGTCACTACGTCACCGGTGCTGCCTTCTCTGATCCAGCTTCTTGGA AGAAATTTTATTTTGTTTATCATCTTTGGCACCATGGAAGAAATGCAGAACAAAGCTGTGGTTTTCTTTGTGTTTTATTTGTGGAGTGCAATTGAAATTTTCAGGTACTCTT TCTACATGCTGACGTGCATTGACATGGATTGGAAGGTGCTCACATGGCTTCGTTACACTCTGTGGATTCCCTTATATCCACTGGGATGTTTGGCGGAAGCTGTCTCAGTGAT TCAGTCCATTCCAATATTCAATGAGACCGGACGATTCAGTTTCACATTGCCATATCCAGTGAAAATCAAAGTTAGATTTTCCTTTTTTCTTCAGATTTATCTTATAATGATA TTTTTAGGTTTATACATAAATTTTCGTCACCTTTATAAACAGCGCAGACGGCGCTATGGACAAAAAAAGAAAAAGATCCACTAAAAAGAAAGATTTAGATGGCTTCTTGCCA GTTTGAGCCTAATCTGATTCTTACAGTTTTACCTTCTTGAACCAATGTAAAAGTTTTTTTAATGTTAAATGATTAAATTCTCAGTGAGGCTATCTTCCTTTTCCCCAGTAAC ATTCCTGAATTTACTGTTATCTTATTGTAGTACTTGCATGACATGGATTCCTGATATCTGATGAGAGGTTCATTCTTGTGTATTCAGTTAATGACACCAAAAGGCTCAGCCC ACCCCAACCCTATCTCATGTTCAGTCTGTCTAATACATGCCAGAGATTTTTTTTTCAAAAAGTGCTTTATCCCTACAATGTACTGACAGTTCTTACAGTTGAGATTTGTTCT TTTCAGCTATTGCTTGTGAAAAAAAGCAAGACTATGTCACTCTATAGAAGGCTGTTAAAGTGACTCAGGCAGGAATTAATTATTCTGTACCTAAGGGGTTACTTGTTTAARG GGATGGCATTGACTTTTTGAAAATCAAGTGGACTGAGTCATTGATAAAACATTTCTAAGAGTGGGGCTAGAGAACATACTTTACATCTGACATCCTTTGGCCTAACAACATC TATTATTATAGTGCICAGCAGTGTGGGCATTGAAGAGGCGCAGAATGCTTTGAAAGAAACTAATCAGAATCTTGGAACATCATGATCATGCCATTCTTAAGTAAATCAACTA TTTTCAACACTGAAGAAAAATGAAACATTATTTAGAAAACAATGAGATTACAAGTTCCAAACTCAGCCAGGAATGTGGCTCACACCTGTAATCCCAGCACTTTGGGACACCT AGGTGGGAGCATCGCTTGAAGCCAGGAGTTCAAGACCAGCTTGGGCAACGTAGTGAGACCCCTATCTCTACAAAAAATAAAAAAATTAGCTGGGTGTGATGGCACACACCTG TTGTCCCAGCTACTCAAGAAGCTGAGATGGGAGGATCCTGAGCTCAGGAGGTCAAGGCTGCAGTGAGCCGAGATTGTGCCACTGCACTGCAGCTGGGGTGACAGTGCAAGAC CCTGTCTCAAACCAAACCAAACCACACACACACAAACACACATACACACACACACACACGAGGTCCAAATGGTAGCAGGGATCCAAAGGGAACACAGTATGTAGGTCAAACT GGCAGTAACAGTGTACAGCCTTTGACAAACTAGAAATATTAGAGTAGGCCAAACACACCTCCAAACTGTAAGGCTGTGCACAAACATAAAAAATGGCAGCCTTCCATCTCCT GCACTGGCTGAGTCCATTTACTTGTGTACTTGTTCTAGTGAGTGGTGGGACTGTACATTTTTGAATAGACCTCAAAAATACTTCATTCTGCTGCTGTTCAGTTGGCTTTTTA AACCTGTCTGCAGTAGGACACTGAAAACAGCAAGAACTTCGGGGTGAACACCCGCTGATCCTTTAACAAGGATTTCTGGCAGGAAACTCACAAAAAGGAGAACTGAAAATTT AGACATACAGTTGGCCATTGTAAAAAACATCAGTTTCCTCTCATACATTCCAAGTAAACCAAGTAAAATAAGTGTTGGAGTAACACTTGCATAAAAGAATTTAAGGAGTGAT AGCTCTTTCTGTTCTGCCATTCCCAACATTCCTGGGGGAAAGGAGACTCAATGAGTTAATACTATTTCACTGAGCCCAAGATGGAAACTTGGTTTGACCTAAAACATCTGAT TAATATΔGGCTAGCTGATTTCTTAAAAATTCGTTGCATTGAAGGATATTTTGCATGTCTGTAACACCTGTCAATACTTGTTTGTATTGATTTCTGATATTCTTGCAGCTGAC TACGTGTAATTGGGCAGATCAGCTTTGCAGTAGATTATGCTGCATCCTCGTGGCAAAATTCTGTATTCTTAGTGATTGTTACAAACCCCTTTATTGCTGTCTGAGAAAGTGA AAGATTGTGTATTTCTATTAAAACATTTACAATC
409
MVRLPLQCVLWGC TAVHPEPPTACREKQYLINSQCCSLCQPGQK VSDCTEFTETEC PCGESEFLDTKNRETHCHQHKYCDPN G RVQQKGTSETDTICTCEEGWHCT SEACESCV HRSCεPGFGVKQIATGVSDTICEPCPVGFFSNVεεAFEKCHPWTεCETKDLWQQAGTNKTDWCGPQDRLRALWIPI IFGILFAILLVLVFIKKVAKKPTN KAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRI8VQERQ
410
GCCTCGCTCGGGCGCCCAGTGGTCCTGCCGCCTGG'ICTCACCTCGCCATGGTTCGTCTGCCTCTGCAGTGCGTCCTCTGGGGCTGCTTGCTGACCGCTGTCCATCCAGAACC ACCCACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTGCTGTTCTTTGTGCCAGCCAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAACGGAATGC CTTCCTTGCGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCT CAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGAT TGCTACAGGGGTTTCTGATACCATCTGCGAGCCCTGCCCAGTCGGCTTCTTCTCCAATGTGTCATCTGCTTTCGAAAAATGTCACCCTTGGACAAGCTGTGAGACCAAAGAC CTGGTTGTGCAACAGGCAGGCACAAACAAGACTGATGTTGTCTGTGGTCCCCAGGATCGGCTGAGAGCCCTGGTGGTGATCCCCATCATCTTCGGGATCCTGTTTGCCATCC TCTTGGTGCTGGTCTTTATCAAAAAGGTGGCCAAGAAGCCAACCAATAAGGCCCCCCACCCCAAGCAGGAACCCCAGGAGATCAATTTTCCCGACGATCTTCCTGGCTCCAA CACTGCTGCTCCAGTGCAGGAGACTTTACATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGAGTCGCATCTCAGTGCAGGAGAGACAGTGAGGCTGCACCCACCCA GGAGTGTGGCCACGTGGGCAAACAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCAGGGGTGCAGGCAGAAGCGGGGAGCTATGCCCAGTCAGTGCCAGCCCCTC
411
MSRGLQLLLLSCAYS APATPEVKVACSEDVDLPCTAPWDPQVPYTVSWVKLLEGGEERMETPQEDHLRGQHYHQKGQNGSFDAPNERPYSLKIPJJTTSCNSGTYRCTLQDP
DGQRN SGKVILRVTGCPAQRKEETFKKYRAEIVLLLA VIFYLTLIIFTCKFARLQSIFPDFSKAG ERAFLPVTSPNKHLGLVTPHKTELV
412
CACAGCTCTGCAGCTCGTGGCAGCGGCGCAGCGCTCCAGCCATGTCGCGCGGCCTCCAGCTTCTGCTCCTGAGCTGCGCCTACAGCCTGGCTCCCGCGACGCCGGAGGTGAA GGTGGCTTGCTCCGAAGATGTGGACTTGCCCTGCACCGCCCCCTGGGATCCGCAGGTTCCCTACACGGTCTCCTGGGTCAAGTTATTGGAGGGTGGTGAAGAGAGGATGGAG ACACCCCAGGAAGACCACCTCAGGGGACAGCACTATCATCAGAAGGGGCAAAATGGTTCTTTCGACGCCCCCAATGAAAGGCCCTATTCCCTGAAGATCCGAAACACTACCA GCTGCAACTCGGGGACATACAGGTGCACTCTGCAGGACCCGGATGGGCAGAGAAACCTAAGTGGCAAGGTGATCTTGAGAGTGACAGGATGCCCTGCACAGCGTAAAGAAGA GACTTTTAAGAAATACAGAGCGGAGATTGTCCTGCTGCTGGCTCTGGTTATTTTCTACTTAACACTCATCATTTTCACTTGTAAGTTTGCACGGCTACAGAGTATCTTCCCA GATTTTTCTAAAGCTGGCATGGAACGAGCTTTTCTCCCAGTTACCTCCCCAAATAAGCATTTAGGGCTAGTGACTCCTCACAAGACAGAACTGGTATGAGCAGGATTTCTGC AGGTTCTTCTTCCTGAAGCTGAGGCTCAGGGGTGTGCCTGTCTGTTACACTGGAGGAGAGAAGAATGAGCCTACGCTGAAGATGGCATCCTGTGAAGTCCTTCACCTCACTG AAAACATCTGGAAGGGGATCCCACCCCATTTTCTGTGGGCAGGCCTCGAAAACCATCACATGACCACATΔGCATGAGGCCACTGCTGCTTCTCCATGGCCACCTTTTCAGCG ATGTATGCAGCTATCTGGTCAACCTCCTGGACATTTTTTCAGTCATATAAAAGCTATGGTGAGATGCAGCTGGAAAAGGGTCTTGGGAAATATGAATGCCCCCAGCTGGCCC GTGACAGACTCCTGAGGACAGCTGTCCTCTTCTGCATCTTGGGGACATCTCTTTGAATTTTCTGTGTTTTGCTGTACCAGCCCAGATGTTTTACGTCTGGGAGAAATTGACA GATCAAGCTGTGAGACAGTGGGAAATATTTAGCAAATAATTTCCTGGTGTGAAGGTCCTGCTATTACTAAGGAGTAATCTGTGTACAAAGAAATAACAAGTCGATGAACΓAT TCCCCAGCAGGGTCTTTTCATCTGGGAAAGACATCCATAAAGAAGCAATAAAGAAGAGTGCCACATTTATTTTTATATCTATATGTACTTGTCAAAGAAGGTTTGTGTTTTT CTGCTTTTGAAATCTGTATCTGTAGTGAGATAGCATTGTGAACTGACAGGCAGCCTGGACATAGAGAGGGAGAAGAAGTCAGAGAGGGTGACAAGATAGAGAGCTATTTAAT GGCCGGCTGGAAATGCTGGGCTGACGGTGCAGTCTGGGTGCTCGCCCACTTGTCCCACTATCTGGGTGCATGATCTTGAGCAAGTTCCTTCTGGTGTCTGCTTTCTCCATTG TAAACCACAAGGCTGTTGCATGGGCTAATGAAGATCATATACGTGAAAATTATTTGAAAACATATAAAGCACTATACAGATTCGAAACTCCATTGAGTCATTATCCTTGCTA TGATGATGGTGTTTTGGGGATGAGAGGGTGCTATCCATTTCTCATGTTTTCCATTGTTTGAAACAAAGAAGGTTACCAAGAAGCCTTTCCTGTAGCCTTCTGTAGGAATTCT TTTGGGGAAGTGAGGAAGCCAGGTCCACGGTCTGTTCTTGAAGCAGTAGCCTAACACACTCCAAGATATGGACACACGGGAGCCGCTGGCAGAAGGGACTTCACGAAGΓGTT GCATGGΔTGTTTTAGCCATTGTTGGCTTTCCCTTATCAAACTTGGGCCCTTCCCTTCTTGGTTTCCAAAGGCATTTATTGCTGAGTTATATGTTCACTGTCCCCCTAAΓATT
AGGGAGTAAAACGGATACCAAGTTGATTTAGTGTTTTTACCTCTGTCTTGGCTTTCATGTTATTAAACGTATGCATGTGAAGAAGGGTGTTTTTCTGT'ITTATATTCAACTC
ATAAGACTTTGGGATAGGAAAAATGAGTAATGGTTACTAGGCTTAATACCTGGGTGATTACATAATCTGTACAACGAACCCCCATGATGTAAGTTTACCTATGTAACAAACC
TGCACTTATACCCATGAACTTAAAATGAAAGTTAAAAATAAAAAACATATACAAATAAAAAAAA
413
MKEEVKGIPVRVALRCRPLVPKEI8EGCQMCLSFVPGEPQVVVGTDKSFTYDFVFDP8TEQEEVFNTAVAP IKGVFKGYNATVLAYGQTGSGKTYSMGGAYTAEQENEPTV GVIPRVIQLLFKEIDKKSDFEFTLKVSYLEIYNEEILDLLCPSREKAQINIREDPKEGIKIVGLTEKTVLVALDTVεCLEQGNNSRTVASTAMNSQSSRSHAIFTISLEQR KSDKNSSFRSKLH VD AGSERQKKTKAEGDRLKEGININRG LCLGNVISALGDDKKGGFVPYRDSK TRL QDSLGGNSHTLMIACVSPADSNLEETLNTLRYADRARKI KNKPIVNIDPQTAELNHLKQQVQQLQVLLLQAHGGTLPGSITVEPSENLQSLMEKNQSLVEENEKLSRGLSEAAGQTAQMLERIILTEQANEKMNAKLEELRQHAACKLD Q LVET EDQEIJKENVEIICNLQςLITQ SDETVAC^!AAAIDTAVEQEAQVE SPE SRSSDAFTTQHA QAQMSKE VELNKATJA KEA ARK^l QNDSQLQPIQYQYQDN IKELELEVINLQKEKEELVLELQTAKKDANQAK1SERRRKRLQELEGQIADLKKKLNEQ8KLLKLKE8TERTV8K NQEIR1MKNQRVQLMRQMKEDAEKFRQWKQKRDKEV IQLKERDRKRQYE LKLEPJ^FQKQSNVLRRKTEEAAAANKRLITOALQKQREVADKRKETQSRGMEGTAARVKN LGNEIEVMVSTEEAKRHLND LEDRKILAQDVAQLKEK KESGENPPPKLRRRTFS TEVRGQVSESEDSITKQIESLETEMEFRSAQIADLQQKLLDAESEDRPKQRWENIATILEAKCALKYLIGELVSSKIQVSK ESSLKQSKTSCA DMQKMLFEERNHFAEIETELQAE VRMEQQHQEKVLYL SQLQQSQMAEKQLEESVSEKEQQ LST KCQDEELEKMREVCEQNQQ LRENEIIKQK TLLQVASRQKHLPK DT SPDSSFEYVPPKPKPSRVKEKFLEQSMDIEDLKYCSEHSVNEHEDGDGDDDEGDDEE KPTKLVKVSRKNIQGCSCKGWCGNKQCGCRKQKSDCGVDCCCDPTKCRNR QQGKOSLGTVERTQDSEGSFK EDPTEVTPGLSFFNPVCATPNSKILKEMCDVEQVLSKKTPPAPSPFDLPELKHVATEYQENKAPGKKKKRALASNTSFFSGCSPIEEEAH
414
GGGAGGCCCAGGGAGAACGGGGAAGGGACATTTAGTTTGAGACGGTGCTGAGATAGGATCATGAAGGAAGAGGTGAAGGGAATTCCTGTAAGAGTGGCGCTGCGTTGTCGCC
CTCTGGTCCCCAAAGAGATTAGCGAGGGCTGCCAGATGTGCCTTTCCTTCGTGCCCGGAGAGCCTCAGGTGGTGGTTGGTACAGATAAATCCTTCACCTACGATTTTGTATT
TGATCCCTCTACTGAACAGGAAGAAGTCTTCAATACAGCAGTAGCGCCACTCATAAAAGGTGTATTTAAAGGATATAA'IGCAACGGTCCTGGCCTATGGGCAGACTGGCTCT
GGAAAAACCTATTCAATGGGAGGTGCATATACTGCAGAGCAAGAGAATGAACCAACAGTTGGGGTTATTCCTAGGGTAATACAACTGCTCTTCAAAGAAATTGATAAAAAGA GTGACTTTGAATTTACTCRGAAAGTGTCTTACTTAGAGATTTACAATGAAGAAATTTTGGATCTTCTATGTCCATCTCGTGAGAAAGCTCAAATAAATATACGAGAGGATCC TAAGGAAGGCATAAAGAΓΓGTGGGACTCACTGAGAAGACTGTTTTGGTTGCCTTGGATACTGTTTCCTGTTTGGAACAGGGCAACAACTCTAGGACTGTGGCCTCCACGGCT ATGAACTCCCAGTCGTCCCGATCTCATGCCATCTTTACAATCTCCTTAGAGCAAGGAAAGAAAAGTGACAAGAATAGCAGCTTTCGCTCCAAGCTGCATCTTGTAGACCTCG CTGGATCAGAAAGACAGAAGAAAACCAAGGCTGAAGGGGATCGTCTAAAAGAGGGTATTAATATTAACCGAGGCCTCCTATGCTTGGGAAATGTAATCAGTGCTCTTGGAGA TGACAAAAAGGGTGGCTΓΓGCGCCCTACAGAGATTCCAAGTTGACTCGACTGCTTCAAGATTCTCTAGGAGGTAATAGCCATACTCTTATGATAGCCTGTGTGAGTCCTGCT GACTCCAATCTAGAGGAAACATTAAATACCCTTCGCTATGCTGACAGAGCAAGAAAAATCAAGAACAAACCTATTGTTAATATTGATCCCCAGACAGCTGAACTTAATCATC TAAAGCAACAGGTACAACAGCTACAAGTCTTGTTGCTACAGGCCCATGGAGGTACCCTGCCTGGATCTATAACTGTGGAACCATCAGAGAATCTACAATCCCTGATGGAGAA GAATCAGTCCCTGGTAGAGGAGAATGAAAAATTAAGTCGTGGTCTGAGCGAGGCAGCTGGTCAGACAGCCCAGATGTTGGAGAGGATCATTTGGACAGAGCAAGCGAATGAA AAAATGAACGCCAAGCTAGAAGAGCTCAGGCAGCATGCGGCCTGCAAACTGGATCTTCAAAAGCTAGTGGAGACTTTGGAAGACCAGGAATTGAAAGAAAATGTAGAGATAA TTTGTAACCTGCAGCAATTGATTACCCAGTTATCGGATGAAACTGTTGCTTGCATGGCTGCAGCCATTGATACTGCGGTGGAGCAAGAAGCCCAAGTAGAAACCAGTCCAGA GACGAGCAGGTCTTCTGACGCTTTTACCACTCAGCATGCTCTCCGTCAAGCGCAGATGTCTAAGGAGCTGGTTGAGTTGAATAAAGCGCTTGCACTGAAAGAGGCCCTGGCT AGGAAGATGACTCAGAATGACAGCCAACTGCAGCCTATTCAGTACCAATACCAGGATAACATAAAAGAGCCAGAATTAGAAGTCATCAATCTGCAAAAGGAAAAGGAAGAAT TGGTTCTTGAACTTCAGACAGCAAAGAAGGATGCCAACCAAGCCAAGTTGAGTGAGCGCCGCCGCAAACGTCTCCAGGAGCTGGAGGGTCAAATTGCTGATCTGAAGAAGAA ACΓGAATGAGCAGTCCAAACTTCTGAAACTAAAGGAATCCACAGAGCGTAC GTCTCCAAACTGAACCAGGAGATACGGATGATGAAAAACCAGCGGGTACAGTTAATGCGT CAAATGAAAGAAGATGCTGAGAAGTTTAGACAGTGGAAGCAGAAAAGAGACAAAGAAGTAATACAGTTAAAAGAACGAGACCGTAAGAGGCAATATGAGCTGCTGAAACTTG AAGAAACTTCCAGAAACAATCCAATGTGCTCAGACGTAAAACGGAGGAGGCAGCAGCTGCCAACAAGCGTCTCAAGGATGCTCTCCAGAAACAACGGGAGGTTGCAGATAA GCGGAAAGAGACTCAGAGCCGTGGAATGGAAGGCACTGCAGCTCGAGTGAAGAATTGGCTTGGAAACGAAATTGAGGTTATGGTCAGTACTGAGGAAGCCAAACGCCATCTG AATGACCTCCTTGAAGATAGAAAGATCCTGGCTCAAGATGTGGCTCAACTCAAAGAAAAAAAGGAATCTGGGGAGAATCCACCTCCTAAACTCCGGAGGCGTACATTCTCCC TTACTGAAGTGCGTGGTCAAGTTTCGGAGTCAGAAGATTCTATTACAAAGCAGATTGAAAGCCTAGAGACTGAAATGGAATTCAGGAGTGCTCAGATTGCTGACCTACAGCA GAAGCTGCTGGATGCAGAAAGTGAAGACAGACCAAAACAACGCTGGGAGAATATTGCCACCATTCTGGAAGCCAAGTGTGCCCTGAAATATTTGATTGGAGAGCTGGTCTCC TCCAAAATACAGGTCAGCAAACTTGAAAGCAGCCTGAAACAGAGCAAGACCAGCTGTGCTGACATGCAGAAGATGCTGTTTGAGGAACGAAATCATTTTGCCGAGATAGAGA AGAGTTACAAGCTGAGCTGGTCAGAATGGAGCAACAGCACCAAGAGAAGGTGCTGTACCTTCTCAGCCAGCTGCAGCAAAGCCAAATGGCAGAGAAGCAGTTAGAGGAATC AGRCAGTGAAAAGGAACAGCAGCTGCTGAGCACACTGAAGTGTCAGGATGAAGAACTTGAGAAAATGCGAGAAGTGTGTGAGCAAAATCAGCAGCTTCTCCGAGAGAATGAA ATCATCAAGCAGAAACTGACCCTCCTCCAGGTAGCCAGCAGACAGAAACATCTTCCTAAGGATACCCTTCTATCTCCAGACTCTTCTTTTGAATATGTCCAGCCTAAGCCAA AACCTTCTCGTGTTAAAGAAAAGTTCCTGGAGCAAAGCATGGACATCGAGGATCTAAAATATTGTTCAGAGCATTCTGTGAATGAGCATGAGGATGGTGATGGTGATGATGA TGAGGGGGATGACGAGGAATGGAAGCCAACAAAATTAGTTAATGTGTCCAGGAAGAACATCCAAGGGTGTTCCTGCAAGGGCTGGTGTGGAAACAAGCAATGTGGGTGCAGG AAGCAAAAGTCAGACTGTGGTGTGGACTGTTGCTGTGACCCCACAAAGTGTCGGAACCGCCAGCAAGGCAAGGATAGCTTGGGCACTGTTGAACGGACCCAGGATTCAGAAA GCTCCTTCAAACTGGAGGATCCTACCGAGGTGACCCCAGGATTGAGCTTCTTTAATCCCGTCTGTGCCACCCCCAATAGCAAGATCCTGAAAGAGATGTGCGATGTGGAGCA GGTGCTGTCAAAGAAGACTCCCCCAGCTCCCTCCCCTTTTGACCTCCCAGAGTTGAAACATGTAGCAACAGAATACCAAGAAAACAAGGCTCCAGGGAAGAAAAAGAAACGG GCTCTGGCCAGCAACACCAGCRTCTTCTCTGGCTGCTCCCCTATCGAAGAAGAGGCCCACTGAAGTTGGAGTCATCATCTCTACCCCCAGTCTGGCTTGGGAGATGCTTTCA GGTTGCAGCCAGAAGGGGTTTTTTAAATGACTTCTCTGGATTTCAGGTTTCTTGCTGTTGAAAAAAGGAACAAAGCGTTACTGAAAAGAAGGTAACCTTTGTTGGATGTGGG CCTTAGCCTCCAGGTCCAGACRACTACTCTATGTTCTCCAGAAGGGTGCTAAGTCACCTACTGAAGAGAGAACCAACTGACTTTCCTATTGACTCATCAGGAACCAGTCCTC AGTCTGGTCAAGTTGTTTCTTATTTGTGAGCAGTTCAGGCTATCTCCTGATGGGGATGAGGCCAAGGCTTTCTTATCTTTTGGTTGTCTCTGCTTAATGGAGGAGCCTGGCC ΓAGGATGGAGGCCTGGCTTAGATCTTTCATTCCACCTCAGGAATGAGGTTGTGATCTTTCCTGTCCTGACCCTCTCTGAATTATGTTTCAATAGTACTCTTGATTGTCTGCC
415
MVERCSRQGCTIT IAYIDY MIVAFMLGNYI LRESSTEPNDSLWFSLQKKMD TEIETLLLNTAPKI IDEQLVCRLSKTDIFI ICRDNKIYLDKNIτRNLK RFYGHRQ L
ECEVFRVEGIKDN DDIKRIIKAREHRNR ADIRDYRPYADLVSEIRILLVGPVGSGKSSFFNSVKSIFHGHVTGQAWGSDTTS ITERYRIYSVKDGKNGKSLPFM CDT
MGLDGAEGAGLC lDIPHILKGC PDRYQFNSRKPITPEHSTFITSPSLKDRIHCVAYVLDINSIDNLYSKM AKVKQVHKEVLNCGIAYVALLTKVEDCSEVLQDNF NMS
RSMTSQSRVMNVHKMLGIPISNI MVGNYASDLELDP KDILILSALRQMLRAADDFLEDLPLEETGAIERALQPCI
416
GCACGAGGAAGCCACAGATCRCTTAAGAACTTTCTGTCTCCAAACCGTGGCTGCTCGATAAATCAGACAGAACAGTTAATCCTCAATTTAAGCCTGATCTAACCCCTAGAAA CAGATATAGAACAATGGAAGRGACAACAAGATTGACATGGAATGATGAAAATCATCTGCGCAACTGCTTGGAAATGTTTCTTTGAGTCTTCTCTATAAGTCTAGTGTTCATG GAGGTAGCATTGAAGATATGGTTGAAAGATGCAGCCGTCAGGGATGTACTATAACAATGGCTTACATTGAT'IACAATATGATTGTAGCCTTTATGCTTGGAAATTATATTAA TTTACGTGAAAGTTCTACAGAGCCAAATGATTCCCTATGGTTTTCACTTCAAAAGAAAAATGACACCACTGAAATAGAAACTTTACTCTTAAA'IACAGCACCAAAAATTATT GATGAGCAACTGGTGTGTCGRTRATCGAAAACGGATATTTTCATTATATGTCGAGATAATAAAATTTATCRAGATAAAATGATAACAAGAAACTTGAAACTAAGGTTTTATG GCCACCGTCAGTATTTGGAAΓGTGAAGTTTTTCGAGTTGAAGGAATTAAGGATAACCTAGACGACATAAAGAGGATAATTAAAGCCAGAGAGCACAGAAATAGGCTTCTAGC AGACATCAGAGACTATAGGCCCTATGCAGACTTGGTTTCAGAAATTCGTATTCTTTTGGTGGGTCCAGTTGGGTCTGGAAAGTCCAGTTTTTTCAATTCAGTCAAGTCTATT TTTCATGGCCATGTGACTGGCCAAGCCGTAGTGGGGTCTGATACCACCAGCATAACCGAGCGGTATAGGATATATTCTGTTAAAGATGGAAAAAATGGAAAATCTCTGCCAT TTARGTTGTGTGACACTATGGGGCRAGATGGGGCAGAAGGAGCAGGACTGTGCATGGATΣACATTCCCCACATCTTAAAAGGTTGTATGCCAGACAGATATCAGTTTAATTC CCGTAAACCAATTACACCTGAGCATTCTACTTTTATCACCTCTCCATCTCTGAAGGACAGGATTCACTGTGTGGCTTATGTCTTAGACATCAACTCTATTGACAATCTCTAC TCTAAAATGTTGGCAAAAGTGAAGCAAGTTCACAAAGAAGTATTAAACTGTGGTATAGCATATGTGGCCTTGCTTACTAAAGTGGATGATTGCAGTGAGGTTCTTCAAGACA ACTTTTTAAACATGAGTAGATCTATGACTTCTCAAAGCCGGGTCATGAATGTCCATAAAATGCTAGGCATTCCTATTTCCAATATTTTGATGGTTGGAAATTATGCTTCAGA TTTGGAACTGGACCCCATGAAGGATATTCTCATCCTCTCTGCACTGAGGCAGATGCTGCGGGCTGCAGATGATTTTTTAGAAGATTTGCCTCTTGAGGAAACTGGTGCAATT GAGAGAGCGTTACAGCCCTGCATTTGAGATAAGTTGCCTTGATTCTGACATTTGGCCCAGCCTGTACTGGTGTGCCGCAATGAGAGTCAATCTCTATTGACAGCCTGCTTCA GATTTTGCTTTTGTTCGTTTTGCCTTCTGTCCTTGGAACAGTCATATCTCAAGTTCAAAGGCCAAAACCTGAGAAGCGGTGGGCTAAGATAGGTCCTACTGCAAACCACCCC ΓCCATATTTCCGTACCATTTACAATTCAGTTTCTGTGACATCTTTTTAAACCACTGGAGGAAAAATGAGATATTCTCTAATTTATTCTTCTATAACACTCTATATAGAGCTA ΓGΓGAGTACTAATCACATTGAATAATAGTTATAAAATTATTGTATAGACATCTGCTTCTTAAACAGATTGTGAGTTCTTTGAGAAACAGCGTGGATTTTACTTATCTGTGTA ΓΓCACAGAGCTTAGCACAGTGCCTGGTAATGAGCAAGCATACTTGCCATTACTTTTCCTTCCCACTCTCTCCAACATCACATTCACTTTAAATTTTTCTGTATATAGAAAGG AAAACTAGCCTGGGCAACATGATGAAACCCCATCTCCACTGC
417
CDPKADSTRLLLGGI-HQKSV DSLREEGDEVELDDIRKEGFGKTLCVESGGPEPGVGCAGRGIITSISMLEQLGAYEEEVGLDYAFYDVLGDWCGGFAMPIREGKA
418
AΓTCGGAGCTGGCTGGAATCTCTCAGCCTCACCTGCCAGACAACACCCCCTCCTTCCTCACCCTGTCTCCTGCATTCTCCTGAAACCTTCATCCACACAATGCCTCCCAACC TCACTGGCTACTACCX3CTTTGTCTCGCAGAAGAACATGGAGGACTACCTGCAAGCCCTAAAATCAGCTTGGCTGTGCGGAAGATCGCGCTGCTGCTGAAGCCGGACAAGGA GATCGAACACCAGGGCAACCACATGACGGTGAGGACGCTCAGCACCTTCCGAAACTACACTGTGCAGTTTGATGTGGGAGTGGAGTTTGAGGAGGACCTCAGGAGCGTGGAC GGACGAAAATGCCAGACCATAGTAACCTGGGAGGAGGAGCACCTGGTGTGTGTGCAGAAAGGGGAGGTCCCCAACCGGGGCTGGAGACACTGGCTGGAGGGAGAGATGCTGT ARCTGGAACTGACTGCAAGGGATGCAGTGTGCGAGCAGGTCTTCAGGAAGGTCAGATAGCCGGAGAGGAGCCAAGATCCCTCCAGACAGCACCAGCTCACAGACGCTCTTGT TGTGCCCCCTTCAAGCCCAGATTGTGCCAGGTCAGCTGTCCCTTCCTCTGGCCACCTTTCCTCCCTCTGGGTCCCTCCTCACCCCTCCCCGTGTTAATCTGTAACTTGCAGC CCCCAGGCCAAAGTCCTTTCTCACACTCCACTGCCCAATAGTGACCTCACTTCCAGGTCAAGGTCTGGCGTCCCAAA GAAAGAAGCAGGCAAAGGGAAGGAGCCCCTGAGA ACAACCAATCTCCGCTCTCTCCTGTCCATTTGACCTCTTCTTTTCCTTCTAAGAAAGAACTAAGCTTTGGGCATTTGGCGATTAGTGAAAATTCTATCCTGATGGACTTCTG GAAAACTGTGACTGGGGTTCAAGAGTTTAAACAGGGGCTACTGGCAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
419
MAALGCARLRWA RGAGRGLCPHGARAKTAAIPAALPSDKATGAPGAGPGVRRRQRSLEEIPRLGQLRFFFQ FVQGYALQ HQ QV YKAKYGPNWMSYIΛPQMHλ/NLASAP EQVMRQEGKYPVRNDMELWKEHRDQHDLTYGPFTTEGHH YQ RQALNQRLLKPAEAALYTDAFNEVIDDFMTRLDQLRAESASGNQV8DMAQLFYYFALEAICYΪ FEK
RIGCLQRSIPEDTVTF RSIG FQNSLYATFLPKWTRPVLPF KRYLDG NAIFSFGKKIilDEKLEDMEAQ QAAGPDGIQVSGYLHF LASGQLSPREAMGS PE LMAG
VDTTSNTLT ALYHLSKDPEIQEALHEEVVGVVPAGQVPQHKDFAH PLLKAVLKETLRLYPVVPTNSRIIEKEIEVDGFLFPKNTQFVFCHYVVSRDPTAFSEPESFQPHR
W RNSQPATPRIQHPFGSVPFGYGVRACIΛRRIAELEMQL LARLIQKYKVVIAPETGELKSVARIVLVPNKKVGLQF QRQC
420 GΓGGATATCCCCGAGTCACCGCGTCCCTCTCCTGCAGCTCCCGCGTCGCTGGGAGGAGCGAGGGAGCGAGCGGGAAGGGGTCTAGCTGGCGTTTGCTCGGCCCTCCCCAGCG CCCGGCTTTGAACCCGCCCTGCACTGCTGTCTGGGCGGGTCCGGGGACTCAGCACTCGACCCAAAGGTGCAGGCGCGCGAGCACAACCCATGGCTGCGCTGGGCTGCGCGAG GCΓGAGGTGGGCGCTGCGAGGGGCCGGCCGTGGCCTCTGCCCCCACGGGGCCAGAGCCAAGGCCGCGATCCCTGCCGCCCTCCCCTCGGACAAGGCCACCGGAGCTCCCGGA GCCGGGCCTGGTGTCCGGCGGCGGCAACGGAGCTTAGAGGAGATTCCACGTCTAGGACAGCTGCGCTTCTTCTTTCAGCTGTTCGTTCAAGGCTATGCCCTGCAACTGCACC AGTTACAGGTGCTTTACAAGGCCAAGTACGGTCCAATGTGGATGTCCTACTTAGGGCCTCAGATGCACGTGAACCTGGCCAGTGCCCCGCTCTTGGAGCAAGTGATGCGGCA AGAGGGAAAGTACCCAGTACGGAACGACATGGAGCTATGGAAGGAGCACCGGGACCAGCACGACCTGACCTATGGGCCGTTCACCACGGAAGGACACCACTGGTACCAGCΓG CGCCAGGCTCTGAACCAGCGGTTGCTGAAGCCAGCGGAAGCAGCGCTCTATACGGATGCTTTCAATGAGGTGATTGATGACTTTATGACTCGACTGGACCAGCTGCGGGCAG AGAGTGCTTCGGGGAACCAGGTGTCGGACATGGCTCAACTCTTCTACTACTTTGCCTTGGAAGCTATTTGCTACATCCTGTTCGAGAAACGCATTGGCTGCCTGCAGCGATC CATCCCCGAGGACACCGTGACCTTCGTCAGATCCATCGGGTTAATGTTCCAGAACTCACTCTATGCCACCTTCCTCCCCAAGTGGACTCGCCCCGTGCTGCCTTTCTGGAAG CGATACCTGGATGGTTGGAATGCCATCTTTTCCTTTGGGAAGAAGCTGATTGATGAGAAGCTCGAAGATATGGAGGCCCAACTGCAGGCAGCAGGGCCAGATGGCATCCAGG TGTCTGGCTACCTGCACTTCTTACTGGCCAGTGGACAGCTCAGTCCTCGGGAGGCCATGGGCAGCCTGCCTGAGCTGCTCATGGCTGGAGTGGACACGACATCCAΔCACGCT GACATGGGCCCTGTACCACCTCTCAAAGGACCCTGAGATCCAGGAGGCCTTGCACGAGGAAGTGGTGGGTGTGGTGCCAGCCGGGCAAGTGCCCCAGCACAAGGACTTTGCC CACATGCCGTTGCTCAAAGCTGTGCTTAAGGAGACTCTGCGTCTCTACCCTGTGGTCCCCACAAACTCCCGGATCATAGAAAAGGAAATTGAAGTTGATGGCTTCCTCTTCC CCAAGAACACCCAGTTTGTGTTCTGCCACTATGTGGTGTCCCGGGACCCCACIGCCTTCTCTGAGCCTGAAAGCTTCCAGCCCCACCGCTGGCTGAGAAACAGCCAGCCTGC TACCCCCAGGATCCAGCACCCATTTGGCTCTGTGCCCTTTGGCTATGGGGTCCGGGCCTGCCTGGGCCGCAGGATTGCAGAGCTGGAGATGCAGCTACTCCTCGCAAGGCTG ATCCAGAAGTACAAGGTGGTCCTGGCCCCGGAGACGGGGGAGTTGAAGAGTGTGGCCCGCATTGTCCTGGTTCCCAATAAGAAAGTGGGCCTGCAGTTCCTGCAGAGACAGT GCTGAGCTGAGTCTCCGCCTTGCTGGGGCTTGTCCTAGAGGCTCCAGCTCTGGCACAGTGGTTCCTGGCTGCTGCCATGTCTCAGATGAGGAGGGAGAGAAGGAGGCCGCCA GACTCGAGAGGTGGGAGGAACTCCTTGCACACACCCTGAGCTTTTGCCACTTCTATCATTTTTGAGCAACTCCCTCTCAGCTAAAAGGCCACCCCTTTATCGCATTGCTGTC CΓTGGGTAGAATATAAAATAAAGGGACTTTTATTTCTTATTGG
421
MQSWSRVYCεiΛKRGHFrTOISHGLQGLSAVPLRTYAEQPIDADVTVIGSGPGGYVAAIKAAQLGFKTVCIEKNETLGGTCLNVGCIPSKALLNNSHYYHMAHGTDFASRGIE
MSEVRLNLDM^EQKSTAVKALTGGIAHLFKQNKVVHVNGYG ITGKNQVTATKADGGTQVIDTKNI IATGSEVTPFPGITIDEDTIVSSTGALSLKKVPEKMVVIGAGVI
GVELGSVWQRLGADVTAVEFLGHVGGVGIDMEISKNFQRILQKQGFKFKLNTKVTGATKKSDGKIDVεiEAASGGKAEVITCDVLLVCIGRRPFTKNLGLEELGIE DPRGR
IPVNTRFQTKIPNIYAIGDWAGPMLAHKAEDEGIICVEσMAGGAVHIDYNCVP8VIYTHPEVAWVGKSEEQLKEEGIE KVGKFPFA NSRAKTNAD DG ^VKI GQKSTD
RVLGAHILGPGAGEMVNEAALA EYGASCEDIARVCHAHPTLSEAFREA LAASFGKSINF
422
GCGCAGGGAGGGGAGACCTTGGCGGACGGCGGAGCCCCAGCGGAGGTGAAAGTATTGGCGGAAAGGAAAATACAGCGGAAAAATGCAGAGCTGGAGTCGTGTGTACTGCTCC TΓGGCCAAGAGAGGCCATTTCAATCGAATATCTCATGGCCTACAGGGACTTTCTGCAGTGCCTCTGAGAACTTACGCAGATCAGCCGATTGATGCTGATGTAACAGTTATAG GΓTCΓGGTCCTGGAGGATATGTTGCTGCTATTAAAGCTGCCCAGTTAGGCTTCAAGACAGTCTGCATTGAGAAAAATGAAACACTTGGTGGAACATGCTTGAATGTTGGTTG TATTCCTTCTAAGGCTTTATTGAACAACTCTCATTATTACCATATGGCCCATGGAACAGATTTTGCATCTAGAGGAATTGAAATGTCCGAAGTTCGCTTGAATTTAGACAAG ARGATGGAGCAGAAGAGTACTGCAGTAAAAGCTTTAACAGGTGGAATTGCCCACTTATTCAAACAGAATAAGGTTGTTCATGTCAATGGATATGGAAAGATAACTGGCAAAA ARCAAGTCACTGCTACGAAAGCTGATGGCGGCACTCAGGTTATTGATACAAAGAACATTCTTATAGCCACGGGTTCAGAAGTTACTCCTTTTCCTGGAATCACGATAGATGA AGATACAATAGTGTCATCTACAGGTGCTTTATCTTTAAAAAAAGTTCCAGAAAAGATGGTTGTTATTGGTGCAGGAGTAATAGGTGTAGAATTGGGTTCAGTTTGGCAAAGA CΓTGGTGCAGATGTGACAGCAGTTGAATTTTTAGGTCATGTAGGTGGAGTTGGAATTGATATGGAGATATCTAAAAACTTTCAACGCATCCTTCAAAAACAGGGGTTTAAAT TRAAATTGAATACAAAGGTTACTGGTGCTACCAAGAAGTCAGATGGAAAAATTGATGTTTCTATTGAAGCTGCTTCTGGTGGTAAAGCTGAAGTTATCACTTGTGATGTACT CΓTGGTTTGCATTGGCCGACGACCCTTTACTAAGAATTTGGGACTAGAAGAGCTGGGAATTGAACTAGATCCTAGAGGTAGAATTCCAGTCAATACCAGATTTCAAACTAAA AΓTCCAAATATCTATGCCATTGGTGATGTAGTTGCTGGTCCAATGCTGGCTCACAAAGCAGAGGATGAAGGCATTATCTGTGTTGAAGGAATGGCTGGTGGTGCTGTGCACA ΓΓGACTACAATTGTGTGCCATCAGTGATTTACACACACCCTGAAGTTGCTTGGGTTGGCAAATCAGAAGAGCAGTTGAAAGAAGAGGGTATTGAGTACAAAGTTGGGAAATT CCCATTTGCTGCTAACAGCAGAGCTAAGACAAATGCTGACACAGATGGCATGGTGAAGATCCTTGGGCAGAAATCGACAGACAGAGTACTGGGAGCACATATTCTTGGACCA GGTGCTGGAGAAATGGTAAATGAAGCTGCTCTTGCTTTGGAATATGGAGCATCCTGTGAAGATATAGCTAGAGTCTGTCATGCACATCCGACCTTATCAGAAGCTTTTAGAG AAGCAAATCTTGCTGCGTCATTTGGCAAATCAATCAACTTTTGAATTAGAAGATTATATATTTTTTTTTCTGAAATTTCCTGGGAGCTTTTGTAGAAGTCACATTCCTGAAC AGGATATTCTCACAGCTCCAAGAATTTCTAGGACTGAATTATGAAACTTTTGGAAGGTATTTAATAGGTTTGGACAAAATGGAATACTCTTATATCTATATTTTACATAAAT ΓΓAGTATTTTGTTTCAGTGCACTAATATGTAAGACAAAAAGGACTACTTATTGTAGTCATCCTGGAATATCTCCGTCAACTCATATTTTCATGCTGTTCATGAAAGATTCAA RGCCCCTGAATTTAAATAGCTCTTTTCTCTGATACAGAAAAGTTGAATTTTACATGGCTGGAGCTAGAATTTGATATGTGAACAGTTGTGTTTGAAGCACAGTGATCAAGTT AΓTTTTAATTTGGTTTTCACATTGGAAACAAGTCAGTCATTCAGATATGATTCAAATGTCTATAAACCAAACTGATGTAAGTAAATGGTCTCTCACTTGTTTTATTTAACCT CRAAATTCTTTCATTTTAGGGGTAGCATTTGTGTTGAAGAGGTTTTAAAGCTTCCATTGTTGTCTGCAACTCTGAAGGGTAATTATATAGTTACCCAAATTAAGAGAGTCTA ΓΓΓACGGAACTCAAATACGTGGGCATTCAAATGTATTACAGTGGGGAATGAAGATACTGAAATAAACGTCTTAAATATTC
423 GLEAARELECAALGT LRDPREAERT LLDCRPFLAFCRRHVRAARPVPVraAL RRRARGPPAAV ACLLPDRALRTRLVRGELARAVVLDEGSASVAE RPDSPAHV LA ALLHETRAGPTAVYFLRGGFDGFQGCCPDLCSEAPAPALPPTGDKTSRSDSRAPλrϊDQGGPVEI PYLFLGSCSHSSDLQGLQACGITAV NVSASCPNHFEGIiFRY SIPV EDNQMVEISAWFQEAIGFIDWVKNSGGRVLVHCQAGISRSATICLAYLMQSRRVRLDEAFDFVKQRRGVISPNFSFMGQ LQFETQV CH
424
GGAGTCGACCGCTCGGGCAGCGCACCGCCACGAGAGCCCGGGACGCGGGAAAGACCGAAAGGAAGAGGAAGAGGCACCGGTGGCCATGGGGCTGGAGGCGGCGCGCGAGCTG GAGTGCGCGGCGCTGGGCACGCTGCTGCGGGATCCGCGGGAGGCGGAACGCACGCTGCTGCTGGACTGCCGCCCCTTCCTGGCCTTCTGCCGGCGCCACGTGCGCGCCGCGC GGCCAGTGCCTTGGAACGCGCTGCTGCGGCGCCGCGCGCGCGGCCCTCCTGCCGCCGTTCTCGCCTGCCTGCTGCCCGACCGCGCGCTGCGGACGCGCCTGGTCCGCGGGGA GCTGGCGCGGGCCGTGGTGCTGGACGAGGGCAGTGCCTCGGTGGCGGAGCTCCGGCCCGACAGCCCGGCTCATGTGCTGCTGGCCGCGCTGCTGCACGAGACCCGCGCGGGG CCCACTGCCGTGTACTTCCTGCGAGGAGGCTTCGACGGCTTCCAGGGCTGCTGTCCCGATCTGTGCTCTGAGGCCCCCGCCCCTGCGCTGCCGCCAACAGGGGACAAAACCA GCCGCTCCGACTCCAGGGCTCCTGTCTACGACCAGGGTGGCCCTGTGGAGATCTTGCCCTACCTGTTCCTGGGCAGCTGCAGTCACTCGTCAGACCTGCAGGGGCTGCAGGC CTGTGGCATCACAGCCGTCCTCAACGTGTCCGCCAGCTGCCCCAACCACTTTGAGGGCCTTTTCCGCTACAAGAGTATCCCTGTGGAGGACAACCAGATGGTGGAGATCAGT GCCTGGTTCCAGGAGGCCATAGGCTTCATTGACTGGGTGAAGAACAGCGGAGGCCGGGTGCTGGTGCACTGCCAGGCGGGTATCTCGCGCTCTGCCACCATCTGTCTGGCAT ACCTCATGCAGAGTCGCCGTGTGCGGCTGGACGAGGCCTTTGACTTCGTTAAGCAGCGCCGGGGGGTCATCTCCCCCAACTTCAGTTTCATGGGGCAGCTGCTGCAGTTTGA GACCCAGGTGCTGTG CACTGAGGTGGTGCCCCTCTGCCTGCCTGCCCCACTGTGCTGGCAGGAGCTGACTGTGGACTGGTGGGCTCCCCTCTGGGCCAGCACAGTCCCCTC ACCTCCGGCAGGGCTGCTACCTCCTCAGAGTTTCAGAAGCCCCCACATGGGGGCTCTAGGAATGCCGGCATGCTGGTCTTTCCGACCTGGTGCTCTTCTGCTGGGGGACTGA GGCTGGCCCTCATTCGGGGTCGGGAACCAAGGGTGTGTCTGCTCTTTCCCTCCCCATCCTCTGGCAGAAATCAGCTAGACGCTATACCGTGGACTCTCCCTGGTCCACCACC ATGTTGAAGCCCTTGGCAGCCTGAGAGCTCCAAGGAACAAGCTGTGACAACCAGGAGCCCTGTCTGTGGGTTCGTCTGCCCAGGGCCTGGAGCCCAAGCCCTGTGTTCCTGG GGAAGCTGGGGACTTGGGAAGTGATGGGTGTGTCATGTTGCGTGTGTCTGTCTGTGAGCCTTTCACACCTGTGCIGGCGCTGGAAAATTATTTGTGCTCAGCTGACATTTAA CACTTCCTCCCCCGCTTCCTCCTAGCCCTGTGGGCAGGGGTTGGAAACTTAGCACTTTATATTTATACAGAACATTCAGGATTTGTCAATAAAATAT'IGTTATATTTAAAAA AAAAAAAAAAAAAAAAAAAAAA
425
MCDAFVGT KLVSSENFDDYMKEVGVGFATRKVAG AKPNMIISVNGDVITIKSESTFKNTEISFILGQEFDEVTADDRKVKSTITLDGGVLVHVQKWDGKSTTIKRKREDD
KLWECVMKGVTSTRVYERA
426
ACAGCACCCTCCTGAAAACTGCAGCTTCCTTCTCACCTTGAAGAATAATCCTAGAAAACTCACAAAATGTGTGATGCTTTTGTAGGTACCTGGAAACTTGTCTCCAGTGAAA
ACTTTGATGATTATATGAAAGAAGTAGGAGTGGGCTTTGCCACCAGGAAAGTGGCTGGCATGGCCAAACCTAACATGATCATCAGTGTGAATGGGGATGTGATCACCATTAA
ATCTGAAAGTACCTTTAAAAATACTGAGATTTCCTTCATACTGGGCCAGGAATTTGACGAAGTCACTGCAGATGACAGGAAAGTCAAGAGCACCATAACCTTAGATGGGGGT
GTCCTGGTACATGTGCAGAAATGGGATGGAAAATCAACCACCATAAAGAGAAAACGAGAGGATGATAAACTGGTGGTGGAATGCGTCATGAAAGGCGTCACTTCCACGAGAG
TTTATGAGAGAGCATAAGCCAAGGGACGTTGACCTGGACTGAAGTTCGCATTGAACTCTACAACATTC GTGGGATATATTGTTCAAAAAGATATTGTTGTTTTCCATGATT rAGCAAGCAACTAATTTTCTCCCAAGCTGATTTTATTCAATATOGTTACGTTGGTTAAATAAACTTTTTTTAGATTCCAAAAAAAAAAAAAAAAAAAAAAAAAAAA
427 YLAVVYPLKFFFLRTRRIAI-MVS SI ILETIFNAVMLWEDETVVEYCDAEKSNFTLCYDKYP EKWQINLNLFRTCTGYAIP VTI ICNRKVYQAVRHNKATENKEKKRI
E
428
ATGAACAGCACATGTATTGAAGAACAGCATGACCTGGATCACTATTTGTTTCCCATTGTTTACATCTTTGTGATTATAGTCAGCATTCCAGCCAATAT1GGATCTCTGTGTG TΒTCTTTCCTGCAACCCAAGAAGGAAAGTGAACTAGGAATTTACCTCTTCAGTTTGTCACTATCAGATTTACTCTATGCATTAACTCTCCCTTTATGGATTGATTATACTTG GAATAAAGACAACTGGACTTTCTCTCCTGCCTTGTGCAAAGGGAGTGCTTTTCTCATGTACATGAAGTTTTACAGCAGCACAGCATTCCTCACCTGCA'ITGCCGTTGATCGG ΓATTTGGCTGTTGTCTACCCTTTGAAGTTTTTTTTCCTAAGGACAAGAAGAATTGCACTCATGGTCAGCCTG'ICCATCTGGATATTGGAAACCATCTTCAATGCTGTCATGT ΓGTGGGAAGATGAAACAGTTGTTGAATATTGCGATGCCGAAAAGTCTAATTTTACTTTATGCTATGACAAATACCCTTTAGAGAAATGGCAAATCAACCTCAACTTGTTCAG GACGTGTACAGGCTATGCAATACCTTTGGTCACCATCCTGATCTGTAACCGGAAAGTCTACCAAGCTGTGCGGCACAATAAAGCCACGGAAAACAAGGAAAAGAAGAGAATC ATAAAACTACTTGTCAGCATCACAGTTACTTTTGTCTTATGCTTTACTCCCTTTCATGTGATGTTGCTGATTCGCTGCATTTTAGAGCATGCTGTGAACTTCGAAGACCACA GCAATTCTGGGAAGCGAACTTACACAATGTATAGAATCACGGTTGCATTAACAAGTTTAAATTGTGTTGCTGATCCAATTCTGTACTGTTTTGTTACCGAAACAGGAAGATA ΓGATATGTGGAATATATTAAAATTCTGCACTGGGAGGTGTAATACATCACAAAGACAAAGAAAACGCATACTTTCTGTGTCTACAAAAGATACTATGGAATTAGAGGTCCTT GAGTAG
429
MASEIHMTGPMC IEN NGRLMANPEALKILSAITQP^WVVAIVG YRTGKSYL^™KLGKKKGFΞLG8T QSH KGIW^WCV HPKKPGHILVL DTEGIJGDVEKGDNQ D
SWIFATAVLLSSTFVYNSIGTINQQAMDQLYYVTELTHRIRS SSPDENENEVEDEADFVSFFPDFVWTLRDPSLDLEADGQPLTPDEYLTYSLKLKKGTSQKDETFNLPRL
CIRKFFP KKCFVFDRP\«RRKLAQLEKLQDEELDPEFVQQVADFCSYIFSNSKTKTLSGGIQVNGPRLESLV TYVNAISSGD PCMENAVLALAQIENSAAVQKAIAHYE
QQMGQKVQ PTES QE LDLHRDSEREAIEVFIRSSFKDVDHLFQKELAAQLEKKRDDFCKQNQEASSDRCSGLLQVIFSPLEEEVKAGIYSKPGGYRLFVQKXIQD K KYY
EEPRKGIQAEEILQTYLKSKESMTDAILQTDQTLTEKEKEIEVERVIAESAQASAKMLQEMQRKNEQrWEQKERSYQEHLKQLTEKMENDRVQLLKEQERTLALKLQEQEQL
LKEGFQKESRIMKNEIQDLQTKMRRRKACTIS
430
ACAGAAGTGCTAGAAGCCAGTGCTCGTGAACTAAGGAGAAAAAGAACAGACAAGGGAACAGCCTGGACATGGCATCAGAGATCCACATGACAGGCCCAATGTGCCTCATTGA GAACACTAATGGGCGACTGATGGCGAATCCAGAAGCTCTGAAGATCCTTTCTGCCATTACACAGCCTATGGTGGTGGTGGCAATTGTGGGCCTCTACCGCACAGGCAAATCC TACCTGATGAACAAGCTGGCTGGAAAGAAAAAGGGCTTCTCTCTGGGCTCCACGGTGCAGTCTCACACTAAAGGAATCTGGATGTGGTGTGTGCCCCACCCCAAGAAGCCAG
GCCACATCCTAGTTCTGCTGGACACCGAGGGTCTGGGAGATGTAGAGAAGGG'IGACAACCAGAATGACTCCTGGATCTTCGCCCTGGCCGTCCTCCTGAGCAGCACCTTCGT GTACAATAGCATAGGAACCATCAACCAGCAGGCTATGGACCAACTGTACTATGTGACAGAGCTGACACATAGAATCCGATCAAAATCCTCACCTGATGAGAATGAGAATGAG GTTGAGGATTCAGCTGACTTTGTGAGCTTCTTCCCAGACTTTGTGTGGACACTGAGAGATTTCTCCCTGGACTTGGAAGCAGATGGACAACCCCTCACACCAGATGAGTACC TGACATACTCCCTGAAGCTGAAGAAAGGTACCAGTCAAΔAAGATGAAACTTTTAACCTGCCCAGACTCTGTATCCGGAAATTCTTCCCAAAGAAAAAATGCTTTGTCTTTGA TCGGCCCGTTCACCGCAGGAAGCTTGCCCAGCTCGAGAAACTACAAGATGAAGAGCTGGACCCCGAATTTGTGCAACAAGTAGCAGACTTCTGTTCCTACATCTTTAGTAAT TCCAAAACTAAAACTCTTTCAGGAGGCATCCAGGTCAACGGGCCTCGTCTAGAGAGCCTGGTGCTGACCTACGTCAATGCCATCAGCAGTGGGGATCTGCCGTGCATGGAGA ACGCAGTCCTGGCCTTGGCCCAGATAGAGAACTCAGCTGCAGTGCAAAAGGCTATTGCCCACTATGAACAGCAGATGGGCCAGAAGGTGCAGCTGCCCACAGAAAGCCTCCA GGAGCTGCTGGACCTGCACAGGGACAGTGAGAGAGAGGCCATTGAAGTCTTCATCAGGAGTTCCTTCAAAGATGTGGACCATCTATTTCAAAAGGAGTTAGCGGCCCAGCTA GAAAAAAAGCGGGATGACTTTTGTAAACAGAATCAGGAAGCATCATCAGATCGTTGCTCAGGTTTACTTCAGGTCATTTTCAGTCCTCTAGAAGAAGAAGTGAAGGCGGGAA TTTATTCGAAACCAGGGGGCTATCGTCTCTTTGTTCAGAAGCTACAAGACCTGAAGAAAAAGTACTATGAGGAACCGAGGAAGGGGATACAGGCTGAAGAGATTCTGCAGAC ATACTTGAAATCCAAGGAGTCTATGACTGATGCAATTCTCCAGACAGACCAGACTCTCACAGAAAAAGAAAAGGAGATTGAAGTGGAACGTGTGAAAGCTGAGTCTGCACAG GCTTCAGCAAAAATGTTGCAGGAAATGCAAAGAAAGAATGAGCAGATGATGGAACAGAAGGAGAGGAGTTATCAGGAACACTTGAAACAACTGACTGAGAAGATGGAGAACG ACAGGGTCCAGTTGCTGAAAGAGCAAGAGAGGACCCTCGCTCTTAAACTTCΔGGAACAGGAGCAACTACTAAAAGAGGGATTTCAAAAAGAAAGCAGAATAATGAAAAATGA GATACAGGATCTCCAGACGAAAATGAGACGACGAAAGGCATGTACCATAAGCTAAAGACCAGAGCCTTCCTGTCACCCCTAACCAAGGCATAATTGAAACAATTTTAGAATT TGGAACAAGCGTCACTACATTTGATAATAATTAGATCTTGCATCATAACACCAAAAGTTTATAAAGGCATGTGGTACAATGATCAAAATCATGTTTTTTCTTAAAAAAAAAA AAAAGACTGTAAATTGTGCAACAAAGATGCATTTACCTCTGTATCAACTCAGGAAATCTCATAAGCTGGTACCACTCAGGAGAAGTTTATTCTTCCAGATGACCAGCAGTAG ACAAATGGATACTGAGCAGAGTCTTAGGTAAAAGTCTTGGGAAATATTTGGGCATTGGTCTGGCCAAGTCTACAATGTCCCAATATCAAGGACAACCACCCTAGCTTCTTAG
TGAAGACAATGTACAGTTATCCATTAGATCAAGACTACACGGTCTATGAGCAATAATGTGATTTCTGGACATTGCCCATGTATAATCCTCACTGATGATTTCAAGCTAAAGC AAACCACCTTATACAGAGATCTAGAATCTCTTTATGTTCTCCAGAGGAAGGTGGAAGAAACCATGGGCAGGAGTAGGAATTGAGTGATAAACAATTGGGCTAATGAAGAAAA CTTCTCTTATTGTTCAGTTCATCCAGATTATAACTTCAATGGGACACTTTAGACCATTAGACAATTGACACTGGATTAAACAAATTCACATAATGCCAAATACACAATGTAT
TTATAGCAACGTATAATTTGCAAAGATGGACTTTAAAAGATGCTGTGTAACTAAACTGAAATAATTCAATTACTTATTATTTAGAATGTTAAAGCTTA'IGATAGTCTTTTCT
GTAGACTTTGTCTTATGTGTCAAAAGTCCTAGGAAAGTGGTTGATGTTTCTTATAGCAATTAAAAATTATTT'rTGAACTGA
431
MSELEQLRQEAEQLP^QIQDARKACNDATLVQITS IMDΞVGRIQMRTRRTLRGHLJ1KIYAMH GYDSRLLVSASQDGK I IWDSYTTNK HAI PLRSS VMTCAYAPSGNYV
ACGGLDNICSIYNLKTREGNVRVSRE PGHTGYLSCCRFLDDSQIVTSSGDTTCALWDIETAQQTTTFTGHSGDVMSLSLSPDMRTFVSGACDASSKLVωiRDGMCRQSFTG
HVSDINAVSFFPNGYAFATGSDDATCRLFDLRADCELLLYSHDNI ICGITSVAFSKSGR LLAGYDDFNCNVWDTLKGDRAGVLAGHDNRVSCLGV DDGMAVATGSWDSF
RI N
432
ACGTCCCCGCCGGGCCCGCGCGCCTCGTGCCTCGCGCCTCGCGCCTCCAGCCACGTCCCCGCCCCGGCTCCGGCGCGCCGCGGAGTTGGCTGCTGGGAGGTGCGGGACTGGG TGTGGCCGGCGGCTCTGGTCTCGGCTGTGAGCTGCGCTCTCCACGCCGGCTCCGCGCTCCAGGGGCTGCTGAGCGCCCAGCGGACACCGGCAGCGCGCGGTCGACGCGGGCC TGAGCTCCCTCCAGCTGTTTTCACTCATTAGCTCCTGAGGTAAACAAATTGAAAAAATGAGCGAACTGGAACAGTTGAGGCAAGAAGCAGAACAACTGCGGAATCAGATTCA GGATGCTCGGAAAGCATGTAATGATGCAACGCTTGTTCAGATTACATCAAATATGGACTCCGTGGGTCGAATACAAATGCGAACAAGACGTACACTGAGGGGCCACCTAGCT AAAATCTATGCTATGCATTGGGGATACGATTCCAGGCTGCTAGTCAGTGCTTCTCAAGATGGAAAATTAATTATTTGGGATAGCTATACAACAAATAAGATGCATGCTATTC CTTTGAGGTCCTCCTGGGTGATGACCTGTGCTTATGCTCCCTCTGGTAATTATGTTGCCTGTGGAGGCTTGGACAACATCTGCTCTATATATAACTTAAAGACCAGAGAGGG AAATGTGAGAGTAAGCCGAGAGTTGCCAGGTCACACAGGGTACTTGTCCTGCTGTCGTTTTTTAGATGACAGCCAAATTGTTACAAGTTCAGGAGATACAACTTGTGCTTTA TGGGACATCGAAACTGCCCAGCAGACCACCACATTCACTGGGCATTCTGGAGATGTGATGAGTCTTTCTTTGAGTCCTGACATGAGGACTTTTGTTTCTGGTGCTTGTGATG CCTCTTCCAAATTATGGGATATTCGAGATGGAATGTGTAGACAGTCTTTCACGGGACATGTCTCAGATATCAATGCTGTCAGTTTTTTCCCAAATGGA'IATGCCTTCGCCAC TGGCTCTGATGATGCCACTTGCCGGCTCTTTGACCTTCGTGCAGATCAAGAGTTATTATTGTATTCTCATGACAATATCATCTGTGGAATCACTTCIGTAGCCTTCTCAAAA AGTGGGCGTCTCTTGTTGGCTGGTTACGATGACTTTAATTGTAATGTATGGGACACGCTAAAAGGAGATCGTGCAGGTGTCCTTGCTGGTCATGACAACCGTGTGAGCTGCT TAGGTGTAACTGATGATGGCATGGCTGTGGCAACAGGCTCTTGGGACAGTTTTCTTAGAATCTGGAATTAACAGTGTCATACATATTTGTTCTCCATTGATATATCTGGAGA AATCAATGCTACAGCCTATAGCTGTGAAAAAATTCTACCTTATATTTGCAGGTGAAGATT TTCTATTAGATTATCTACAAAAACAAGCTTTCAGTAAACTACCAAAAAAAA AGTGGGGGTGGAGGAAAAAAGGCAAAGGCGCCTTCTGAGATCAAAAGGACCAGTGTATTAATTTGAGGGGTTGGGTTATTTTAACCTTGGTGAATTGTTGTGTGTACTCAGA GTGTATTTTCTTTGTGTAGAACAGAATGTACACATTATAGCAGCTCGCCATTGTGTTTGCATTTTTTAAGAAGTACATTTTTAACTTTGTATACACAAGAAATGTCATATTT TTGAGTTTTGTAATGGAAGAACCAGGCACAGAAACAGACAGAAATGATACTGTATGTGTGTGTATTTATGTCTGAAGAAAGTCCCCTTGAATTCTGATATCTCTTTGAATCT AAGAGATCCTGATAGCTTCATGTTTAAGAGCATTGACAGGTGGGGCACCTCTGAGGGGAGTTCATTGTTTCTCATGCATCATTTGCCATATACTATTAATCAAAGTGCTTGC TTGCAGTCCTTTGAGGGGACAGATAATCTGAAGGCCAGAGATTAGAGATTTCACTGATATTTTGGACATACATAAGAAACATCATTATAATTAATAAAAAGTAGGTAATAGC ATATAAATGGTTCTTGACATTTTAAAAGCCTGGTTATGATCAGTTGACACTTTGAGTACCCCCCTAAATAGCTGGACTTTCCTTTTCATTTCATAT'ITGGAACTAAGTTTGT AGCGTATACTCATCTTTCAGAAGTTTGGTAAACATTGGGATTGTCCCTGCATCTGAACATCTTTCCCAGTGCTATCAGTATACATCTAGAGAGGAAATGCAATGTGACAGTG TTACATTTGGAGAGAAGTGTGAAATCTAACCAATCGCTAGCACATATTTGTTGTAACACGGTGGTTTATTTCATGTTTGCATACTATAAAATCTGAATTGATGTGAAATATC TGTGCCTTTAAATTICTTAAACCTTTAAGCTTTTTGTTCTGTTTTGCAACATTTTGTAGTATTTCTTCCCTTCCTTAGCACAAAATACTGGTTTCTAAGTGGTTTTGCTTCA AAGGATGTCTAGATGTAAGTGATTCCACTTAAAGCCAAAATAAAAATTCCTAAAGCAGTTCTTAAAGGAGTTAGAGAGCTATATTAAACAGTTTTTCTGTGGT
433 GTATPDGREDQERL VSVEDAQMHTVTIWLTVRPDNTVASLKDMVF DYGFPPVLQQWVIGQRLARDQETLHSHGVRQNGDSAYLYL SARNTSLNPQE QRERQ RMLED
LGFKDLTLQPRGPLEPGPPKPGVPQEPGRGQPDAVPEPPPVGWQCPGCTFINKPTREGCEMCCRARPEAYQVPASYQPDEEERARLAGEEEALRQYQQRKQQQQEGNYLQHV
Q DQRS VLNTEPAECPVCYSVLAPGEAWLRECLHTFCREC QGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKA TPEDYQRFLDLGISIAENRSAFSYHCKTPDCKG
WCFFEDDVNEFTCPVCFHWCLLCKAIHEQMNCKEYQEDLTALRAQNDVAARQTTEMLKVNOJQQGEAMRCPQCQIW
GGCRCRVNGI PCHPSCQNCH
434
GGGAGTCCGGGGACCCGCGATCAGCCCCGGAGGACGGGGTGGGGTCGCCCCAAACAGGAGCGCCGGGACCGCTGGGACCCCGCACTCGGCGTCCGCCGCCGCCGGGTAGCCG GGCAGTGGAGGTCCCGGATGAGGCGACAATTTTTCCGGCCCCCCCTCCCAGTCCCGCCCCACTTCCGGGGCCGCCACTTTCACTTTCTCTTCCGCCGAAGCCGCTCCCCTTG CGAAGAACTGGGGCCTCCCGGGAGGAGAGAGGGCTTTGCCTTGAAACCCGGGACGCCAGGGGCGCTCCCGCAAGTGGGGGTCCTCCGGGACTTGGAACGCCCCGGCTGGGTG GΓGTCCGGGCGTCCTTTCCCCGCTTCTTCCCACCTCGGCTGGTCCCGTTTCCTCCTGCGCCCAGTGCGGACCTGTCTCGGCGCCCGCTGCCCTCTCACCGCCCCACGCAGGA ΓCCCGGCCTGGTCATCGGGCAGTGTGATGCTTCCCGACTGCCGCGGGGACAGCGAGGCACACACAGGGCTTGGGCCGCGCCGGAGGCCACACGGCCTGGCTGAGTTGCTCCT GGTCTCCCGCCTCTCCCAGGCGACCCGGAGGTAGCATTTCCCAGGAGGCACGGTCCCCCCCAGGGGGATGGGCACAGCCACGCCAGATGGACGAGAAGACCAAGAAAGGCTG ΓGGGTGAGCGTGGAGGATGCTCAGATGCACACCGTCACCATCTGGCTCACAGTGCGCCCTGATATGACAGTGGCGTCTCTCAAGGACATGGTTTTTCTGGACTATGGCTTCC CACCAGTCTTGCAGCAGTGGGTGATTGGGCAGCGGCTGGCACGAGACCAGGAGACCCTGCACTCCCATGGGGTGCGGCAGAATGGGGACAGTGCCTACCTCTATCTGCTGTC AGCCCGCAACACCTCCCTCAACCCTCAGGAGCTGCAGCGGGAGCGGCAGCTGCGGATGCTGGAAGATCTGGGCTTCAAGGACCTCACGCTGCAGCCGCGGGGCCCTCTGGAG CCAGGCCCCCCAAAGCCCGGGGTCCCCCAGGAACCCGGACGGGGGCAGCCAGATGCAGTGCCTGAGCCCCCACCGGTGGGCTGGCAGTGCCCCGGGTGCACCTTCATCAACA AGCCCACGCGGCCTGGCTGTGAGATGTGCTGCCGGGCGCGCCCCGAGGCCTACCAGGTCCCCGCCTCATACCAGCCCGACGAGGAGGAGCGAGCGCGCCTGGCGGGCGAGGA GGAGGCGCTGCGTCAGTACCAGCAGCGGAAGCAGCAGCAGCAGGAGGGGAACTACCTGCAGCACGTCCAGCTGGACCAGAGGAGCCTGGTGCTGAACACGGAGCCCGCCGAG RGCCCCGTGTGCTACTCGGTGCTGGCGCCCGGCGAGGCCGTGGTGCTGCGTGAGTGTCTGCACACCTTCTGCAGGGAGTGCCTGCAGGGCACCATCCGCAACAGCCAGGAGG CGGAGGTCTCCTGCCCCTTCATTGACAACACCTACTCGTGCTCGGGCAAGCTGCTGGAGAGGGAGATCAAGGCGCTCCTGACCCCTGAGGATTACCAGCGATTTCTAGACCT GGGCATCTCCATTGCTGAAAACCGCAGTGCCTTCAGCTACCATTGCAAGACCCCAGATTGCAAGGGATGGTGCITCTTTGAGGATGATGTCAATGAGTTCACCTGCCCTGTG ΓGTTTCCACGTCAACTGCCTGCTCTGCAAGGCCATCCATGAGCAGATGAACTGCAAGGAGTATCAGGAGGACCTGGCCCTGCGGGCTCAGAACGATGTGGCTGCCCGGCAGA CGACAGAGATGCTGAAGGTGATGCTGCAGCAGGGCGAGGCCATGCGCTGCCCCCAGTGCCAGATCGTGGTACAGAAGAAGGACGGCTGCGACTGGATCCGCTGCACCGTCTG CCACACCGAGATCTGCTGGGTCACCAAGGGCCCACGCTGGGGCCCTGGGGGCCCAGGAGACACCAGCGGGGGCTGCCGCTGCAGGGTAAATGGGATTCCTTGCCACCCAAGC RGTCAGAACTGCCACTGAGCTAAAGATGGTGGGGCCACATGCTGACCCAGCCCCACATCCACATTCTGTTAGAATGTAGCTCAGGGAGCTTCGTGGACGGCCTTGCTTGCTG ΓAGCGTTGTAGGGGCCCTGCCTGCACTGCGGTTGTCCACGGTCACATCTGCCCCAGTGCCTTTGTCCTTCCCITGGGGCTTGCCGGCCAGACTTCTCTCCCCTGCGGCTCCC ACCTCTGCCTGACCCCAGCCTTAAACATAGCCCCTGGCCAGAGGCCTTGCTGGGTGGAGCCTCTGTGTGACTCCATACTCCTCCCACCACAACACTCATCTGTCAAACACCA AGCACTCTCAGCCTCCCCGCCTTCAGCTGTCAGCTTTCTGGGGCTAACTTCTCTGCCTTTGTGGTTGGAGGCCTGAGGCCTCTTGGAACTCTTGCTAACCTGTTCAGAGCCA GGAAGGAGACTGCACAGTTTTGAAAGCACAGCCCGTCAGGTCCGGCTCTGCGTCTCCCTCTCTGCAGCCTGTGTAAGCTATTATAATTAAAATGGTTTTCCGGGAA
435
MSKGPAVGIDLGTTYSCVGVFQHGKVEIIANDQGNRTTPSYVAFTDTERLIGDAAKNQVAMNPTNTVFDAKRLIGRRFDDAWQSDMKHWPFMWNDAGRPKVQVEYKGETK SFYPEEVSΞMV TK^LKEI EA IΛKTV NA V VPA F Π^SQRQATKDAGTIAGLNV RIINEPTAAAIAYG DKK GAER RΛIFD GGG FDVSIL IEDGIFEVKSTAG DTHLGGEDFDNRMV^MFIAEFK KHKKDISE KRAVRRLRTACERAKRTLSSS QASIEIDSLYEGIDFY SITRARFEEL ADLFRGTLDPVEK LRDAKLDKSQIHDIVL VGGSTRIPKIQKLLQDFFNGKE NKSINPDEAVAYGAAVQAAILSGDKSENVQDLLLLDVTPLSLGIETAGGVMTVLIKRNTTIPTKQTQTFTTYSDNQPGV IQVYEGERA MRKDNNLLGKFE TGIPPAPRGVPQIEVTFDIDANGILNVSAVDKSTGKENKITITNDKGRLSKEDIERMVQEAEKYKAEDEKQRDKVSSKN8LKSYAFNMKATVEDEKI,QG KINDEDKQKILDKCNEIIN DKNQTAEKEEFEHQQKEL.EKVCNPIITKLYQSAGGMPGGMPGGMPGGFPGGGAPPSGGASEGPTIEEVD
436
CGGTGCTCAGTTGAACTGCGCRGCAGCTCTTGGTTTTTTGTGGCTTCCTTCGTTATTGGAGCCAGGCCTACACCCCAGCAACCATGTCCAAGGGACCTGCAGTTGGTATTGA TCTTGGCACCACCTACTCTTGRGTGGGTGTTTTCCAGCACGGAAAAGTCGAGATAATTGCCAATGATCAGGGAAACCGAACCACTCCAAGCTATGTCGCCTTTACGGACACT GAACGGTTGATCGGTGATGCCGCAAAGAATCAAGTTGCAATGAACCCCACCAACACAGTTTTTGATGCCAAACGTCTGATTGGACGCAGATTTGATGATGCTGTTGTCCAGT CTGATATGAAACATTGGCCCΓΓTATGGTGGTGAATGATGCTGGCAGGCCCAAGGTCCAAGTAGAATACAAGGGAGAGACCAAAAGCTTCTATCCAGAGGAGGTGTCTTCTAT GGTTCTGACAAAGATGAAGGAAATTGCAGAAGCCTACCTTGGGAAGACTGTTACCAATGCTGTGGTCACAGTGCCAGCTTACTTTAATGACTCTCAGCGTCAGGCTACCAAA GATGCTGGAACTATTGCTGGRCTCAATGTACTTAGAATTATTAATGAGCCAACTGCTGCTGCTATTGCTTACGGCTTAGACAAAAAGGTTGGAGCAGAAAGAAACGTGCTCA TCTTTGACCTGGGAGGTGGCACTTTTGATGTGTCAATCCTCACTATTGAGGATGGAATCTTTGAGGTCAAG'ICTACAGCTGGAGACACCCACTTGGGTGGAGAAGATTTTGA CAACCGAATGGTCAACCATTΓΓATTGCTGAGTTTAAGCGCAAGCATAAGAAGGACATCAGTGAGAACAAGAGAGCTGTAAGACGCCTCCGTACTGCTTGTGAACGTGCTAAG CGTACCCTCTCTTCCAGCACCCAΒGCCAGTATTGAGATCX3ATTCTCTCTATGAAGGAATCGACTTCTATACCTCCATTACCCGTGCCCGATTTGAAGAACTGAATGCTGACC TGTTCCGTGGCACCCTGGACCCAGTAGAGAAAGCCCTTCGAGATGCCAAACTAGACAAGTCACAGATTCATGATATTGTCCTGGTTGGTGGTTCTACTCGTATCCCCAAGAT TCAGAAGCTTCTCCAAGACΓΓCTTCAATGGAAAAGAACTGAATAAGAGCATCAACCCTGATGAAGCTGTTGCTTATGGTGCAGCTGTCCAGGCAGCCATCTTGTCTGGAGAC AAGTCTGAGAATGTTCAAGATΓTGCTGCTCTTGGATGTCACTCCTCTTTCCCTTGGTATTGAAACTGCTGGTGGAGTCATGACTGTCCTCATCAAGCGTAATACCACCATTC CTACCAAGCAGACACAGACCTRCACTACCTATTCTGACAACCAGCCTGGTGTGCTTATTCAGGTTTATGAAGGCGAGCGTGCCATGACAAAGGATAACAACCTGCTTGGCAA GRTTGAACTCACAGGCATACCRCCTGCACCCCGAGGTGTTCCTCAGATTGAAGTCACTTTTGACATTGATGCCAATGGTATACTCAATGTCTCTGCTGTGGACAAGAGTACG EGAAAAGAGAACAAGATTACTATCACTAATGACAAGGGCCGTTTGAGCAAGGAAGACATTGAACGTATGGTCCAGGAAGCTGAGAAGTACAAAGCTGAAGATGAGAAGCAGA GGGACAAGGTGTCATCCAAGAATTCACTTGAGTCCTATGCCTTCAACATGAAAGCAACTGTTGAAGATGAGAAACTTCAAGGCAAGATTAACGATGAGGACAAACAGAAGAT RCTGGACAAGTGTAATGAAATTATCAACTGGCTTGATAAGAATCAGACTGCTGAGAAGGAAGAATTTGAACATCAACAGAAAGAGCTGGAGAAAGTTTGCAACCCCATCATC ACCAAGCTGTACCAGAGRGCAGGAGGCATGCCAGGAGGAATGCCTGGGGGATTTCCTGGTGGTGGAGCTCCTCCCTCTGGTGGTGCTTCCTCAGGGCCCACCATTGAAGAGG
TTGATTAA 437
MSKGP VGIDLGTTYSCVGVFQHGKVEIIANDCGNRTTPSYVAFTDTER IGD7ΛAKNQ A^TOP NTVFDAKRLIGRRFDDA VQSDMIΑ^ PF^^VV DAGR KVQVEYKGE K SF PEEVSS^WLT MKEIAEAY GK V MAV TV AYFM)SQ Q TKDAG IAGIJW RIINEPTΔAAIAYGLDKKVG ERNV IFDLGGG FD SILTIEDGIFEVKS AG DΓH GGEDFDNRMVNHFIAEFKRKΉKKDISENKRAVRR RTACERAKRTLSSSTQASIEIDSLYEGIDFYTSITRARFEELNAD FRGTLDPVEKALRDAKLDKSQIHDIVL VGGSTRIPKIQKL QDFFNGKELNKSINPDEAVAYGAAVQAAI SGDKSENVQDLLLLDVTPLSLGIETAGGVMTVLIKRNTTIPTKQTQTFTTYSDNQPGV IQVYEGERA MTKD^RA LGKFELTGIPPAP VPQIEVTFDID NGIL WSAVDKSTGKENKITITNDKΣR SKEDIER^RVQEAEKYKAEDEKQRDKVSSKNSLKSYAFN^IKATVEDEIΑJQG KINDEDKQKILDKCNEIINW ,DKNQTAEKEEFEHQQKELEKVCNPIITKLYQSAGG PGGMPGGMPGGFPGGGAPPSGGA88GPTIEEVD
438
TCTTGGCACCACCTACRCTRGRGTGGGTGTTTTCCAGCACGGAAAAGTCGAGATAATTGCCAATGATCAGGGAAACCGAACCACTCCAAGCTATGTCGCCTTTACGGACACT GAACGGTTGATCGGTGAΓGCCGCAAAGAATCAAGTTGCAATGAACCCCACCAACACAGTTTTTGATGCCAAACGTCTGATTGGACGCAGATTTGATGATGCTGTTGTCCAGT CTGATATGAAACATTGGCCCTTTATGGTGGTGAATGATGCTGGCAGGCCCAAGGTCCAAGTAGAATACAAGGGAGAGACCAAAAGCTTCTATCCAGAGGAGGTGTCTTCTAT GGRTCTGACAAAGATGAAGGAAATTGCAGAAGCCTACCTTGGGAAGACTGTTACCAATGCTGTGGTCACAGTGCCAGCTTACTTTAATGACTCTCAGCGTCAGGCTACCAAA GATGCTGGAACTATTGCR∞TCTCAATGTACTTAGAATTATTAATGAGCCAACTGCTGCTGCTATTGCTTACGGCTTAGACAAAΔAGGTTGGAGCAGAAAGAAACGTGCTCA TCTTTGACCTGGGAGKTGGCACTTTTGATGTGTCAATCCTCACTATTGAGGATRJGAATCTTTGAGGTCAAGTCTACAGCTGGAGACACCCACTTGGGTGGAGAAGATTTTGA CAACCGAATGGTCAACCAΓTTTATTGCTGAGTTTAAGCGCAAGCATAAGAAGGACATCAGTGAGAACAAGAGAGCTGTAAGACGCCTCCGTACTGCTTGTGAACGTGCTAAG CGTACCCTCTCTTCCAGCACCCAGGCCAGTATTGAGATCGATTCTCTCTATGAAGGAATCGACTTCTATACCTCCATTACCCGTGCCCGATT'IGAAGAACTGAATGCTGACC TGTTCCGTGGCACCCRGGACCCAGTAGAGAAAGCCCTTCGAGATGCCAAACTAGACAAGTCACAGATTCATGATATTGTCCTGGTTGGTGGTTCTACTCGTATCCCCAAGAT TCAGAAGCTTCTCCAAGACTRCTTCAATGGAAAAGAACTGAATAAGAGCATCAACCCTGATGAAGCTGTTGCTTATGGTGCAGCTGTCCAGGCAGCCATCTTGTCTGGAGAC AAGTCTGAGAATGTTCAAGAΓTTGCTGCTCTTGGATGTCACTCCTCTTTCCCTTGGTATTGAAACTGCTGGTGGAGTCATGACTGTCCTCATCAAGCGTAATACCACCATTC CTACCAAGCAGACACAGACCRRCACRACCTATTCTGACAACCAGCCTGGTGTGCTTARTCAGGTTTATGAAGGCGAGCGTGCCATGACAAAGGATAACAACCTGCTTGGCAA GTTTGAACTCACAGGCARACCTCCTGCACCCCGAGGTGTTCCTCAGATTGAAGTCACRTTTGACATTGATGCCAATGGTATACTCAATGTCTCTGCTGTGGACAAGAGTACG GGAAAAGAGAACAAGARRACRATCACTAATGACAAGGGCCGTTTGAGCAAGGAAGACATTGAACGTATGGTCCAGGAAGCTGAGAAGTACAAAGC'RGAAGATGAGAAGCAGA GGGACAAGGTGTCARCCAAAAARTCACTTGAGTCCTATGCCTTCAACATGAAAGCAACTGTTGΔΔGΔTGAGAAACTTCAAGGCAAGATTAACGATGAGGACAAACAGAAGAT TCTGGACAAGTGTAATGAAATTATCAACTGGCTTGATAAGAATCAGACTGCTGAGAAGGAAGAATTTGAACATCAACAGAAAGAGCTGGAGAAAGTTTGCAACCCCATCATC ACCAAGCTGTACCAGAGTGCAGGAGGCATGCCAGGAGGAATGCCTGGGGGATTTCCTGGTGGTGGAGCτCCTCCCTCTGGTGGTGCTTCCTCAGGGCCCACCATTGAAGAGG TTGATTAA
439 EERSYWQSQVNQDIC YGSIPPDVEEK RLEWPYQEQLLLREHYQKKFKNSTYSRSSVDVLYTFANCSGLDLI FGLNALLRTADLQWNSSNAQLLLDYCSSKGYNISWELGN
K WLGETSSAYGGGA L SDTFAAGF^WLDKLGLSA MGIE VM QVFFGAGNYHL DE F□P DYWL8LLFKKL GTKVLMASVQGSKRRKLR HCTNTD PRYKEG DLT YAINLHNVTKYLRLPYPFSNKQVDKYL RPLGPHG LSKSVQLNGLTLKMVDDQT PPLMEKPLRPGSSLGLPAFSYSFFVIRNAKVAACI
440
CAGCGCTGCTCCCCGGGCGCTCCTCCCCGGGCGCTCCTCCCCAGGCCTCCCGGGCGCTTGGATCCCGGCCATCTCCGCACCCTTCAAGTGGGTGTGGGTGATTTCCTGGCGG GGGGAGCAGCCAGGTGAGCCCAAGATGCTGCTGCGCTCGAAGCCTGCGCTGCCGCCGCCGCTGATGCTGCTGCTCCTGGGGCCGCTGGGTCCCCTCTCCCCTGGCGCCCTGC CCCGACCTGCGCAAGCACAGGACGTCGTGGACCTGGACTTCTTCACCCAGGAGCCGCTGCACCTGGTGAGCCCCTCGTTCCTGTCCGTCACCATTGACGCCAACCTGGCCAC GGACCCGCGGTTCCTCATCCTCCTGGGTTCTCCAAAGCTTCGTACCTTGGCCAGAGGCTTGTCTCCTGCGTACCTGAGGTTTGGTGGCACCAAGACAGACTTCCTAATTTTC GATCCCAAGAAGGAATCAACCTTTGAAGAGAGAAGTTACTGGCAATCTCAAGTCAACCAGGATATTTGCAAATATGGATCCATCCCTCCTGATGTGGAGGAGAAGTTACGGT TGGAATGGCCCTACCAGGAGCAATTGCTACTCCGAGAACACTACCAGAAAAAGTTCAAGAACAGCACCTACTCAAGAAGCTCTGTAGATGTGCTATACACTTTTGCAAACTG CTCAGGACTGGACTTGATCTTTGGCCTAAATGCGTTATTAAGAACAGCAGATTTGCAGTGGAACAGTTCTAATGCTCAGTTGCTCCTGGACTACTGCTCTTCCAAGGGGTAT AACATTTCTTGGGAACTAGGCAATGAACCTAACAGTTTCCTTAAGAAGGCTGATATTTTCATCAATGGGTCGCAGTTAGGAGAAGATTTTATTCAATTGCATAAACTTCTAA GAAAGTCCACCTTCAAAAATGCΔAAACTCTATGGTCCTGATGTTGGTCAGCCTCGAAGAAAGACGGCTAAGATGCTGAAGAGCTTCCTGAΔGGCTGGTGGAGAAGTGATTGA TTCAGTTACATGGCATCACTACTATTTGAATGGACGGACTGCTACCAGGGAAGATTTTCTAAACCCTGATGTATTGGACATTTTTATTTCATCTGTGCAAAAAGTTTTCCAG GTGGTTGAGAGCACCAGGCCTGGCAAGAAGGTCTGGTTAGGAGAAACAAGCTCTGCATATGGAGGCGGAGCGCCCTTGCTATCCGACACCTTTGCAGCTGGCTTTATGTGGC TGGATAAATTGGGCCTGTCAGCCCGAATGGGAATAGAAGTGGTGATGAGGCAAGTATTCTTTGGAGCAGGAAACTACCATTTAGTGGATGAAAACTTCGATCCTTTACCTGA TTATTGGCTATCTCTTCTGTTCAAGAAATTGGTGGGCACCAAGGTGTTAATGGCAAGCGTGCAAGGTTCAAAGAGAAGGAAGCTTCGAGTATACCTTCATTGCACAAACACT GACAATCCAAGGTATAAAGAAGGAGATTTAACTCTGTATGCCATAAACCTCCATAATGTCACCAAGTACTTGCGGTTACCCTATCCTTTTTCTAACAAGCAAGTGGATAAAT ACCTTCTAAGACCTTTGGGACCTCATGGATTACTTTCCAAATCTGTCCAACTCAATGGTCTAACTCTAAAGATGGTGGATGATCAAACCTTGCCACCTTTAATGGAAAAACC TCTCCGGCCAGGAAGTTCACTGGGCTTGCCAGCTTTCTCATATAGTTTTTTTGTGATAAGAAATGCCAAAGTTGCTGCTTGCATCTGAAAATAAAATATACTAGTCCTGACA CTGAATTTTTCAAGTATACTAAGAGTAAAGCAACTCAAGTTATAGGAAAGGAAGCAGATACCTTGCAAAGCAACTAGTGGGTGCTTGAGAGACACTGGGACACTGTCAGTGC TAGATTTAGCACAGTATTTTGATCTCGCTAGGTAGAACACTGCTAATAATAATAGCTAATAATACCTTGTTCCAAATACTGCTTAGCATTTTGCATGTTTTACTTTTATCTA AAGTTTTGTTTTGTTTTATTATTTATTTATTTATTTATTTTGTGACGGAGAGAGATTCCATCTCAAAAAAACAAGTTATTAAAAATGTATATGAATGCTCCTAATATGGTCA GGAAGCAAGGAAGCGAAGGATATATTATGAGTTTTAAGAAGGTGCTTAGCTGTATAT'ITATCTTTCAAAATGTATTAGAAGATTTTAGAATTCTTTCCTTCATGTGCCATCT CTACAGGCACCCATCAGAAAAAGCATACTGCCGTTACCGTGAAACTGGTTGTAAAAGAGAAACTATCTATTTGCACCTTAAAAGACAGCTAGATTTTGCTGATTTTCTTCTT TCGGTTTTCTTTGTCAGCAATAATATGTGAGAGGACAGATTGTTAGATATGATAGTATAAAAAATGGTTAATGACAATTCAGAGGCGAGGAGATTCTGTAAACTTAAAATTA CTATAAATGAAATTGATTTGTCAAGAGGATAAATTTTAGAAAACACCCAATACCTTATAACTGTCTGTTAATGCTTGCTTTTTCTCTACCTTTCTTCCTTGTTTCAGTTGGG AAGCTTTTGGCTGCAAGTAACAGAAACTCCTAATTCAAATGGCTTAAGCAATAAGGAAATGTATATTCCCACATAACTAGACGTTCAAACAGGCCAGGCTCCAGCACTTCAG TACGTCACCAGGGGATCTGGGTTCTTCCCAGCTCTCTGCTCTGCCATCTTTAGCGCTGGCTICATTCTCAGACTCTGGTAGCATGATGGCTGTAGCTGTTTCATGGGCCCCT TCAAACCTCATAGCAACCAGAGGAAGAAAATGAGCCATTTTTTGAGTCTCCTTCATAGACTTGAATAACTCTTTTTCAGAGCTTCTCACAGCAAACCTCTCCTCATGTCTCC TCATGTCTTATTGTTCAGAAATGGGTAATGTGGCCATTTCACCAGTCACTGCCAACAACAACGAGGTTCCTATAATTGTCTCTGAGTAACCCTTTGGAATGGAGAGGGTGTT GGTCAGTCTACAAACTGAACACTGCAGTTCTGCGCTTTTTACCAGTGAAAAAATGTAATTATTTTCCCCTCTTAAGGATTAATATTCTTCAAATGTATGCCTGTTATGGATA TAGTATCTTTAAAATTTTTTATTTTAATAGCTTTAGGGGTACACACTTTTTGCTTACAGGGGTGAATTGTGTAGTGGTGAAGACTCGGCTTTTAATGTACTTGTCACCTGAG TGATGTACATTGTACCCAATAGGTAATTTTTCATCCATTACCCTCCTTCCGCCCTCTTCCCTTCTGAGTCTCCAACATCCCTTATACCACTGTGTATGTTCTTGTGTACCTA CAGCTAAGCTTCCACTTATAAGTGAGAACATGCAGTATTTGGTTTTCCATTCCTGAGTTACTTCCCTTAGGATAACAGCCCCCAGTTCCGTCCAAGTTGCTGCAAAATACAT TATTCTTCTTTATGGCTGAGTAATAGTCCATGGTACATATATACCACATTTTCTTTATCCACTTATCAGTTGATGGACACTTAGGTTAATTCCATTCAATTTCATTCAATTT AAGTATATTTGTAAGGAGCTAAAGCTGAAAATTAAATTTTAGATCTTTCAATACTCTTAAATTTTATATGTAAGTGGTTTTTATATTTTCACATTTGAAATAAAGTAATTTT TATAACCTTGAAAAAAAAAAAAAAAAAAAA
441
MLQLWKWRPARQLE HRLILL IAFSLGSMGFLAYYVETSPKAKEPLPLPLGDCSEGGAAGPGPARPPVPPRPPRPPETARTEPW VFVESAYSQLGQEIVAILESSRFR YSTE APGRGDMPTLTDNTHGRYVLVIYENLLKYVNLDA ΕREL DRYCVEYGVGUGFFRAHEHS SAQLKGFPLFLHSNLGLRDYQVNPSAPLLHLTRPSRLEPGPLPG DDWTIFQSNHSTYEPVIJΛS RPAEPAVPGPVLRPΛR PTVVQDLGLHDGIQRVLFGHGLΞFWLHKLIFVDAVAYLTGKRLCLD DRYILVDIDDIFVGKEGTRMKVADVEA LLTTQNKLRTLVPNFTFNLGFSGKFYHTGTEEEDAGDDM LKHRKEF WFPH1WSHMQPHLFH RSVLADQMRLNKQFALEHGIPTDLGYAVAPHH8GVYPIHTQLYEA KS V GIQVTSTEEYPH RPARYRRGFIHNGIMV PRQTCGLFTHTIFYNEYPGGSRELDRSIRGGELFLTVLLNPISIFMTHLSNYGNDR GLYTFESLVRFLQCWTRLRLQT PPVPIIAQKYFELFPQERSPLWQNPCDDKRHKDIWSKEKTCDR PKFLIVGPQKTGTTAIHFFLS HPAVTSSFPSPSTFEEIQFFNSPNYHKGIDWYMDFFPVPSNASTDF FEKSATYFDSEWPRRGAALLPRAKIITVLTNPADRAYS YQHQRAHGDPVALNYTFYQVISASSQTPLALRSLQNRCLVPGYYSTHLQR LTYYPSGQLLIVDGQE RTNP AASMESIQKFLGITPFLNYTRT RFDDDKGFWCQGLEGGKTRCLGRSKGRRYPDMDTESRLFLTDFFRNHNLELSK LSRLGQPVPSWLREELQHSSLG
442
CGCGGCTCAGTAATTGAAGGCCTGAAACGCCCATGTGCCACTGACTAGGAGGCTTCCCTGCTGCGGCACTTCATGACCCAGCGGCGCGCGGCCCAGTGAAGCCACCGTGGTG TCCAGCATGGCCGCGCTGCTCCTGGGCGCGGTGCTGCTGGTGGCCCAGCCCCAGCTAGTGCCTTCCCGCCCCGCCGAGCTAGGCCAGCAGGAGCTTCTGCGGAAAGCGGGGA CCCTCCAGGATGACGTCCGCGATGGCGTGGCCCCAAACGGCTCTGCCCAGCAGTTGCCGCAGACCATCATCATCGGCGTGCGCAAGGGCGGCACGCGCGCACTGCTGGAGAT GCTCAGCCTGCACCCCGACGTGGCGGCCGCGGAGAACGAGGTCCACTTCTTCGACTGGGAGGAGCATTACAGCCACGGCTTGGGCTGGTACCTCAGCCAGATGCCCTTCTCC TGGCCACACCAGCTCACAGTGGAGAAGACCCCCGCGTATTTCACGTCGCCCAAAGTGCCTGAGCGAGTCTACAGCATGAACCCGTCCATCCGGCTGCTGCTCATCCTGCGAG ACCCGTCGGAGCGCGTGCTATCTGACTACACCCAAGTGTTCTACAACCACATGCAGAAGCACAAGCCCTACCCGTCCATCGAGGAGTTCCTGGTGCGCGATGGCAGGCTCAA TGTGGACTACAAGGCCCTCAACCGCAGCCTCTACCACGTGCACATGCAGAACTGGCTGCGCTTTTTCCCGCTGCGCCACATCCACATTGTGGACGGCGACCGCCTCATCAGG
GACCCCTTCCCTGAGATCCAAAAGGTCGAGAGGTTCCTAAAGCTGTCGCCGCAGA'ICAATGCTTCGAACTTCTACITTAACAAAACCAAGGGCTTTTACTGCCTGCGGGACA GCGGCCGGGACCGCTGCTTACATGAGTCCAAAGGCCGGGCGCACCCCCAAGTCGATCCCAAACTACTCAATAAACTGCACGAATATTTTCATGAGCCAAATAAGAAGTTCTT CGAGCTTGTTGGCAGAACATTTGACTGGCACTGAT'ITGCAATAAGCTAAGCTCAGAAACTTTCCTACTGTAAGTTCTGGTGTACATCTGAGGGGAAAAAGAATTTTAAAAAA GCATTTAAGGTATAATTTATTTGTAAAATCCATAAAG'rACTTCTGTACAGTATTAGATTCACAATTGCCATATATAC'IAGTTATATTTTTCTACTTGTTAAATGGAGGGCAT TTTGTATTGTTTTTCATGGTTGTTAACATTGTGTAATATGTCTCTATATGAAGGAACTAAACTATTTCACTGA
443
MDSIGSSGLRQGEETLSCSEEG PGPSDSSE VQECLQQFKVTRAQ QQIQASLLGSMEQAiRGQASPAPAVRMLPTYVGSTPHGTEQGDFVVLELGATGASLRVL VT TG
IEGHRVEPRSQEFVIPQEVMLGAGQQLFDFAAHCLSEF DAQPVNKQGLQLGFSFSFPCHQTGLDRSTLISWTKGFRCSGVEGQDWQ RDAIRRQGAYNIDWAWNDTV
GT^mGCEPGVRPCE GLVVDTGTNACYMEEA H AV DEDRGRVCVSVEWGS εDr3A GPV TTFDHTLDHESLNPGAQRFEKMIGG YIΛELVRL LAHTJA CGVLFGGC
TSPAL SQG8ILLEHVAEMEDPSTGAARVHAILQDLGLSPGASDVE VQHVCAAVCTRAAQLCAAALAAVLEC QH8REQQTLQVAVATGGRVCERHPRFCSVLQGTVML,LA
PECDVELIPSVD-^RGVAM^AVAARIAAHRRLLEETLAPFRLmDQI ^VQAQMRK^^
ITSEIYSIPETVAOGSGQQ FDHIVDCIVDFQQKQGLSGQS PLGFTFSFPCRQLGLDOGILLNWTKGFKASDCEGQDWSLLREAITRRQAVE NWAIVNDTVGTM SCG
YEDPRCEIGLIVGTGTNACYMEE RNVAGVPGDSGRMCINME GAFGDLXSS ANLSTRFDASVDQASINPGKQRFEKMISGMY GEIVRHILLHLTSIiGV FRGQQIQRLQT DIFKTKF SEIESDSIA RQVRAILEDLGLPLTSDDAL^WIJEVCQAVSQRAAQLCGAGVAAVVEKIRGNRGLEEIJA SVG\roGT YK HP FεS VAATVRE^-APRCVVTF
LQSEDGSGKGAALVTAVACRLAQ TRV
444
GACAAGAGCTCAGACCTGAGGAGAGTGACTAGC1TCTCTGTGTCCCAGGTGGCCACCTTCCACTGTGGAAGCTCATGGACTCCATTGGGTCTTCAGGGTTGCGGCAGGGGGA
AGAAACCCTGAGTTGCTCTGAGGAGGGCTTGCCCGGGCCCTCAGACAGCTCAGAGCTGGTGCAGGAGTGCCTGCAGCAGTTCAAGGTGACAAGGGCACAGCTACAGCAGATC CAAGCCAGCCTCTTGGGTTCCATGGAGCAGGCGCTGAGGGGACAGGCCAGCCCTGCCCCTGCGGTCCGGATGCTGCCTACATACGTGGGGTCCACCCCACATGGCACTGAGC AAGGAGACTTCGTGG GCTGGAGCTGGGGGCCACAGGGGCCTCACTGCGTGTTTTGTGGGTGACTCTAACTGGCATTGAGGGGCATAGGGTGGAGCCCAGAAGCCAGGAGTT TGTGATCCCCCAAGAGGTGATGCTGGGTGCTGGCCAGCAGCTCTTTGACTTTGCTGCCCACTGCCTGTCTGAGTTCCTGGATGCGCAGCCTGTGAACAAACAGGGTCTGCAG CTTGGCTTCAGCTTCTCTTTCCCTTGTCACCAGACGGGCTTGGACAGGAGCACCCTCATTTCCTGGACCAAAGGTTTTAGGTGCAGTGGTGTGGAAGGCCAGGATGTGGTCC AGCTGCTGAGAGATGCCATTCGGAGGCAGGGGGCCTACAACATCGACGTGGTTGCTGTGGTGAACGACACAGTGGGCACCATGATGGGCTGTGAGCCGGGGGTCAGGCCGTG TGAGGTTGGGCTAGTTGTAGACACGGGCACCAACGCGTGTTACATGGAGGAGGCACGGCATGTGGCAGTGCTGGACGAAGACCGGGGCCGCGTCTGCGTCAGCGTCGAGTGG GGCTCCTTAAGCGATGATGGGGCGCTGGGACCAGTGCTGACCACCTTCGACCATACCCTGGACCATGAGTCCCTGAATCCTGGTGCTCAGAGGTTTGAGAAGATGATCGGAG GCCTGTACCTGGGTGAGCTGGTGCGGCTGGTGCTGGCTCACTTGGCCCGGTGTGGGGTCCTCTTTGGTGGCTGCACCTCCCCTGCCCTGCTGAGCCAAGGCAGCATCCTCCr GGAACACGTGGCTGAGATGGAGGACCCCTCTACTGGGGCAGCCCGTGTCCATGCTATCCTGCAGGACTTGGGCCTGAGCCCTGGGGCTTCGGATGTTGAGCTTGTGCAGCAC GTCTGTGCGGCCGTGTGCACGCGGGCTGCCCAGCTCTGTGCTGCCGCCCTGGCCGCTGTTCTCTCCTGCCTCCAGCACAGCCGGGAGCAACAAACACTCCAGGTTGCTGTGG CCACCGGAGGCCGAGTGTGTGAGCGGCACCCCAGGTTCTGCAGCGTCCTGCAGGGGACAGTGATGCTCCTGGCCCCGGAATGCGATGTCTCCTTAATCCCCTCTGTGGATGG TGGTGGCCGGGGAGTGGCGATGGTGACTGCTGTGGCTGCCCGTCTGGCTGCCCACCGGCGCCTGCTGGAGGAGACCCTGGCCCCATTCCGGTTGAACCATGATCAACTGGCT GCGGTTCAGGCACAGATGCGGAAGGCCATGGCCAAGGGGCTCCGAGGGGAGGCCTCCTCCCTTCGCATGCTGCCCACTTTCGTCCGGGCCACCCCTGACGGCAGCGAGCGAG GGGATTTCCTGGCCCTGGACCTCGGGGGCACGAACTTCCGTGTCCTCCTGGTACGTGTGACCACAGGCGTGCAGATCACCAGCGAGATCTACTCCATTCCCGAGACTGTGGC CCAGGGTTCTGGGCAGCAGCTCTTTGACCACATCGTGGACTGCATCGTGGACTTCCAGCAGAAGCAGGGCCTGAGCGGGCAGAGCCTCCCACTGGGTTTTACCTTCTCCTTC CCATGTAGGCAGCTTGGCCTAGACCAGGGCATCCTCCTGAACTGGACCAAGGGTTTCAAGGCATCAGACTGCGAGGGCCAAGATGTCGTGAGTCTGTTGCGGGAAGCCATCA CTCGCAGACAGGCAGTGGAGCTGAATGTGGTTGCCATTGTCAATGACACGGTGGGGACCATGATGTCCTGTGGCTATGAGGACCCCCGTTGCGAGATAGGCCTCATTGTCGG AACCGGCACCAATGCCTGCTACATGGAGGAGCTCCGGAATGTGGCGGGCGTGCCTGGGGACTCAGGCCGCATGTGCATCAACATGGAGTGGGGCGCCTTTGGGGACGATGGC TCTCTGGCCATGCTCAGCACCCGCTTTGATGCAAGTGTGGACCAGGCGTCCA'ICAACCCCGGCAAGCAGAGGTTTGAAAAGATGATCAGCGGCATGTACCTGGGGGAGATCG TCCGCCACATCCTTTTACATTTAACCAGCCTTGGCGTTCTCTTCCGGGGCCAGCAGATCCAGCGCCTTCAGACCAGOGACATCTTCAAGACCAAGTTCCTCTCTGAGATCGA AAGTGACAGCCTGGCCCTGCGGCAGGTCCGAGCCATCCTAGAGGATCTGGGGCTACCCCTGACCTCAGATGACGCCCTGATGGTGCTAGAGGTGTGCCAGGCTGTGTCCCAG AGGGCTGCCCAGCTCTGTGGGGCGGGTGTAGCTGCCGTGGTGGAGAAGATCCGGGGGAACCGGGGCCTGGAAGAGCTGGCAGTGTCTGTGGGGGTGGATGGAACGCTCTACA AGCTGCACCCGCGCTTCTCCAGCCTGGTGGCGGCCACAGTGCGGGAGCTGGCCCCTCGCTGTGTGGTCACGTTCCTGCAGTCAGAGGATGGGTCCGGCAAAGGTGCGGCCCT GGTCACCGCTGTTGCCTGCCGCCTTGCGCAGTTGACTCGTGTCTGAGGAAACCTCCAGGCTGAGGAGGTCTCCGCCGCAGCCTTGCTGGAGCCGGGTCGGGGTCTGCCTGTT TCCCAGCCAGGCCCAGCCACCCAGGACTCCTGGGACATCCCATGTGTGACCCCTCTGCGGCCATTTGGCCTTGCTCCCTGGCTTTCCCTGAGAGAAGTAGCACTCAGGTTAG CAATATATATATATAATTTATTTACAAAAAAAAAAAAA
445
MEGAGGAOT)KKKiεSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVMRLTISYLRTOK^
SDNVNKYMG TQFE TGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGRTMNIKSAT KVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLIC
EPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMIJAKRGGYVWVETQATVIYNTKNSQPQCIV
CVNYVVSGIIQHDLIFSLQQTECV KPVESSDMKNTQ FTKVESEDTSSLFDKLKKEPDALTLIiAPAAGDTIIS DFGSNDTETDDQQLEEVPLYNDVMLPSPNEKXiQNINL
AMSP PTAETPKPLRSSADPALNQEVALKLEPNPESLELSFTMPQIQDQTPSPSDG8TRQ88PEPNSPSEYCFYVDSDMVNEFKLELVEKLFAEDTEAKNPF8TQDTDLDLE
MLAPYIPMDDDFQLRSFDQLSPLESSSA8PE8A8PQSTVTVFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIA8PSPTHIHKETTSAT88PYRDTQSRTASPNRA
GKGVIEQTEKSHPRSP1WLSVALSQRTTVPEEELNPKILALQNAQRKRKMEHDG8LFQAVGIGT LQQPDDHAATTS SWKRVKGCKSSEQNGMEQKTIILIPSDLACRLLG
QSMDESG PQLTSYDCEVNAPIQGSRNLLQGEE LRALDQVN
446
CACGAGGCAGCACTCTCTTCGTCGCTTCGGCCAGTGTGTCGGGCTGGGCCCTGACAAGCCACCTGAGGAGAGGCTCGGAGCCGGGCCCGGACCCCGGCGATTGCCGCCCGCT TCTCTCTAGTCTCACGAGGGGTTTCCCGCCTCGCACCCCCACCTCTGGACTTGCCTTTCCTTCTCTTCTCCGCGTGTGGAGGGAGCCAGCGCTTAGGCCGGAGCGAGCCTGG GGGCCGCCCGCCGTGAAGACATCGCGGGGACCGATTCACCATGGAGGGCGCCGGCGGCGCGAACGACAAGAAAAAGATAAGTTCTGAACGTCGAAAAGAAAAGTCTCGAGAT GCAGCCAGATCTCGGCGAAGTAAAGAATCTGAAGTTTTTTATGAGCTTGCTCATCAGTTGCCACTTCCACATAATGTGAGTTCGCATCTTGATAAGGCCTCTGTGATGAGGC TTACCATCAGCTATTTGCGTGTGAGGAAACTTCTGGATGCTGGTGATTTGGATATTGAAGATGACATGAAAGCACAGATGAATTGCTTTTATTTGAAAGCCTTGGATGGTTT TGTTATGGTTCTCACAGATGATGGTGACATGATTTACATTTCTGATAATGTGAACAAATACATGGGATTAACTCAGTTTGAACTAACTGGACACAGTGTGTTTGATTTTACT CATCCATGTGACCATGAGGAAATGAGAGAAATGCTTACACACAGAAATGGCCTTGTGAAAAAGGGTAAAGAACAAAACACACAGCGAAGCTTTTTTCTCAGAATGAAGTGTA CCCTAACTAGCCGAGGAAGAACTATGAACATAAAGTCTGCAACATGGAAGGTATTGCACTGCACAGGCCACATTCACGTATATGATACCAACAGTAACCAACCTCAGTGTGG GTATAAGAAACCACCTATGACCTGCTTGGTGCTGATTTGTGAACCCATTCCTCACCCATCAAATATTGAAATTCCTTTAGATAGCAAGACTTTCCTCAGTCGACACAGCCTG GATATGAAATTTTCTTATTGTGATGAAAGAATTACCGAATTGATGGGATATGAGCCAGAAGAACTTTTAGGCCGCTCAATTTATGAATATTATCATGCTTTGGACTCTGATC ATCTGACCAAAACTCATCATGATATGTTTACTAAAGGACAAGTCACCACAGGACAGTACAGGATGCTTGCCAAAAGAGGTGGATATGTCTGGGTTGAAACTCAAGCAACTGT CATATATAACACCAAGAATTCTCAACCACAGTGCATTGTATGTGTGAATTACGTTGTGAGTGGTATTATTCAGCACGACT'IGATTTTCTCCCTTCAACAAACAGAATGTGTC CTTAAACCGGTTGAATCTTCAGATATGAAAATGACTCAGCTATTCACCAAAGTTGAATCAGAAGATACAAGTAGCCTCTTTGACAAACTTAAGAAGGAACCTGATGCTTTAA CTTTGCTGGCCCCAGCCGCTGGAGACACAATCATATCTTTAGATTTTGGCAGCAACGACACAGAAACTGATGACCAGCAACTTGAGGAAGTACCATTATATAATGATGTAAT GCTCCCCTCACCCAACGAAAAATTACAGAATATAAATTTGGCAATGTCTCCATTACCCACCGCTGAAACGCCAAAGCCACTTCGAAGTAGTGCTGACCCTGCACTCAATCAA GAAGTTGCATTAAAATTAGAACCAAATCCAGAGTCACTGGAACTTTCTTTTACCATGCCCCAGATTCAGGATCAGACACCTAGTCCTTCCGATGGAAGCACTAGACAAAGTT CACCTGAGCCTAATAGTCCCAGTGAATATTGTTTTTATGTGGATAGTGATATGGTCAATGAATTCAAGTTGGAATTGGTAGAAAAACTTTTTGCTGAAGACACAGAAGCAAA GAACCCATTTTCTACTCAGGACACAGATTTAGACTTGGAGATGTTAGCTCCCTATATCCCAATGGATGATGACTTCCAGTTACGTTCCTTCGATCAGTTGTCACCATTAGAA AGCAGTTCCGCAAGCCCTGAAAGCGCAAGTCCTCAAAGCACAGTTACAGTATTCCAGCAGACTCAAATACAAGAACCTACTGCTAATGCCACCACTACCACTGCCACCACTG ATGAATTAAAAACAGTGACAAAAGACCGTATGGAAGACATTAAAATATTGATTGCATCTCCATCTCCTACCCACATACATAAAGAAACTACTAGTGCCACATCATCACCATA TAGAGATACTCAAAGTCGGACAGCCTCACCAAACAGAGCAGGAAAAGGAGTCATAGAACAGACAGAAAAATCTCATCCAAGAAGCCCTAACGTGTTATCTGTCGCTTTGAGT CAAAGAACTACAGTTCCTGAGGAAGAACTAAATCCAAAGATACTAGCTTTGCAGAATGCTCAGAGAAAGCGAAAAATGGAACATGATGGTTCACTTTTTCAAGCAGTAGGAA TTGGAACATTATTACAGCAGCCAGACGATCATGCAGCTACTACATCACTTTCTTGGAAACGTGTAAAAGGATGCAAATCTAGTGAACAGAATGGAATGGAGCAAAAGACAAT TATTTTAATACCCTCTGATTTAGCATGTAGACTGCTGGGGCAATCAATGGATGAAAGTGGATTACCACAGCTGACCAGTTATGATTGTGAAGTTAATGCTCCTATACAAGGC AGCAGAAACCTACTGCAGGGTGAAGAATTACTCAGAGCTTTGGATCAAGTTAACTGAGCTTTTTCTTAATTTCATTCCTTTTTTTGGACACTGGTGACTCACTACCTAAAGC AGTCTATTTATATTTTCTACATCTAATTTTAGAAGCCTGGCTACAATACTGCACAAACTTGGTTAGTTCAATTTTTGATCCCCTTTCTACTTAATTTACATTAATGCTCTTT TTTAGTATGTTCTTTAATGCTGGATCACAGACAGCTCATTTTCTCAGTTTTTTGGTATTTAAACCATTGCATTGCAGTAGCATCATTTTAAAAAATGCACCTTTTTATTTAT TTATTTTTGGCTAGGGAGTTTATCCCTTTTTCGAA'ITATTTTTAAGAAGATGCCAATATAATTTTTGTAAGAAGGCAGTAACCTTTCATCATGATCATAGGCAGTTGAAAAA TTTTTACACCTTTTTTTTCACATTTTACATAAATAATAATGCTTTGCCAGCAGTACGTGGTAGCCACAATTGCACAATATATTTTCTTAAAAAATACCAGCAGTTACTCAΓG
GCTGTATGGTTTATTATTTAAATGGGTAAAGCCATTTACATAATATAGAAAGATATGCATATATCTAGAAGGTATGTGGCATTTATTTGGATAAAATTCTCAATTCAGAGAA ATCATCTGATGTTTCTATAGTCACTTTGCCAGCTCAAAAGAAAACAATACCCTATGTAGTTGTGGAAGTTTATGCTAATATTGTGTAACTGATATTAAACCTAAATGTTCTG CCTACCCTGTTGGTATAAAGATATTTTGAGCAGACTGTAAACAAGAAAAAAAAAATCATGCATTCTTAGCAAAATTGCCTAGTATGTTAATTTGCTCAAAATACAATGTTTG ATTTTATGCACTTTGTCGCTATTAACATCCTTTTTLTCATGTAGATTTCAATAATTGAGTAATTTTAGAAGCATTATTTTAGGAATATATAGTTGTCACAGTAAATATCRTG TTTTTTCTATGTACATTGTACAAATTTTTCATTCCTTTTGCTCTTTGTGGTTGGATCTAACACTAACTGTATTGTTTTGTTACATCAAATAAACATCTTCTGTGGAAAAAAA AAAAAAAAAAAAA
447
WSSGVKNTPRWRRKAPHGRERKEKGKKRKRCIWSTFKliRHKKKSLPREIIDGT8E^EGKRSQKMP8TPRRVTQGAA8PGH^
KARTKCARKSRSKEKKKEKDICSSSKRRFQKNIHRRGKPKSDTVDFHCSKSPVTCGEAKGILYKKKMKHGESVKCIRNEDGT LTPNEFEVEGKGRNAKN KRNIRCEGMT
GELLKSGLL CPPRINLKRE NSK
448
ATGGCGAGCAGCGGAGTCAAGAACACACCACGATGGCGGAGAAAAGCCCCTCATGGGAGGGAAAGGAAAGAGAAAGGAAAGAAAAGAAAAAGATGTATCTGGTCAACTCCAA AAAGGAGACATAAGAAAAAAAGCCTCCCAAGAGAGATCATTGATGGCACTTCAGAAATGAATGAAGGAAAGAGGTCCCAGAAGATGCCTAGTACACCACGAAGGGTCACACA AGGGGCAGCCTCACCTGGGCATGGCATCCAAGAGAAGCTCCAAGTGGTGGATAAGGTGACTCAAAGGAAAGACGACTCAACCTGGAACTCAGAGGTCATGATGAGGGTCCAA AAGGCAAGAACTAAATGTGCCCGAAAGTCCAGATCGAAAGAAAAGAAAAAGGAGAAAGATATCTGTTCAAGCTCAAAAAGGAGATTTCAGAAAAATATTCACCGAAGAGGAA AACCCAAAAGTGACACΓGTGGATTTTCACTGTTCTAAGTCCCCCGTGACCTGTGGTGAGGCGAAAGGGATTTTATATAAGAAGAAAATGAAACACGGATCCTCAGTGAAGTG CATTCGGAATGAGGATGGAACTTGGTTAACACCAAATGAATTTGAAGTCGAAGGAAAAGGAAGGAACGCAAAGAACTGGAAACGGAATATACGTTGTGAAGGAATGACCCTA GGAGAGCTGCTGAAGAGRGGACTTTTGCTCTGTCCTCCAAGAATAAATCTCAAGAGAGAGTTAAATAGCAAGTGAATTTCTACTACCCTCTCAGTCACCATGTTGCAGACTT TCCCTGTCTGGAGGCTCACCTTAGAGCTTCTGAGTTTCCAAGCCCGGAATT
449
MSTNGDDHQVKDSLEQLRCHFTWEIJSIDDDEMPDLENRVLDQIEF DTKYSVGIHNLLAYVKHLKGQNEEALKSLKEAENLNQEEHDNQANVRSLVTWGNPAWMYYHMGRLA
EAQTYLDKVENICKKLSNPFRYRMECPEIDCEEGWALLKCGGKNYERAKACFEKVLEVDPENPEεSAGYAiεAYRLDGFKLATKNHKPFS LPLRQAVRLNPDNGYIKVLLA
LKLQDEGQEAEGEKYIEEAI-AMISSQTYVFRYAAKFYRRKGSVDKALELLKKALQETPTEVLLHHQIG CYKAQMIQIKEATKGQPRGQNREKLDKMIRSAIFHFESAVEKK TFEVAH DI UWIE G^m KAEENFQKL CMK VEETMQDIHFYYG FQEFQKKSDV AIIHYLKAIKIEQASL RDKSINSLK V RKLRRKALDLESLS GFVYK
LEGNMNEALEYYERALRLAADFENSVRQGP
450
CCAGATCTCAGAGGAGCCTGGCTAAGCAAAACCCTGCAGAACGGCTGCCTAATTTACAGCAACCATGAGTACAAATGGTGATGATCATCAGGTCAAGGATAGTCTGGAGCAA TTGAGATGTCACTTTACATGGGAGTTATCCATTGATGACGATGAAATGCCTGATTTAGAAAACAGAGTCTTGGATCAGATTGAATTCCTAGACACCAAATACAGTGTGGGAA TACACT-ACCTACTAGCCΓATGTGAAACACCTGAAAGGCCAGAATGAGGAAGCCCTGAAGAGCTTAAAAGAAGCTGAAAACTTAATGCAGGAAGAACATGACAACCAAGCAAA TGTGAGGAGTCTGGTGACCTGGGGCAACTTTGCCTGGATGTATTACCACATGGGCAGACTGGCAGAAGCCCAGACTTACCTGGACAAGGTGGAGAACATTTGCAAGAAGCTT TCAAATCCCTTCCGCTAΓAGAATGGAGTGTCCAGAAATAGACTGTGAGGAAGGATGGGCCTTGCTGAAGTGTGGAGGAAAGAATTATGAACGGGCCAAGGCCTGCTTTGAAA AGGTGCTTGAAGTGGACCCTGAAAACCCTGAATCCAGCGCTGGGTATGCGATCTCTGCCTATCGCCTGGATGGCTTTAAATTAGCCACAAAAAATCACAAGCCATTTTCTTT GCTTCCCCTAAGGCAGGCTGTCCGCTTAAATCCAGACAATGGATATATTAAGGTTCTCCTTGCCCTGAAGCTTCAGGATGAAGGACAGGAAGCTGAAGGAGAAAAGTACATT GAAGAAGCTCTAGCCAACATGTCCTCACAGACCTATGTCTTTCGATATGCAGCCAAGTTTTACCGAAGAAAAGGCTCTGTGGATAAAGCTCTTGAGTTATTAAAAAAGGCCT
TGCAGGAAACACCCACTTCTGTCTTACTGCATCACCAGATAGGGCTTTGCTACAAGGCACAAATGATCCAAA'ICAAGGAGGCTACAAAAGGGCAGCCTAGAGGGCAGAACAG
AGAAAAGCTAGACAAAATGATAAGATCAGCCATATTTCATTTTGAATCTGCAGTGGAAAAAAAGCCCACATTTGAGGTGGCTCATCTAGACCTGGCAAGAATGTATATAGAA GCAGGCAATCACAGAAAAGCTGAAGAGAATTTTCAAAAATTGTTATGCATGAAACCAGTGGTAGAAGAAACAATGCAAGACATACATTTCTACTATGGTCGGTTTCAGGAAT TTCAAAAGAAATCTGACGTCAATGCAATTATCCATTATTTAAAAGCTATAAAAATAGAACAGGCATCATTAACAAGGGATAAAAGTATCAATTCTTTGAAGAAATTGGTTTT AAGGAAACTTCGGAGAAAGGCATTAGATCTGGAAAGCTTGAGCCTCCTTGGGTTCGTCTATAAATTGGAAGGAAATATGAATGAAGCCCTGGAGTACTATGAGCGGGCCCTG AGACTGGCTGCTGACTTΓGAGAACTCTGTGAGACAAGGTCCTTAGGCACCCAGATATCAGCCACTTTCACATT'ICAT'ITCATTTTATGCTAACATTTACTAATCATCTTTTC TGCTTACTGTTTTCAGAAACATTATAATTCACTGTAATGATGTAATTCTTGAATAATAAATCTGACAAAATAT"I
451
MSTNGDDHQVKDSLEQ RCHFTWELSIDDDEMPDLENRVLDQIEFLDTKYSVGIHNLLAYVKHLKGQNEEALKSLKEAENLMQEEHDNQANVRSLV WGNFAWMYYHMGR A EAQTYLDKVENICKKLSNPFRYRMECPEIDCEEGWALLKCGGKNYERAKACFEKVLEVDPENPEεεAGYAISAYRLDGFKLATKNHKPFSL PLRQAVRLNPDNGYIKVLIA K QDEGQEAEGEKYIEEALANMSSQTYVFRYAAKFYRRKGSVDKALELLKKALQETPTSVLLHHQIGLCYKAQMIQIKEATKGQPRGQNREKLDKMIR8AIFHFESAVEKK PTFEVAHLDIJU^YIEAGNHRKAEENFQKLLCNKPVVEETMQDIHFYYGRFQEFQKKSDVNAIIHYLKAIKIEQASLTRDKSINSLKKLV RKLRRKALDLESLSLLGFVYK LEGNMNEALEYYERALRLAADFENSVRQGP
452
CCAGATCTCAGAGGAGCCTGGCTAAGCAAAACCCTGCAGAACGGCTGCCTAATTTACAGCAACCATGAGTACAAATGGTGATGATCATCAGGTCAAGGATAGTCTGGAGCAA TTGAGATGTCACTTTACATGGGAGTTATCCATTGATGACGATGAAATGCCTGATTTAGAAAACAGAGTCTTGGATCAGATTGAATTCCTAGACACCAAATACAGTGTGGGAA TACACAACCTACTAGCCTATGTGAAACACCTGAAAGGCC^GAATGAGGAAGCCCTGAAGAGCTTAAAAGAAGCTGAAAACTTAATGCAGGAAGAACATGACAACCAAGCAAA TGTGAGGAGTCTGGTGACCTGGGGCAACTTTGCCTGGATGTATTACCACATGGGCAGACTGGCAGAAGCCCAGACTTACCTGGACAAGGTGGAGAACATTTGCAAGAAGCTT TCAAATCCCTTCCGCRATAGAATGGAGTGTCCAGAAATAGACTGTGAGGAAGGATGGGCCTTGCTGAAGTGTGGAGGAAAGAATTATGAACGGGCCAAGGCCTGCTTTGAAA AGGTGCTTGAAGTGGACCCTGAAAACCCTGAATCCAGCGCTGGGTATGCGATCTCTGCCTATCGCCTGGATGGCTTTAAATTAGCCACAAAAAATCACAAGCCATTTTCTTT GCTTCCCCTAAGGCAGΣCTGTCCGCTTAAATCCAGACAATGGATATATTAAGGTTCTCCTTGCCCTΒAAGCTTCAGGATGAAGGACAGGAAGCTGAAGGAGAAAAGTACATT GAAGAAGCTCTAGCCAACATGTCCTCACAGACCTATGTCTTTCGATATGCAGCCAAGTTTTACCGAAGAAAAGGCTCTGTGGATAAAGCTCTTGAGTTATTAAAAAAGGCCT TGCAGGAAACACCCACΓTCTGTCTTACTGCATCACCAGATAGGGCTTTGCTACAAGGCACAAATGATCCAAATCAAGGAGGCTACAAAAGGGCAGCCTAGAGGGCAGAACAG AGAAAAGCTAGACAAAATGATAAGATCAGCCATATTTCATTTTGAATCTGCAGTGGAAAAAAAGCCCACATTTGAGGTGGCTCATCTAGACCTGGCAAGAATGTATATAGAA GCAGGCAATCACAGAAAAGCTGAAGAGAATTTTCAAAAATTGTTATGCATGAAACCAGTGGTAGAAGAAACAATGCAAGACATACATTTCTACTATGGTCGGTTTCAGGAAT TTCAAAAGAAATCTGACGTCAATGCAATTATCCA'ITATTTAAAAGCTATAAAAATAGAACAGGCATCATTAACAAGGGATAAAAGTATCAATTCTTTGAAGAAATTGGTTTT AAGGAAACTTCGGAGAAAGGCATTAGATCTGGAAAGCTTGAGCCTCCTTGGGTTC'GTCTATAAATTGGAAGGAAATATGAATGAAGCCCTGGAGTACTATGAGCGGGCCCTG AGACTGGCTGCTGACRRTGAGAACTCTGTGAGACAAGGTCCTTAGGCACCCAGATATCAGCCACTTTCACATTTCATTTCATTTTATGCTAACATTTACTAATCATCTTTTC TGCTTACTGTTTTCAGAAACATTATAATTCACTGTAATGATGTAATTCTTGAATAATAAATCTGACAAAATATT
453
NMKEEHEVAVLGAPPSTILPRSTVINIHSETSVPDHVVWSLFNTLFLNWCCLGFIAFAYSVKSRDRKMVGDVTGAQAYASTAKCLNIWALILGILMTIGFILLLVFG8VTVY
HIMLQIIQEKRGY
454
GCTCACTGAGCACCGTCCCAGCATCCGGACACCACAGCGGCCCTTCGCTCCACGCAGAAAACCACACTTCTCATACCTTCACTCAACACTTCCTTCCCCAAAGCCAGAAGAT GCACAAGGAGGAACATGAGGTGGCTGTGCTGGGGGCACCCCCCAGCACCATCCTTCCAAGGTCCACCGTGATTAACATCCACAGCGAGACCTCCGTGCCCGACCATGTCGTC TGGTCCCTGTTCAACACCCTCTTCTTGAACTGGTGCTGTCTGGGCTTCATAGCATTCGCCTACTCCGTAAAGTCTAGGGACAGGAAGATGGTTGGCGACGTGACCGGGGCCC AGGCCTATGCCTCCACCGCCAAGTGCCTGAACATCTGGGCCCTGATTCTGGGCATCCTCATGACCATTGGATTCATCCTGTTACTGGTATTCGGCTCTGTAACAG CTACCA TATTATGTTACAGATAATACAGGAAAAACGGGGTTACTAGTAGCCGCCCATAGCCTGCAACCTTTGCACTCCACTGTGCAATGCTGGCCCTGCACGCTGGGGCTGTTGCCCC TGCCCCCTTGGTCCTGCCCCTAGATACAGCAGTTTATACCCACACACCTGTCTACAGTGTCATTCAATAAAGTGCACG1GCTTGTGA
455
^1AG8REVVAMDCE^WGLGPHRESG1J^CSLVNVHGAVLYDKFI PEGEITDYR R SGVTPQHMVGATPFAVARLEILQLLKGKLVVGHDLKHDFQALKEDMSGYTIYDTST
DRLLWREAKLDHCRRVSLRVLSERLLHKSIQNSLLGHSSVEDARATMELYQISQRIRARRGLPRLAVSD
456
GGGTCCCCAAGGAACATGGCTGGGAGCCGTGAGGTGGTGGCCATGGACTGCGAGATGGTGGGGCTGGGGCCCCACCGGGAGAGTGGCCTGGCTCGTTGCAGCCTCGTGAACG TCCACGGTGCTGTGCΓGTACGACAAGTTCATCCGGCCTGAGGGAGAGATCACCGATTACAGAACCCGGGTCAGCGGGGTCACCCCTCAGCACATGGTGGGGGCCACACCATT TGCCGTGGCCAGGCTAGAGATCCTGCAGCTCCTGAAAGGCAAGCTGGTGGTGGGTCATGACCTGAAGCACGACTTCCAGGCACTGAAAGAGGACATGAGCGGCTACACAATC TACGACACGTCCACTGACAGGCΓGΓTGTGGCGTGAGGCCAAGCTGGACCACTGCAGGCGTGICTCCCTGCGGGTGCTGAGTGAGCGCCTCCTGCACAAGAGCATCCAGAACA GCCTGCTTGGACACAGCTCGGTGGAAGATGCGAGGGCAACGATGGAGCTCTATCAAATCTCCCAGAGAATCCGAGCCCGCCGAGGGCTGCCCCGCCTGGCTGTGTCAGACTG AAGCCCCATCCAGCCCGTTCCGCAGGGACTAGAGGCTTTCGGCTTTTTGGGACAGCAACTACCTTGCTTTTGGAAAATACATTTTTAATAGTAAAGTGGCTCTATATTTTCT
CTACGCC
457
MAGSRE\WA^πDCE^WGLGPH ESGLARCSL rυHGA L DKFIR EGEI DYR R ΞGVTPQHM GATPFAVARLEILQLLKGK VVGHD KHDFQA KEDMSGY IYDTεT
DRLLWREAKLDHCRRVSLRVLSERLLHK8IQNSLLGHSSVEDARATMELYQISQRIRARRGLPRLAV8D
458
GGGTCCCCAAGGAACARGGCTGGGAGCCGTGAGGTGGTGGCCATGGACTGCGAGATGGTGGGGCTGGGGCCCCACCGGGAGAGTGGCCTGGCTCGTTGCAGCCTCGTGAACG TCCACGGTGCTGTGCΓGTACGACAAGTTCATCCGGCCTGAGGGAGAGATCACCGATTACAGAACCCGGGTCAGCGGGGTCACCCCTCAGCACATGGTGGGGGCCACACCATT TGCCGTGGCCAGGCTAGAGAΓCCTGCAGCTCCTGAAAGGCAAGCTGGTGGTGGGTCATGACCTGAAGCACGACTTCCAGGCACTGAAAGAGGACATGAGCGGCTACACAATC TACGACACGTCCACTGACAGGCTGTTGTGGCGTGAGGCCAAGCTGGACCACTGCAGGCGTGTCTCCCTGCGGGTGCTGAGTGAGCGCCTCCTGCACAAGAGCATCCAGAACA GCCTGCTTGGACACAGCΓCGGTGGAAGATGCGAGGGCAACGATGGAGCTCTATCAAATCTCCCAGAGAATCCGAGCCCGCCGAGGGCTGCCCCGCCTGGCTGTGTCAGACTG AAGCCCCATCCAGCCCGΓTCCGCAGGGACTAGAGGCTTTCGGCTTTTTGGGACAGCAACTACCTTGCTTTTGGAAAATACATTTTTAATAGTAAAGTGGCTCTATATTTTCT
CTACGCC
459 SIHSFSSAFLFEIEVQVTIGFGGRMVTEECPLAILILIVQNIVGLMINAIMLGCIFMKTAQAHRRAETLIFSKHAVIALRHGRLCFMLRVGDLRK8MI ISATIHMQWRKTT 8PEGEWPLHQVDIPMENGVGGNSIFLVAPLI IYHVIDANSPLYDLAPSDLHHHQDLEIIVILEGWETTGITTQARTSYLΔDEIL GQRPVPIVAEEDGRYSVDYSKFGNT VKVPTPLCTARQLDEDHSLLEALTLASARGPLRKRSVPMAKAKPKFSISPDSLS
460
ATGCTGTCCCGCAAGGGCATCATCCCCGAGGAATACGTGCTGACACGCCTGGCAGAGGACCCTGCCAAGCCCAGGTACCGTGCCCGCCAGCGGAGGGCCCGCTTTGTGTCCA AGAAAGGCAACTGCAACGTGGCCCACAAGAACATCCGGGAGCAGGGCCGCTTCCTGCAGGACGTGTTCACCACGCTGGTGGACCTCAAGTGGCCACACACATTGCTCATCTT CACCArGTCCTTCCTGTGCAGCTGGCTGCTCTTCGCCATGGCCTGGTGGCTCATCGCCTTCGCCCACGGTGACCTGGCCCCCAGCGAGGGCACTGCTGAGCCCTGTGTCACC AGCATCCACTCCTTCTCGTCTGCCTTCCTTTTCTCCATTGAGGTCCAAGTGACTATTGGCTTTGGGGGGCGCATGGTGACTGAGGAGTGCCCACTGGCCATCCTGATCCTCA TCGTGCAGAACATCGTGGGGCTCATGATCAACGCCATCATGCTTGGCTGCATCTTCATGAAGACTGCCCAAGCCCACCGCAGGGCTGAGACCCTCATCTTCAGCAAGCATGC GGTGArCGCCCTGCGCCACGGCCGCCTCTGCTTCATGCTACGTGTGGGTGACCTCCGCAAGAGCATGATCATCAGCGCCACCATCCACATGCAGGTGGTACGCAAGACCACC AGCCCCGAGGGCGAGGTGGTGCCCCTCCACCAGGTGGACATCCCCATGGAGAACGGCGTGGGTGGCAACAGCATCTTCCTGGTGGCCCCGCTGATCATCTACCATGTCATTG ATGCCAACAGCCCACTCTACGACCTGGCACCCAGCGACCTGCACCACCACCAGGACCTCGAGATCATCGTCATCCTGGAAGGCGTGGTGGAAACCACGGGCATCACCACCCA GGCCCGCACCTCCTACCTGGCCGATGAGATCCTGTGGGGCCAGCGCTTTGTGCCCATTGTAGCTGAGGAGGACGGACGTTACTCTGTGGACTACTCCAAGTTTGGCAACACC GTCAAAGTGCCCACACCACTCTGCACGGCCCGCCAGCTTGATGAGGACCACAGCCTACTGGAAGCτCTGACCCTCGCCTCAGCCCGCGGGCCCCTGCGCAAGCGCAGCGTGC CCATGGCCAAGGCCAAGCCCAAGTTCAGCATCTCICCAGATTCCCTGTCCTGA
461
MATRVL8M8ARLGPVPQPPAPQDEPVFAQLKPVLGAANPARDAALFPGEELKHAHHRPQAQPAPAQAPQPAQPPATGPRLPPEDLVQTRCEMEKYLTPQLPPVPI I PEHKKY
RRDSASWDQFFTDTEGLPYSINMNVFLPDITHLRTGLYKSQRPCVTHIKTEPVAIFSHQSETTAPPPAPTQALPEFTSIFESHQTAAPEVNNIFIKQELPTPDLHLSVPTQ
QGHLYQLLNTPD DMPSSTNQTAA^IDTLNVSMSAAMAGLNTHTSAVPQTAVKQFQGMPPCTYTMPSQFLPQQAT FPPSPPS8EPGSPDRQAEN QNLTPPPSYA TIASKL
AIHNPNLPTTLP\™SQNIQPVRYNRRSNPDLEKRRIHYCDYPGCTKVYTKSSHLKAHLRTHTGEKPYKCTWEGCDWRFARSDELTRHYRKHTGAKPFQCGVCNRSFSRSDHL
ALHMKRHQN
462
GGTACGTGCGCTCGCGGTRCTCTCGCGGAGGTCGGCGGTGGCGGGAGCGGGCTCCGGAGAGCCTGAGAGCACGGTGGGGCGGGGCGGGAGAAAGTGGCCGCCCGGAGGACGT TGGCGTTTACGTGTGGAAGAGCGGAAGAGTTTTGCTTTTCGTGCGCGCCTTCGAAAACTGCCTGCCGCTGTCTGAGGAGTCCACCCGAAACCTCCCCTCCTCCGCCGGCAGC CCCGCGCTGAGCTCGCCGACCCAAGCCAGCGTGGGCGAGGTGGGAAGTGCGCCCGACCCGCGCCTGGAGCTGCGCCCCCGAGTGCCCATGGCTACAAGGGTGCTGAGCATGA GCGCCCGCCTGGGACCCGRGCCCCAGCCGCCGGCGCCGCAGGACGAGCCGGTGTTCGCGCAGCTCAAGCCGGTGCTGGQCGCCGCGAATCCGGCCCGCGACGCGGCGCTCTT CCCCGGCGAGGAGCTGAAGCACGCGCACCACCGCCCGCAGGCGCAGCCCGCGCCCGCX3CAGGCCCCGCAGCCGGCCCAGCCGCCCGCCACCGGCCCGCGGCTGCCTCCAGAG GACCΓGGTCCAGACAAGAΓGΓGAAATGGAGAAGTATCTGACACCTCAGCTTCCTCCAGTTCCTATAATTCCAGAGCATAAAAAGTATAGACGAGACAGTGCCTCAGTCGTAG ACCAGTTCTTCACTGACACΓGAAGGGTTACCTTACAGTATCAACATGAACGTCTTCCTCCCTGACATCACTCACCTGAGAACTGGCCTCTACAAATCCCAGAGACCGTGCGT AACACACATCAAGACAGAACCTGTTGCCATTTTCAGCCACCAGAGTGAAACGACTGCCCCTCCTCCGGCCCCGACCCAGGCCCTCCCTGAGTTCACCAGTATATTCAGCTCA CACCAGACCGCAGCTCCAGAGGTGAACAATATTTTCATCAAACAAGAACTTCCTACACCAGATCTTCATCTTTCTGTCCCTACCCAGCAGGGCCACCTGTACCAGCTACTGA ATACACCGGATCTAGAΓAΓGCCCAGTTCTACAAATCAGACAGCAGCAATGGACACTCTTAATGTTTCTATGTCAGCTGCCATGGCAGGCCTTAACACACACACCTCTGCTGT TCCGCAGACTGCAGTGAAACAATTCCAGGGCATGCCCCCTTGCACATACACAATGCCAAGTCAGTTTCTTCCACAACAGGCCACTTACTTTCCCCCGTCACCACCAAGCTCA GAGCCTGGAAGTCCAGARAGACAAGCAGAGATGCTCCAGAATTTAACCCCACCTCCATCCTATGCTGCTACAA'ITGCTTCTAAACTGGCAAT'ICACAATCCAAATTTACCCA CCACCCTGCCAGTTAACRCACAAAACATCCAACCTGTCAGATACAATAGAAGGAGTAACCCCGATTTGGAGAAACGACGCATCCACTACTGCGATTACCCTGGTTGCACAAA AGTTTATACCAAGTCTΓCΓCATTTAAAAGCTCACCTGAGGACTCACACTGGTGAAAAGCCATACAAGTGTACCIGGGAAGGCTGCGACTGGAGGTTCGCGCGATCGGATGAG CTGACCCGCCACTACCGGAAGCACACAGGCGCCAAGCCCTTCCAGTGCGGGGTGTGCAACCGCAGCTTCTCGCGCTCTGACCACCTGGCCCTGCATATGAAGAGGCACCAGA ACTEAGCACTGCCCGTGRGACCCGTTCCAGGTCCCCTGGGCTCCCTCAAATGACAGACCTAACTATTCCTGTGTAAAAACAACAAAAACAAAAAAAAAACAAGAAAACCACA ACTAAAACTGGAAATGΓAΓAΓTTTGTATATTTGAGAAAACAGGGAATACATTGTATTAATACCAAAGTGTTTGGTCATTTTAAGAATCTGGAATGCTTGCTGTAATGTATAT GGCTTTACTCAAGCAGAΓCΓCATCTCATCTCATGACAGGCAGCCAGTCTCAACATGGGTAAGGGGTGGGGGTGAAGGGGAGTGTGTGCAGCGTTTTTACCTAGGCACCATCA TTTAATGTGACAGTGTΓCAGΓAAACAAATCAGTTGGCAGGCACCAGAAGAAGAATGGATTGTATGTCAAGATTTTACTTGGCATTGAGTAGTTTTTTTCAATAGTAGGTAAT TCCTTAGAGATACAGTAΓACCTGGCAATTCACAAATAGCCATTGAACAAATGTGTGGGTTTTTAAAAATTATATACATATATGAGTTGCCTATATTTGCTATTCAAAATTTT GTAAATATGCAAATCAGCΓΓΓATAGGTTTATTACAAGTTTTTTAGGATTCTTTTGGGGAAGAGTCATAATTCTTTTGAAAATAACCATGAATACACTTACAGTTAGGATTTG TGGTAAGGTACCTCTCAACAΓTACCAAAATCATTTCTTTAGAGGGAAGGAATAATCATTCAAATGAACTTTAAAAAAGCAAATTTCATGCACTGATTAAAATAGGATTATTT TAAATACAAAAGGCATΓTΓAΓATGAATTATAAACTGAAGAGCTTAAAGATAGTTACAAAATACAAAAGTTCAACCTCTTACAATAAGCTAAACGCAATGTCATTTTTAAAAA GAAGGACTTAGGGGTCGTΓΓΓCACATATGACAATGTTGCATTTATGATGCAGTTTTCAAGTACCAAAACGTTGAATTGATGATGCAGTTTTCATATATCGAGATGTTCGCTC GTGCAGTACTGTTGGTRAAARGACAATTTATGTGGATTTTGCATGTAATACACAGTGAGACACAGTAATTTTATCTAAATTACAGTGCAGTTTAGTTAATCTATTAATACTG ACTCAGTGTCTGCCTTRAAARATAAATGATATGTTGAAAACTTAAGGAAGCAAATGCTACATATATGCAATATAAAATAGTAATGTGATGCTGATGCTGTTAACCAAAGGGC AGAATAAATAAGCAAAATGCCAAAAGGGGTCTTAATTGAAATGAAAATTTAATTTTGTTTTTAAAATATTGTTTATCTTTATTTATTTTGTGGTAATATAGTAAGTTTTTTT AGAAGACAATTTTCATAACΓΓGAΓAAATTATAGTTTTGTTTGTTAGAAAAGTTGCTCTTAAAAGATGTAAATAGATGACAAACGATGTAAATAATTTTGTAAGAGGCTTCAA AATGTTTATACGTGGAAACACACCTACATGAAAAGCAGAAATCGGTTGCTGTTTTGCTTCTTTTTCCCTCTTATTTTTGTATTGTGGTCATTTCCTATGCAAATAATGGAGC AAACAGCTGTATAGTTGTAGAATTTTTTGAGAGAATGAGATOTTTATATATTAACGACAATTTTTTTTTTGGAAAATAAAAAGTGCCTAAAAGAAAAAAAAAAAAAAAAAA
463
MLRIVEPYVTWGFPNLKSVRELILKRGQAKVKNKTIPLTDNTVIEEHLGKFGVICLEDLIHEIAFPGKHFQEISWFLCPFHLSVARHATKNRVGFLKEMGTPGYRGERINQL I QLN
464
ACTAGAAAGATGGCGGAGCAAGACAGAAGAAAGGAAAAGGGCTCAGGTTTAAGCGACTGGAATCATTCCTACATGATTCCTGGCGGCAGAAACGTGACAAGGTGCGTCTCAG ACGACTAGAAGTGAAACCTCAΓGCCTTGGAATTGCCAGATAAACATTCCTTGGCCTTTGTTGTACGCATCGAAAGGATTGACGGCGTGAGTTTACTGGTGCAGAGAACCATT GCAAGACTTCGCCTAAAGAAAAΓΓTTTAGTGGTGTCTTTGTAAAAGTCΛCCCCCCAGAATCTAAAAATGCTGCGTATAGTGGAACCTTATGTGACCTGGGGATTTCCAAATC RGAAGTCTGTCCGAGAACTCARRTTGAAACGTGGACAAGCCAAGGTCAAGAATAAGACCATCCCTCTGACAGACAATACAGTGATTGAGGAGCACCTGGGGAAGTTTGGCGT CATTTGCTTGGAAGACCΓCATΓCATGAAATTGCCTTCCCAGGGAAGCATTTCCAGGAGATCTCATGGTTCTTGTGCCCTTTCCACCTCTCAG'IGGCCCGTCATGCTACCAAA AATAGAGTGGGCTTCCTCAAGGAGATGGGCACACCTGGCTATCGGGGTGAACGCATCAATCAGCTCATCCGTCAGCTGAACTAGACCCAGGTGCCAAACTGCGGTAAATTTT ΓTATCAGTGAAGTGGAAGCATGΓGTTTTGTTTTGGAAATTTI ATCAAGTATCTTCAGAGAAGATTATTTCCTGCTTTATCTTCAGAAACTGGAAAGGGTCAAAGAAAAGAC AGTAGCTAGTCTCAAACΓCCTGACCTCAAGTGATCCACAAGCCTGGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCAACTGCGCCCAGCTCTTGTGTACCTTATGTGAG GAAGTCCTGCTCAATCAGGATCGGTCACGCAGGCCCTGATCTTGCTACTCTGGTTCCATGTCCTATGGAAGACCAAAGTTTACCAAGATAGATTTTTCCCTTCATAGTGGCA GATAGTGTTAACCCCTGCACCATCRGTAACTCAGAAATCCCCACCATTTCTTCCCCTGGGCTTCAGAATAGAATTGCCTGGTTTCTCTGATGATCAGCATGGTTCCTTAAAA CCCAAATCAGCAAGGAAΓGAACAATTTTGTTTGGCATGGATGAAA AGCACTGTTTGGCTCGTTAGGCCCCAGGCAGGCAGGCACCTTAATTTTTTCCTTGCATATTCTAG TCTTCAGAAGCATTGCCΓΓΓΓGTCCΓACTGGTAGTGACATAGACCAATAACAGGGCATCTGGGGATTTTAATCCTGAAAACAGTGAGTCTGATACTGCTTGTGTTTTTCATC AGTGTCCACCCCAAΣRGGGRCTTCCTGCTATTCTCTTCACTTAGTTGCCCCTCACTTGCCATCTGAGCAATTGGCAAGGATGTGCCAGGCCTAGGTTAAACTTGGAAACATG CTTGACCATTCTATTCCCΓGGTCCTTTAAGATCAGTTTGGCTGCAAT TTGGCTCCTTGGACCCTCAAGCATAGCTGGTAAATCAAGTTAGAGATGTAACTGCCTTAAAACA TGCCAGCTTAGGCTGGGCACGGTGGCTCACACCTGTAΔTCTCAACACTTCAGGAGGCTGAGGCAGGCAGATCACTTGAGGTCAGGAGTTCGAGACCAGCCTGACCAACATGG AGAAATTCTGTCCCTACTGAAAATACAAAATTAGCCGGATGTGGTGGTGCATGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAAGAGAATTGCTTGAACCCAGGGAGGC AGAGGTTGCAGTGAGCCGAGATCACACCATTGCACTCCACCTTGGGCAACAAAAGCAAAACTCTGTCTC
465
MAPVYEGMASHVQVFSPHTLQSSAFCSVKKLKVEPSSNWDMTGYGSHSKVYSQSKNIPPSQPASTTVSTSLPVPNPSLPYEQTIVFPGSTGHIVVTSASSTSVTGQVLGGPH
NLMRRSTVSLLDTYQKCGLKRKSEEIENTSSVQIIEEHPPMIQNNASGATVATATTSTATSKNSGSNSEGDYQLVQHEVLCSMTNTYEVLEFLGRGTFGQWKCWKRGTNEI
VAIKILKNRPSYARQGQIEVSILARLSTESADDYNFVRAYECFQHKNHTCLVFEMLEQNLYDFLKQNKFSPLPLKYIRPVLQQVATALMKLKSLGLIHADLKPENIMLVDPS
RQPYRVKVIDFGSAEHVSKAVCSTYLQSRYYRAPEIILGLPFCEAIDM SLGCVIAELPLGWPLYPGASEYDQIRYISQTQGLPAEYLLSAGTKTTRFFNRDTDSPYPLWRL
KTPDDHEAETGIKSKEARK IFNC DD^WQ NM TDLEGSDMLVEKD EFIDLLKKML IDADKRITPIETL HPFVTM H LDF HSTHVKSCFQNMEICKRRVNMYDT WQSKTPFI HVAPSTSTπT TFNNQLTTVH QAPEE SA ISLJlNPEVSI N^PSTLYQPSAASMAAVAQRSMP Q G AQICARPDPFQQ LIVCPPGFQGLQASPSK^
AGYSVRMENAVPIVTQAPGAQPLQIQPGLIΛQQAWPSGTQQILLPPA QQLTGVATHTSVQHATVIPETMAGTQQLADWRNTHAHGSHYNPIMQQPALLTGHVTLPAAQPLN
VGVAHV RQQPTSTTSSRKSKQHQSSVRNVSTCEVSSSQAISSPQRSKRVKENTPPRCAMVHSSPACSTSVTCG GDVASSTTRERQRQTIVIPDTPSPTVSVITISSDTDE
EEEQKHAPTSTVSKQRK VISCVTVHDSPYSDSSSNTSPYSVQQRAGHNNANAFDTKGSLENHCTGNPRTIIVPPLKTQASEVLVECD8LVPVNTSHHSSSYKSKSSSNVTS
T8GHSSGSSSGAITYRQQRPGPHFQQQQPLNLSQAQQHITTDRTGSHRRQQAYITPTMAQAPYSFPHNSPSHGTVHPHLAAAAAAAHLPTQPHLYTYTAPAALGSTGTVAHL
VASQGSARHTVQHTAYPASIVHQVPVSMGPRVLPSPTIHPSQYPAQFAHQTYISASPASTVYTGYPLSPAKVNQYPYI
466
CGGCCGCTTTTTTCTCAAGATGGCAGATTCCCACTGAGGCTGAGGGGGCCGAGCTCGCGCGCCGCGTTCCCTTCTCCGTTGCCATGAACCGCGGACACCCCGGCCCCGATGG CCCCCGTGTACGAAGGTATGGCCTCACATGTGCAAGTTTTCTCCCCTCACACCCTTCAATCAAGTGCCTTCTGTAGTGTGAAGAAACTAAAAGTAGAGCCAAGTTCCAACTG GGACATGACTGGGTACGGCTCCCACAGCAAAGTGTACAGCCAGAGCAAGAACATACCACCTTCTCAGCCAGCCTCCACAACCGTCAGCACCTCCTTGCCGGTCCCAAACCCA AGCCTACCTTACGAGCAGACCATCGTCTTCCCAGGAAGCACCGGGCACATCGTGGTCACCTCAGCAAGCAGCACTTCTGTCACCGGGCAAGTCCTCGGCGGACCACACAACC TAATGCGTCGAAGCACTGTGAGCCTCCTTGATACCTACCAAAAATGTGGACTCAAGCGTAAGAGCGAGGAGATCGAGAACACAAGCAGCGTGCAGATCATCGAGGAGCATCC ACCCATGATTCAGAATAATGCAAGCGGGGCCACTGTCGCCACTGCCACCACGTCTACTGCCACCTCCAAAAACAGCGGCTCCAACAGCGAGGGCGACTATCAGCTGGTGCAG CATGAGGTGCTGTGCTCCATGACCAACACCTACGAGGTCTTAGAGTTCTTGGGCCGAGGGACGTTTGGACAAGTGGTCAAGTGCTGGAAACGGGGCACCAATGAGATCGTAG CCATCAAGATCCTGAAGAACCGCCCATCCTATGCCCGACAAGGTCAGATTGAAGTGAGCATCCTGGCCCGGTTGAGCACGGAGAGTGCCGATGACTATAACTTCGTCCGGGC CTACGAATGCTTCCAGCACAAGAACCACACGTGCTTGGTCTTCGAGATGTTGGAGCAGAACCTCTATGACTTTCTGAAGCAAAACAAGTTTAGCCCCTTGCCCCTCAAATAC ATTCGCCCAGTTCTCCAGCAGGTAGCCACAGCCCTGATGAAACTCAAAAGCCTAGGTCTTATCCACGCTGACCTCAAACCAGAAAACATCATGCTGGTGGATCCATCTAGAC AACCATACAGAGTCAAGGTCATCGACTTTGGTTCAGCCAGCCACGTCTCCAAGGCTGTGTGCTCCACCTACTTGCAGTCCAGATATTACAGGGCCCCTGAGATCATCCTTGG TTTACCATTTTGTGAGGCAATTGACATGTGGTCCCTGGGCTGTGTTATTGCAGAATTGTTCCTGGGTTGGCCGTTATATCCAGGAGCTTCGGAGTATGATCAGATTCGGTAT ATTTCACAAACACAGGGTTTGCCTGCTGAATATTTATTAAGCGCCGGGACAAAGACAACTAGGTTTTTCAACCGTGACACGGACTCACCATATCCTTTGTGGAGACTGAAGA CACCAGATGACCATGAAGCΔGΔGACAGGGATTAAGTCAAAAGAAGCAAGAAAGTACATTTTCAACTGTTTAGATGATATGGCCCAGGTGAACATGACGACAGATTTGGAAββ GAGCGACATGTTGGTAGAAAAGGCTGACCGGCGGGAGTTCATTGACCTGTTGAAGAAGATGCTGACCATTGATGCTGACAAGAGAATCACTCCAATCGAAACCCTGAACCAT CCCTTTGTCACCATGACACACTTACTCGATTTTCCCCACAGCACACACGTCAAATCATGTTTCCAGAACATGGAGATCTGCAAGCGTCGGGTGAATATGTATGACACGGTGA
ACCAGAGCAAAACCCCTTTCATCACGCACGTGGCCCCCAGCACGTCCACCAACCTGACCATGACCTTTAACAACCAGCTGACCACTGTCCACAACCAGGCTCCCTCCTCTAC CAGTGCCACTATTTCCTTAGCCAATCCCGAAGTCTCCATACTAAACTACCCATCTACACTCTACCAGCCCTCAGCGGCATCCATGGCTGCAGTGGCCCAGCGGAGCATGCCC CTGCAGACAGGAACAGCCCAGATTTGTGCCCGGCCTGACCCGTTCCAGCAAGCTCTCATCGTGTGTCCCCCCGGCTTCCAAGGCTTGCAGGCCTCTCCCTCTAAGCACGCTG GCTACTCGGTGCGAATGGAAAATGCAGTTCCCATCGTCACTCAAGCCCCAGGAGCTCAGCCTCTTCAGATCCAACCAGGTCTGCTTGCCCAGCAGGCTTGGCCAAGTGGGAC CCAGCAGATCCTGCTTCCCCCAGCATGGCAGCAACTGACTGGAGTGGCCACCCACACATCAGTGCAGCATGCCACCGTGATTCCCGAGACCATGGCAGGCACCCAGCAGCTG GCGGACTGGAGAAATACGCATGCTCACGGAAGCCATTATAATCCCATCATGCAGCAGCCTGCACTATTGACCGGTCATGTGACCCTTCCAGCAGCACAGCCCTTAAATGTGG GTGTGGCCCACGTGATGCGGCAGCAGCCAACCAGCACCACCTCCTCCCGGAAGAGTAAGCAGCACCAGTCATCTGTGAGAAATGTCTCCACCTGTGAGGTGTCCTCCTCTCA GGCCATCAGCTCCCCACAGCGATCCAAGCGTGTCAAGGAGAACACACCTCCCCGCTGTGCCATGGTGCACAGTAGCCCGGCCTGCAGCACCTCGGTCACCTGTGGGTGGGGC GACGTGGCCTCCAGCACCACCCGGGAACGGCAGCGGCAGACAATTGTCATTCCCGACACTCCCAGCCCCACGGTCAGCGTCATCACCATCAGCAGTGACACGGACGAGGAGG AGGAACAGAAACACGCCCCCACCAGCACTGTCTCCAAGCAAAGAAAAAACGTCATCAGCTGTGTCACAGTCCACGACTCCCCCTACTCCGACTCCTCCAGCAACACCAGCCC CTACTCCGTGCAGCAGCGTGCTGGGCACAACAATGCCAATGCCTTTGACACCAAGGGGAGCCTGGAGAATCACTGCACGGGGAACCCCCGAACCATCATCGTGCCACCCCTG AAAACCCAGGCCAGCGAAGTATTGGTGGAGTGTGATAGCCTGGTGCCAGTCAACACCAGTCACCACTCGTCCTCCTACAAGTCCAAGTCCTCCAGCAACGTGACCTCCACCA GCGGTCACTCTTCAGGGAGCTCATCTGGAGCCATCACCTACCGGCAGCAGCGGCCGGGCCCCCACTTCCAGCAGCAGCAGCCACTCAATCTCAGCCAGGCTCAGCAGCACAT CACCACGGACCGCACTGGGAGCCACCGAAGGCAGCAGGCCTACATCACTCCCACCATGGCCCAGGCTCCGTACTCCTTCCCGCACAACAGCCCCAGCCACGGCACTGTGCAC CCGCATCTGGCTGCAGCCGCTGCCGCTGCCCACCTCCCCACCCAGCCCCACCTCTACACCTACACTGCGCCGGCGGCCCTGGGCTCCACCGGCACCGTGGCCCACCTGGΓGG CCTCGCAAGGCTCTGCGCGCCACACCGTGCAGCACACTGCCTACCCAGCCAGCATCGTCCACCAGGTCCCCGTGAGCATGGGCCCCCGGGTCCTGCCCTCGCCCACCATCCA CCCGAGTCAGTATCCAGCCCAATTTGCCCACCAGACCTACATCAGCGCCTCGCCAGCCTCCACCGTCTACACTGGATACCCACTGAGCCCCGCCAAGGTCAACCAGTACCCT TACATATAAACΔCTGGAGGGGAGGGAGGGAGGGAGGGAGGGAGAGAATGGCCCGAGGGAGGAGGGAGAGAAGGAGGGAGGCGCTCCTGGGACCGTGGGCGCTGGCCTTTTAT ACTGAAGATGCCGCACAO«YICAATGCAAACGGGGCAGGGGCGGGGGGGGGGGGGGCAGAGGGCAGGGGGACGGGTCGGGACACCAGTGAAACTTGAACCGGGAAGTGGGAG GACGTAGAGCAGAGAAGAGAACATTTTTAAAAGGAAGGGATTAAAGAGGGTGGGAAATCTATGGTTTTTATTTTAAAAAA
467
MTHGEELGSDVHQDSIVLTYLEGLLMHQAAGGSGTAVDKKSAGHNEEDQNFNISGSAFPTCQSNGPVLNTHTYQGSGMLHLKKARLLQSSEDWNAAKRKRLSDSIMNLNVKK
EALLAGMVDSVPKGKQDSTLLASLLQSF8SRLQTVAL8QQIRQ8LKEQGYALSHDSLKVEKDLRCYGVASSHLKTLLKKSKVKDQKPDTNLPDVTKNLIRDRFAESPHHVGQ
SGTK™8EP SCAARLQA AS^WEKRASPATSPKPSVACSQIJΛL SSEAH QQYSREKA K QNANQAASE LA MARLQENGQKDVGSYQ PKGMSSH NGQARTSSSKL
MASKSSATVFQNPMGIIPSSPKNAGYKNSLERNNIKQAANNSLLLHLLKSQTIPKPMNGHSHSERGSIFEESSTPTTIDEYSDNNPSFTDDSSGDESSYSNCVPIDLSCKHR
TEKSE8DQPVSLDKFTQSLLNT DPKVPDVDIKEDQDT8KNSKLNSHQKVTLLQLLLGHKNEENVEKNTSPQGVHNDVSKFNTQNYARTSVIESPSTNRTTPVSTPPLLTSS
KAGSPINLSQHSLVIKWNSPPYVCSTQSEKLTNTA8NHSMDLTK8KDPPGEKPAQNEGAQNSATFSASKLLQNLAQCGMQ8SMSVEEQRPS QLLTGNTDKPIGMIDRLNSP
LLSNKTNAVEENKAPSSQPTGPEPGLSGEEIENLLERRTVLQLLLGNPNKGKSEKKEKTPLRDESTQEHSERALSEQILMVKIKSEPCDDLQIPUTNVHLSHDAKSAPFLGM
APAVQRSAPALPVSEDFKSEPVSPQDFSFSKKGLL8RLLRQNQDSYLADDSDRSHPJ(NEMALLESKNLCMVPKKRKLYTEPLENPFKKMK NIVDAAHNHSAPEVLYGSLLN
QEELKFSRNDLEFKYPAGHGSASESEHRSWARESKSFNVLKQLLLSENCVRDLSPHRSNSVADSKKKGHKNNVTNSKPEFSISSLNGLMYSSTQPSSCMDNRTFSYPGWKT
PVSPTFPEHLGCAGSRPESGLLNGCSMPSEKGPIKWVITDAEKNEYEKDSPRLTKTNPILYYMLQKGGNSVTSRETQDKDI REASSAESVSQVTAKEELLPTAETKASFFN
LRSPYNSHMGNNASRPHSANGEVYGLLGSVLTIKKESE
468
GGGAATATATTCACTAAGGATTCTATCTGCTTACTGCTACAGACCTATGTGTTAAGGAATTCTTCTCCTCCTCCTTGCGTAGAAGTTGATCAGCACTGTGGTCAGACTGCAT
TTATCTTGTCATTGCCAGAAGAAATCTTGGACAGAATGTAACAGTACGTCTCTCTCTGATTGCGATGGAAGGTGATAAACTGATACTCCTTTATTAAAGTTACATCGCACTC
ACCACAGAAAACCATTCTTTAAAGTGAATAGAAACCAAGCCCTTGTGAACACTTCTATTGAACATGACTCATGGAGAAGAGCITGGCTCTGATGTGCACCAGGATTCTATTG
TTTTAACTTACCTAGAAGGATTACTAATGCATCAGGCAGCAGGGGGATCAGGTACTGCCGTTGACAAAAAGTCTGCTGGGCATAATGAAGAGGATCAGAACTTTAACATTTC
TGGCAGTGCATTTCCCACCTGTCAAAGTAATGGTCCAGTTCTCAATACACATACATATCAGGGATCTGGCATGCTGCACCTCAAAAAAGCCAGACTGTTGCAGTCTTCTGAG
GACTGGAATGCAGCAAAGCGGAAGAGGCTGTCTGATTCTATCATGAATTTAAACGTAAAGAAGGAAGCTTTGCTAGCTGGCATGGTTGACAGTGTCCGTAAAGGCAAACAGG
ATAGCACATTACTGGCCTCTTTGCTTCAGTCATTCAGCTCTAGGCTGCAGACTGTTGCTCTGTCACAACAAATCAGGCAGAGCCTCAAGGAGCAAGGATATGCCCTCAGTCA
TGATTCTTTAAAAGTGGAGAAGGATTTAAGGTGCTATGGTGTTGCATCAAGTCACTTAAAAACTTTGTTGAAGAAAAGTAAAGTTAAAGATCAAAAGCCTGATACGAATCTT
CCTGATGTGACTAAAAACCTCATCAGAGATAGGTTTGCAGAGTCTCCTCATCATGTTGGACAAAGTGGAACAAAGGTCATGAGTGAACCGTTGTCATGTGCTGCAAGATTAC
AGGCTGTTGCAAGCATGGTGGAAAAAAGGGCTAGTCCTGCCACCTCACCTAAACCTAGTGTTGCTTGTAGCCAGTTAGCATTACTTCTGTCAAGCGAAGCCCATTTGCAGCA
GTATTCTCGAGAACACGCTTTAAAAACGCAAAATGCAAATCAAGCAGCAAGTGAAAGACTTGCTGCTATGGCCAGATTGCAAGAAAATGGCCAGAAGGATGTTGGCAGTTAC
CAGCTCCCAAAAGGAATGTCAAGCCATCTTAATGGTCAGGCAAGAACATCATCAAGCAAACTGATGGCTAGCAAAAGTAGTGCTACAGTGTTTCAAAATCCAATGGGTATCA
TTCCTTCTTCCCCTAAAAATGCAGGTTATAAGAACTCACTGGAAAGAAACAATATAAAACAAGCTGCTAACAATAGTTTGCTTTTACATCTTCTTAAAAGCCAGACTATACC
TAAGCCAATGAATGGACACAGTCACAGTGAGAGAGGAAGCATTTTTGAGGAAAGTAGTACACCTACAACTATTGATGAATATTCAGATAACAATCCTAGTTTTACAGATGAC
AGCAGTGGTGATGAAAGTTCTTATTCCAACTG GTTCCCATAGACTTGTCTTGCAAACACGGAACTGAAAAATCAGAATCTGACCAACCTGTTTCCCTGGATAACTTCACTC
AATCCTTGCTAAACACTTGGGATCCAAAAGTCCCAGATGTAGATATCAAAGAAGATCAAGATACCTCAAAGAATTCTAAGCTAAACTCACACCAGΔAAGTAACACTTCTTCA ATTGCTACTTGGCCATAAGAATGAAGAAAATGTAGAAAAAAACACCAGCCCTCAGGGAGTACACAATGATGTGAGCAAGTTCAATACACAAAATTA'IGCAAGGACTTCTGTG ATAGAAAGCCCCAGTACAAATCGGACTACTCCAGTGAGCACTCCACCTTTACTTACATCAAGCAAAGCAGGGTCTCCCATCAATCTCTCTCAACACTCTCTGGTCATCAAAT GGAATTCCCCACCATATGTCTGCAGTACTCAGTCTGAAAAGCTAACAAATACTGCATCTAACCACTCAATGGACCTTACAAAAAGCAAAGACCCACCAGGAGAGAAACCAGC CCAAAATGAAGGTGCACAGAACTCTGCAACGTTTAGTGCCAGTAAGCTGTTACAAAATTTAGCACAATGTGGAATGCAGTCATCCATGTCAGTGGAAGAGCAGAGACCCAGC AAACAGCTGTTAACTGGAAACACAGATAAACCGATAGGTATGATTGATAGATTAAATAGCCCTTTGCTCTCAAATAAAACAAATGCAGTTGAAGAAAATAAAGCATTTAGTA GTCAACCAACAGGTCCTGAACCAGGGCTTTCTGGTTCTGAAATAGAAAATCTGCTTGAAAGACGTACTGTCCTCCAGTTGCTCCTGGGGAACCCAACAAAGGGAAGAGTGAA AAAAAAAGAGAAAACTCCCTTAAGAGATGAAAGTACTCAGGAACACTCAGAGAGAGCTTTAAGTGAACAAATAC'TGA'TGGTGAAAATAAAATCTGAGCCTTGTGATGACTTA
CAAATTCCTAACACAAATGTGCACTTGAGCCATGATGCTAAGAGTGCCCCATTCTTGGGTATGGCTCCTGCTGTGCAGAGAAGCGCACCTGCCTTACCAGTGTCCGAAGACT TTAAATCGGAGCCTGTTTCACCTCAGGATTTTTCTTTCTCCAAGAATGGTCTGCTAAGTCGATTGCTAAGACAAAATCAAGATAGTTACCTGGCAGATGATTCAGACAGGAG TCACAGAAATAATGAAATGGCACTTCTAGAATCAAAGAATCTTTGCATGGTCCCTAAGAAAAGGAAGCTTTATACTGAGCCATTAGAAAATCCATTTAAAAAGATGAAAAAC AACATTGTTGATGCTGCAAACAATCACAGTGCCCCAGAAGTACTGTATGGGTCCTTGCTTAACCAGGAAGAGCTGAAATTTAGCAGAAATGATCTTGAATTTAAATATCCTG CTGGTCATGGCTCAGCCAGCGAAAGTGAACACAGGAGTTGGGCCAGAGAGAGCAAAAGCTTTAATGTTCTGAAACAGCTGCTTCTCTCAGAAAACTGTGTGCGAGATTTGTC CCCGCACAGAAGT/AACTCTGTGGCTGACAGTAAAAAGAAAGGACACAAAAATAATGTGACCAACAGCAAACCTGAATTTAGCATTTCTTCTTTAAATGGACTGATGTACAGT TCCACTCAGCCCAGCAGTTGCATGGATAACAGGACAITTTCATACCCAGGTGTAGTAAAAACTCCTGTGAGTCCTACTTTCCCTGAGCACTTGGGCTGTGCAGGGTCTAGAC CAGAATCTGGGCTTTTGAATGGGTGTTCCATGCCCAGTGAGAAAGGACCCATTAAGTGGGTTATCACTGATGCGGAGAAGAATGAGTATGAAAAAGACTCTCCAAGATTGAC CAAAACCAACCCAA'IACTATATTACATGCTTCAAAAAGGAGGCAATTCTGTTGCCAGTCGAGAAACACAAGACAAGGACATTTGGAGGGAGGCTTCATCTGCTGAAAGTGTC TCACAGGTCACAGCCAAAGAAGAGTTACTTCCTACTGCAGAAACGAAAGCTTCTTTCTTTAATTTAAGAAGCCCTTACAATAGCCATATGGGAAATAATGCTTCTCGCCCAC ACAGCGCAAATGGAGAAGTTTATGGACTTCTGGGAAGCGTGCTAACGATAAAGAAAGAATCAGAATAAAATGTACCTGCCATCCAGTTTTGGATCTTTTTAAAACTAATGAG TATGAACTTGAGATCTGTATAAATAAGAGCATGATTTGAAAAAAGCATGGTATAATTGAAACTTTTTTCATTTTGAAAAGTATTGGTTAC GGTGATGTTGAAATATGCATA CTAATTTTTGCTTAACATTAGATGTCATGAGGAAACTACTGAACTAGCAATTGGTTGTTTAACACTTCTGTATGCGTCAGATAACAACTGTGAGTAGCCIATGAATGAAATT CTTTTATAAATATTAGGCATAAATTAAAATGTAAAACTCCATTCATAGTGGATTAATGCATTTTGCTGCCTTTATTAGGGTACTTTATTTTGCTTTTCAGAAGTCAGCCTAC ATAACACATTTTTAAAGTCTAAACTGTTAAACAACTCTTTAAAGGATAATTATCCAATAAAAAAAAACCTAGTGCTGATTCACAGCTTATTATCCAATTCAAAAATAAATTA GAAAAATATATGCTTACATTTTTCACTTTTGCTAAAAAGAAAAAAAAAGGTGTTTATTTTTAACTCTTGGAAGAGGTTTTGTGGTTCCCAATGTGTCTGTCCCACCCTGAGC CTTTTCAATATATATTTCTTTAAACCTTGTGCTACTTAGTAAAAATTGATTACAATTGAGGGAAGTTTGATAGATCC'ITTAAAAAAAAGGCAGATTTCCATTTTTTGTATTT TAACTACTTTACTAAATTAATACTCCTCCTTTTACAAATTAGAAAAGTTAACATTTATCTTTAGGTGGTTTCCTGAAAAGTTGAATATTTAAGAAATTGTTTTTAACAGAAG CAAAATGGCTTTTCTTTGGACAGTTTTCACCATCTCTTGTAAAAGTTAATTCTCACCATTCCTGTGGTACCTGCGAGTGTTATGACCAGGATTCCTTAAACCTGAACTCAGA CCACTTGCATTAGAACCATCTGGAGCACTTGTTTTAAAATGCAGATTCATAGGCAGCATCTCAGATCTACAGAACAAGAATCTCTGCTAAGTGGACCTGGAATCTTCCATCT GCATCTTAACATGCTCTCTAGGTGTTTCTTGTGTTTGAGAACCATGACTTATGACTTTCCTCAGAACATGAGACTGTAAAACAAAAACAAAAAACTATGTGATGCCTCTATT TTCCCCAATACAGTCACACATCAGCTCAAAATTTGCAATATTGTAGTTATATATTACCGTTATATCTTTGGAAATCCGGGTTCAGAACACTTTTTATGACAAAAATTGGGTG GAGGGGATAACTTTCATATCTGGCTCAACATCTCAGGAAAATCTGTGATTATTTGTGTGTTCTAATGAGTAACATCTACTTAGTTAGCCTTAGGGATGGAAAAACAGGGCCA CTTACCAAACTCAGGTGATTCCAGGATGGTTTGGAAACTTCTCCTGAATGCATCCTTAACCTTTATTAAΔACCATTGTCCTAAGAACAATGCCAACAAAGCTTACAACATTT AGTTTAAACCCAAGAAGGACACTAAACTAGATTGACTAATAAAAGTACAAGGCACATATACGTGACAGAATTGGTACTCAATCACTCCATTGGATCTTTTACTTTAAAGTAG TGATGAAAAGTACATGTTGATACTGTCTTAGAAGAAATTAATATATTAGTGAAGCCACATGGGGTTTCAGTTGCGAAACAGGTCTGTTTTTATGTTCAGTTTGTACAATCCA CAATTCATTCACCAGATATTTTGTTCTTAATTGTGTTCCAGGTTAGCAAATGACCIATCAAAAATTATTCTATAATCACTACTAGTTAGGATATTGATTTAAAATTGTTCTA
CTTGAAGTGGTTTCTAAGATTTTTATATTTAAAAA'IAGGTGTGATTTCCTAATATGATCTAAAACCCTAAATGGTTA'TTTTTCCTCAGAATGATTTGTAAATAGCTACTGGA AATATTATACAGTAATAGGAGTGGGTATTATGCAACATCATGGAGAGTGAAGGCATAGGCTTATTCTGACATAAAATTCCACTGGCCAGTTGAATATATTCTATTCCATGTC CATACTCTGACAATCTTATTGTCAACACTATATAAA'rAAGCTTTTAAACAAGTCATTTTTCTTGATCGTTGTGGAAGGTTTGGAGCCTTAGAGGTATGTCAGAAAAAATATG TTGGTATTCTCCCTTGGGTAGGGGGAAATGACCTTTTTACAAGAGAGATGAAATTTAGGTCAGGGAAAAGACCAAGGGCCAGCATGCTACTTTTGTGTGTGTGTGTGTGGGT TTTGTTTTGTTTITTTTGGTTGGCTGGTTGTTTTCATTATTATTAACAAAGGAATGAGAATATGTAATACTTAAATAAACATGACCACGAAGAATGCTGTTCTGATTTACTA GAGAATGTTCCCAATTTGAATTTAGGGTGATTTTAAAGAACAGTGAGAAAGGGCATACATCCACAGATTCACTTTGTTTATGCATATGTAGATACAAGGATGCACATATACA CATTTTCAAGGACTATTTTAGATATCTAGACAATTTCTTCTAATΔAAGTCATTTGTGAAΔGGGTACTACAGCTTATTGACATCAGTAAGGTAGCATTCATTACCTGTTTATT CTCTGCTGCATCTTACAGAAGAGTAAACTGGTGAGAGTATATATTTTATATATATATATATATATAATATGTATATATATATATATTGACTTGTTACATGAAGATGTTAAAA TCGGTTTTTAAAGGTGATGTAAATAGTGATTTCCTTAATGAAAAATACATATTTTGTATTGTTCTAATGCAACAGAAAAGCCTTTTAATCTCTTTGGTTCCTGTATATTCCA TGTATAAGTGTAAATATAATCAGACAGGTTTAAAAGTTGTGCATGTATGTATACAGTTGCAAGTCTGGACAAATGTATAGAATAAACCTTTTATTTAAGTTGTGATTACCTG CTGCATGAAAAGTGGCATGGGGGACCCTGTGCATCTGTGCATTTGGCAAAATGTCTTAACAAATCAGATCAGATGTTCATCCTAACATGACAGTATTCCATTTCTGGACATG ACGTCTGTGGTTTAAGCTTTGTGAAAGAATGTGCTTTGATTCGAAGGGTCTTAAAGAATTTTTTTAATCGTCAACCACTTTTAAACATAAAGAATTCACACAACTACTTTCA TGAATTTTTTAATCCCATTGCAAACATTATTCCAAGAGTATCCCAGTATTAGCAATACTGGAATATAGGCACATTACCATTCATAGTAAGAATTCTGGTGTTTACACAACCA AATTTGATGCGATCTGCTCAGTAATATAATTTGCCATTTTTATTAGAAATTTAATTTCTTCATGTGATGTCATGAAACTGTACATACTGCAGTGTGAATTTTTTTGTTTTGT TTTTTAATCTTTTAGTGTTTACTTCCTGCAGTGAATTTGAATAAATGAGAAAAAATGCAAAAAAAAAAAAAAAAAAAAA
469 ~
MNSPKSKKAKKKEEPSQNDISPKTKSLRKKKEPIEKKWSSKTKKVTKNEEPSEEEIDAPKPKKMKKEKEMNGETREKSPKLKNGFPHPEPDCNPSEAASEESNSEIEQEIP
VEQKEGAFSNFPISEETIKLLKGRGVTFLFPIQAKTFHHVYSGKDLIAQARTGTGKTFSFAIPLIEKLHGELQDRKRGRAPQVLVLAPTRELANQVSKDFSDITKKLSVACF
YGGTPYGGQFERMRNGIDILVGTPGRIKDHIQNGKLDLTKLKHWLDEVDQMLDMGFADQVEEILSVAYKKDSEDNPQTLLFSATCPH VFNVAKKYMKSTYEQVDLIGKKT
QKTAITVEHLAIKCHWTQRAAVIGDVIRVYSGHQGRTIIFCETKKEAQELSQNSAIKQDAQSLHGDIPQKQREITLKGFRNGSFGVLVATNVAARGLDIPEVDLVIQSSPPK
DVESYIHRSGRTGRAGRTGVCICFYQHKEEYQLVQVEQKAGIKFKRIGVPSATEIIKASSKDAIRLLDSVPPTAISHFKQSAEKLIEEKGAVEALAAALAHISGATSVDQRS
LINSNVGFVTMILQCSIEMPNISYAWKELKEQLGEEIDSKVKGMVFLKGKLGVCFDVPTASVTEIQEKWHDSRRWQLSVATEQPELEGPREGYGGFRGQREGSRGFRGQRDG
NRRFRGQREGSRGPRGQRSGGGNKSNR8QNKGQKRSFSKAFGQ
470
CTACCTCTTCCTCTCCACGCGGTTGAGAAGACCGGTCGGCCTGGGCAACCTGCGCTGAAGATGC SGGAAAACTCCGTAGTGACGCTGGTTTGGAATCAGACACCGCAATGA AAAAAGGGGAGACACTGCGAAAGCAAACCGAGGAGAAAGAGAAAAAAAGAGAAGCCAAAATCTGATAAGACTGAAOAGATAGCAGAAGAGGAAGAAACTGTTTTCCCCAAAG CTAAACAAGTTAAAAAGAAAGCAGAGCCTTCTGAAGTTGACATGAATTCTCCTAAATCCAAAAAGGCAAAAAAGAAAGAGGAGCCATCTCAAAATGACATTTCTCCTAAAAC CAAAAGTTTGAGAAAGAAAAAGGAGCCCATTGAAAAGAAAGTGGTTTCTTCTAAAACCAAAAAAGTGACAAAAAA GAGGAGCCTTCTGAGGAAGAAATAGATGCTCCTAAG CCCAAGAAGATGAAGAAAGAAAAGGAAATGAATGGAGAAACTAGAGAGAAAAGCCCCAAACTGAAGAATGGATTTCCTCATCCTGAACCGGACTGTAACCCCAGTGAAGCTG CCAGTGAAGAAAGTAACAGTGAGATAGAGCAGGAAATACCTGTGGAACAAAAAGAAGGCGC'ITTCTCTAATTTTCCCATATCTGAAGAAACTATTAAACTTCTCAAAGGCCG AGGAGTGACCTTCCTATTICCTATACAAGCAAAGACATTCCATCATGTTTACAGCGGGAAGGACTTAATTGCACAGGCACGGACAGGAACTGGGAAGACATTCTCCTTTGCC ATCCCTTTGATTGAGAAACTTCATGGGGAACTGCAAGACAGGAAGAGAGGCCGTGCCCCTCAGGTACTGGTTCTTGCACCTACAAGAGAGTTGGCAAATCAAGTAAGCAAAG ACTTCAGTGACATCACAAAAAAGCTGTCAGTGGCTTGTTTTTATGGTGGAACTCCCTATGGAGGTCAATTTGAACGCATGAGGAATGGGATTGATATCCTGGTTGGAACACC AGGTCGTATCAAAGACCACATACAGAATGGCAAACTAGATCTCACCAAACTTAAGCATGTTGTCCTGGATGAAGTGGACCAGATGTTGGATATGGGATTTGCTGATCAAGTG GAAGAGATTTTAAGTGTGGCATACAAGAAAGATTCTGAAGACAATCCCCAAACATTGCTTTTTTCTGCAACTTGCCCTCATTGGGTATTTAATGTTGCCAAGAAATACATGA AATCTACATATGAACAGGTGGACCTGATTGGTAAAAAGACTCAGAAAACGGCAATAACTGTGGAGCATCTGGCTATTAAGTGCCACTGGACTCAGAGGGCAGCAGTTATTGG GGATGTCATCCGAGTATATAGTGGTCATCAAGGACGCACTATCATCTTTTGTGAAACCAAGAAAGAAGCCCAGGAGCTGTCCCAGAATTCAGCTATAAAGCAGGATGCTCAG TCCTTGCATGGAGACATTCCACAGAAGCAAAGGGAAATCACCCTGAAAGGTTTTAGAAATGGTAGTTTTGGAGTTTTGGTGGCAACCAATGTTGCTGCACGTGGGTTAGACA TCCCTGAGGTTGATTTGGTTATACAAAGCTCTCCACCAAAGGATGTAGAGTCCTACATTCATCGATCCGGGCGGACAGGCAGAGCTGGAAGGACGGGGGTGTGCATCTGCTT TTATCAGCACAAGGAAGAATATCAGTTAGTACAAGTGGAGCAAAAAGCGGGAATTAAGTTCAAACGAATAGGTGTTCCTTCTGCAACAGAAATAATAAAAGCTTCCAGCAAA GATGCCATCAGGCTTTTGGATTCCGTGCCTCCCACTGCCATTAGTCACTTCAAACAATCAGCTGAGAAGCTGATAGAGGAGAAGGGAGCTGTGGAAGCTCTGGCAGCAGCAC TGGCCCATATTTCAGGTGCCACGTCCGTAGACCAGCGCTCCTTGATCAACΓCAAATGTGGGTTTTGTGACCATGATCTTGCAGTGCTCAATTGAAATGCCAAATATTAGTΓA TGCTTGGAAAGAACTTAAAGAGCAGCTGGGCGAGGAGATTGATTCCAAAGTGAAGGGAATGGTTTTTCTCAAAGGAAAGCTGGGTGTTTGCTTTGATGTACCTACCGCATCA GTAACAGAAATACAGGAGAAATGGCATGATTCACGACGCTGGCAGCTCTCTGTGGCCACAGAGCAACCAGAACTGGAAGGACCACGGGAAGGATA GGAGGCTTCAGGGGAC AGCGGGAAGGCAGTCGAGGCTTCAGGGGACAGCGGGACGGAAACAGAAGATTCAGAGGACAGCGGΣAAGGCAGTAGAGGCCCGAGAΒGACAGCGATCAGGAGGTGGCAACAA AAGTAACAGATCCCAAAACAAAGGCCAGAAGCGGAGTTTCAGTAAAGCATTTGGTCAATAATTAGAAATAGAAGATTTATATAGCAAAAAGAGAATGA GTTTGGCAATATA GAACTGAACATTATTTTTCATGCAAAGTTAAAAGCACATTGTGCCTCCTTTTGACCACTTGCCAAGTCCCTGTCTCTTTCAGACACAGACAAGCTTCATTTAAATTATTRCA TCTGATCATTATCATTTATAACTTTATTGTTACTTCATCAGTTTTTCCTTTTGAAAGGTGTATGAATTCATTACATTTTTATTCTAATGTATTATCTGTAGATTAGAAGATA AAATCAAGCATGTATCTGCCTATACTTTGTGAGTTCACCTGTCTTTATACTCAAAAGTGTCCCTTAATAGTGTCCTTCCCTGAAATAAATACCTAAGGGAGTGTAACAGTCr CrGGAGGACCACTTTGAGCCTTTGGAAGTTAAGGTTTCCTCAGCCACCTGCCGAACA TTTCTCATGTGGTCCTATTATTTGTCTACTGAGACTTAATACTGAGCAATGTTT ΓGAAACAAGATTTCAAACTAATCTGGGTTGTAATACAGTTTATACCAGTGTATGCTCTAGACTTGGAAGATGTAG'TATGTTTGATGTGGATTACCTATAC'I'IATGTTCGTTΓ
ΓGATACATTTTTAGCTTCTCATTATAAGGTGATTCATGCTTTAGTGAATTCTTCATAGATAGTATATATAAAAGTACATTTTAATAGAAAGCCAGGGTTTTAAGGAATTTCA CATGTATAAGGTGGCTCCATAGCTTTATTTGTAAGTAGGCTGGATAAATGGTGCTTAAATGGTAATGTACTCCACTTCTTCCTATTGGAAGATTAACATTATTTACCAAGAA GGACTTAAGGGAGTAAGGGGCGCAGATTAGCATTGCTCAAGAGTATGTAAAAAAAAAAAAAAAAAAAAAAA
471
MKAARFV SAGSLNGAGLVPREVEHFSRYS 8PLSNKQLLDFGSENACERTSFAF RQEL VR ANI KEIDI PTQ VNTSSVQLV S YIQSL^^DLVEFHEKSPDDQKA LSDFVDTLIKVRNRHHNWPT«QGIIEYKX)ACTVDPVTNQNLQYFLDRFYM RISTRMLMNQHILIFSDSQTGNPSHIGSIDPNCDVVAVVQDAFECSR LCDQYYLSSPE LKLTQVNGKFPDQPIHIVYVPSHLHHMLFELFKNAMRATVEHQENQPSLTPIEVIVVLGKEDLTIKISDRGGGVPLRIIDRLFSYTYSTAPTPV DNSRNAPLAGFGYGLPI SRLYAKYFQGDLNLYSLSGYGTDAIIYLKALSSESIEKLPVFNKSAFKHYQMSSEADDWCIPSREPKNLAKEVAM
472
CCAACATTTATTTTGATTCTTTGGTCATCCAGAAGTATATATTTTAATTTTACCTGGATTCGGAATAATTTCTCATATTA'TTAGACAAGTATCAGGAAAAAAGGAAACTTTT
GGATCTTTAGGAATAATTTATGCAATACTTGCCA'ITGGATTATTAGGATTTATTGTATGAGCCCATCATATATTCACAGTAGGTATAGACGTTGACACCCGAGCTTATTTTA
CTTCTGCTACTATAATTATTGCTGTACCTACAGGAATTAAAATTTTTAGATGACTAGCCACTCTTCATGGAGCTCAAT'IAACTTATTCCCCAGCTATTTTATGAGCCTTAGG
GTTTGTATTCTTATTTACTGTTGGTGGATTAACAGGAGTAGTTTTAGCTAATTCATCTGTTGATATTATTCTTCATGATACATATTATGTCGTTGCTCATTTCCATTATGTC
TTATCAATAGGAGCTGTATTTGCTATTATAGCAGGTT
473
MPAPRJΛEQPRVPGERQPLLPRGARGPRR RRAAGAAVLLVE LERAAFFGVANLVLYLNSTNFNWTGEQATRAALVFIΛASYLI.APVGG LADVYLGRYRAVALSLLLYL
AASGLLPATAFPDGRSεFCGEMPASPLGPACPεAGCPRSSPSPYCAPVLYAGLLLLGLAASSVRSNLTSFGADQVNωLGRDATRRFFN FY SINLGAVLSLLVVAFIQQNI
SFLLGYSIPVGCVGLAFFIFLFATPVFITKPPMGSQVSS^ΛKIALQNCCPQLWQRH8ARDRQCARVLADERSPQPGASPQEDIANFQVLVKI P^IVTLVPY MVYFQMQS
YVLQGLHLHIPNIFPANPANiεVALRAQGεεYTIPEAWLLLANWWLILVPLKDRLIDPLLLRC LLPSALQKMALGMFFGFTSVIVAGVLEMERLHYIHHNETVSQQIGE
VLYNAAPLSIWQIPQYLLIGISEIFASIPGLEFAYSEAPRSMQGAIMGIFFCLSGVG8LLGSSLVALLSLPGGWLHCPKDFGNINNCRMDLYFFLLAGIQAVTALLFVWIA
GRYERASQGPASHSRF8RDRG
474
GGAGTTGAGAATTAGGGAGGAGGTGGTAGAGTCCGGGTAGTGAGCGGAGGGACAGGAAGGGTAGGGCAAGAAAGGGAGAGGGGACAGGAGGGAAGGGTGGGCCAAAGCGGTG AGAAAGGAGGGCCAGCCAGTTGGGTGGGGGAGAGGGCCGAGGCCCGGGGGCAGGAGTGCAGGGCTCTGAGGCGGGGAGAGGAGAGGAGAGAAGAGCCGCGGGGGGCCCAGCC CGGAGCCAGGATGCCCGCGCCGCGCGCCCGGGAGCAGCCCCGCGTGCCCGGGGAGCGCCAGCCGCTGCTGCCTCGCGGTGCGCGGGGCCCTCGACGOTGGCGGCGGGCGGCG GGCGCGGCCGTGCTGCTGGTGGAGATGCTGGAGCGCGCCGCCTTCTTCGGCGTCACCGCCAACCTCGTGCTGTACCTCAACAGCACCAACTTCAACTGGACCGGCGAGCAGG CGACGCGCGCCGCGCTGGTATTCCTGGGCGCCTCCTACCTGCTGGCGCCCGTGGGCGGCTGGCTGGCCGACGTGTACCTGGGCCGCTACCGCGCGGTCGCGCTCAGCCTGCT GCTCTACCTGGCCGCCTCGGGCCTGCTGCCCGCCACCGCCTTCCCCGACGGCCGCAGCTCCTTCTGCGGAGAGATGCCCGCGTCGCCGCTGGGACCTGCCTGCCCCTCGGCC GGCTGCCCGCGCTCCTCGCCCAGCCCCTACTGCGCGCCCGTCCTCTACGCGGGCCTGCTGCTACTCGGCCTGGCCGCCAGCTCCGTCCGGAGCAACCTCACCTCCTTCGGTΒ CCGACCAGGTGATGGATCTCGGCCGCGACGCCACCCGCCGCTTCTTCAACTGGTTTTACTGGAGCATCAACCTGGGTGCTGTGCTGTCGCTGCTGGTGGTGGCGTTTATTCA GCAGAACATCAGCTTCCTGCTGGGCTACAGCATCCCTGTGGGCTGTGTGGGCCTGGCATTTTTCATCTTCCTCTTTGCCACCCCCGTCTTCATCACCAAGCCCCCGATGGGC AGCCAAGTGTCCTCTATGCTTAAGCTCGCTCTCCAAAACTGCTGCCCCCAGCTGTGGCAACGACACTCGGCCAGAGACCGTCAATGTGCCCGCGTGCTGGCCGACGAGAGGT CTCCCCAGCCAGGGGCTTCCCCGCAAGAGGACATCGCCAACTTCCAGGTGCTGGTGAAGATCTTGCCCGTCATGGTGACCCTGGTGCCCTACTGGATGGTCTACTTCCAGAT GCAGTCCACCTATGTCCTGCAGGGTCTTCACCTCCACATCCCAAACATTTTCCCAGCCAACCCGGCCAACATCTCTGTGGCCCTGAGAGCCCAGGGCAGCAGCTACACGATC CCGGAAGCCTGGCTCCTCCTGGCCAATGTTGTGGTGGTGCTGATTCTGGTCCCTCTGAAGGACCGCTTGATCGACCCTTTACTGCTGCGGTGCAAGCTGCTTCCCTCTGCTC TGCAGAAGATGGCGCTGGGGATGTTCTTTGGTTTTACCTCCGTCATTGTGGCAGGAGTCCTGGAGATGGAGCGCTTACACTACATCCACCACAACGAGACCG GTCCCAGCA GATTGGGGAGGTCCTGTACAACGCGGCACCACTGTCCATCTGGTGGCAGATCCCTCAGTACCTGCTCATTGGGATCAGTGAGATCTTTGCCAGCATCCCAGGCCTGGAGTTT GCCTACTCAGAGGCCCCGCGCTCCATGCAGGGCGCCATCATGGGCATCTTCTTCTGCCTGTCGGGGGTGGGCTCACTGTTGGGCTCCAGCCTAGTGGCACTGCTGTCCTTGC CCGGGGGCTGGCTGCACTGCCECAAGGACTTTGGGAACATCAACAATTGCCGGATGGACCTCTACTTCTTCCTGCTGGCTGGCATTCAGGCCGTCACGGCTCTCCTATTTGT CTGGATCGCTGGACGCTATGAGAGGGCGTCCCAGGGCCCAGCCTCCCACAGCCGTTTCAGCAGGGACAGGGGCTGAACAGGCCCTATTCCAGCCCCCTTGCTTCACTCTACC GGACAGACGGCAGCAGTCCCAGCTCTGGTTTCCTTCTCGGTTTATTCTGTTAGAATGAAATGGTTCCCATAAATAAGGGGCATGAGCCCTTCCTCCC
475
MKPHFRNTVERMYRDTFSYNFYNRPILSRRNTVLCYEVKTKGPSRPPLDAKIFRGQVYSELKYHPEMRFFHWFSK RKLHRDQEYEVT YISWSPCTKCTRDMATFLAEDP
KVTLTIFVARLYYFWDPDYQEALRSLCQKRDGPPATMKIMNYDEFQHCWSKFVYSQRELFEPWNNLPKYYILLHIMLGEILRHSMDPPTFTFNFNNEPWVRGRHETYLCYEV
ERMHNDT VLLNQRRGFLCNQAPHKHGFLEGRHAELCFLDVIPF KLDLDQDYRVTCFTSWSPCFSCAQEMAKFISKNKHVSLCIFTARIYDDQGRCQEGLRTLAEAGAKIS
IMTYSEFKHCWDTFVDHQGCPFQPWDGLDEHSQDLSGRLRAILQNQEN
476
CTGCCAGGGGGAGGGCCCCAGAGAAAACCAGAAAGAGGGTGAGAGACTGAGGAAGATAAAGCGTCCCAGGGCCTCCTACACCAGCGCCTGAGCAGGAAGCGGGAGGGGCCAT GACTACGAGGCCCTGGGAGGTCACTTTAGGGAGGGCTGTCCTAAAACCAGAAGCTTGGAGCAGAAAGTGAAACCCTGGTGCTCCAGACAAAGATCTTAGTCGGGACTAGCCG GCCAAGGATGAAGCCTCACTTCAGAAACACAGTGGAGCGAATGTATCGAGACACATTCTCCTACAACTTTTATAATAGACCCATCCTTTCTCGTCGGAATACCGTC GGCTG TGCTACGAAGTGAAAACAAAGGGTCCCTCAAGGCCCCCTTTGGACGCAAAGATCTTTCGAGGCCAGGTGTATTCCGAACTTAAGTACCACCCAGAGATGAGATTCTTCCACT GGTTCAGCAAGTGGAGGAAGCTGCATCGTGACCAGGAGTATGAGGTCACCTGGTACATATCCTGGAGCCCCTGCACAAAGTGTACAAGGGATATGGCCACGTTCCTGGCCGA GGACCCGAAGGTTACCCTGACCATCTTCGTTGCCCGCCTCTACTACTTCTGGGACCCAGATTACCAGGAGGCGCTTCGCAGCCTGTGTCAGAAAAGAGACGGTCCGCGTGCC ACCATGAAGATCATGAATTATGACGAATTTCAGCACTGTTGGAGCAAGTTCGTGTACAGCCAAAGAGAGCTATTTGAGCCTTGGAATAATCTGCCTAAATATTATATATTAC TGCACATCATGCTGGGGGAGATTCTCAGACACTCGATGGATCCACCCACATTCACTTTCAACTTTAACAATGAACCTTGGGTCAGAGGACGGCATGAGACTTACCTGTGΓΓA TGAGGTGGAGCGCATGCACAATGACACCTGGGTCCTGCTGAACCAGCGCAGGGGCTTTCTATGCAACCAGGCTCCACATAAACACGGTTTCCTTGAAGGCCGCCATGCAGAG CTGTGCTTCCTGGACGTGATTCCCTTTTGGAAGCTGGACCTGGACCAGGACTACAGGGTTACCTGCTTCACCTCCTGGAGCCCCTGCTTCAGCTGTGCCCAGGAAATGGCTA AATTCATTTCAAAAAACAAACACGTGAGCCTGTGCATCTTCACTGCCCGCATCTATGA'IGATCAAGGAAGATGTCAGGAGGGGCTGCGCACCCTGGCCGAGGCTGGGGCCAA AATTTCAATAATGACATACAGTGAATTTAAGCACTGCTGGGACACCTTTGTGGACCACCAGGGATGTCCCTTCCAGCCCTGGGATGGACTAGATGAGCACAGCCAAGACCTG AGTGGGAGGCTGCGGGCCATTCTCCAGAATCAGGAAAACTGAAGGATGGGCCTCAGTCTCTAAGGAAGGCAGAGACCTGGGTTGAGCCTCAGAATAAAAGATCTTCTTCCAA GAAATGCAAACAGGCTGTTCACCACCATCTCCAGCTGATCACAGACACCAGCAAAGCAATGCACTCCTGACCAAGTAGATTCTTTTAAAAATTAGAGTGCATTACTTTGAAT CAAAAATTTATTTATATTTCAAGAATAAAGTACTAAGATTGTGCTCAATACACAGAAAAGTTTCAAACCTACTAATCCAGCGACAATTTGAATCGGTTTTGTAGGTAGAGGA ATAAAATGAAATACTAAATCTTTCTGTAAAAAAAAAA
477
MSSIGTGYDLSASTFSPDGRVFQVEYAMKAVENSSTAIGIRCKDGVVFGVEKLVLSKLYEEGSNKKLFmmRRVGMAVAGLLADARSLADIAREEASNFRSNFGYNIPLKHL ADRVAMYVHAYTLYSAVRPFGCSFMLGSYSVNDGAQLYMIDPSGVSYGYWGCAIGKARQAAKTEIEKLQMKEMTCRDIVKEVAKIIYIVHDEVKDKAFELELSWVGELTNGR HEIVPKDIREEAEKYAKESLKEEDESDDDNM
478
TTTTTTTTTTTTAAAGAGGCAGAGTCTCTATTGCGCCAGCTAGAGTACAGGGGTATGGCC^^
TCCTAAGTAGCTGTGACTACAGGCATGTGATACTGCACCTGGCTAAATTTTAAATTTTTTTTGTAGAGATAGGTTCTCACTGCGTTGGCCAGGCTGGTCTCATACTCCTGGG
CGCGAGGGATCCTCCCACCTCAACCTCCCAAAGTACTGGGATTACAGGCTTGAGCCATGGCACCCAGCCTCAAGTAGTTTCTATGTACACTGTTTTATTTAATCATGCCCr
AATACTTATCGACAAGAGTTTCTATTTTTAAGTATGTAAAAGGCTAAGATGCTGGGGAACATAATAAATATCTATAGTACAGATCTGCCTTTTGAATAATTCACAAAATTTC
TTACCTGCAGCCAAAAGGTCTAACAGCACTGTAGAGTGTATATGCATGCACATACATGGCCACTCTGTCTGCAAGATGTTTTAGTGGAATGTTGTAGCCAAAGTTAGATCTG
AAGTTGGAAGCTTCTTCTCTTGCTATGCTGCTAAAGAACGAGCATCTGCCAACAAACCCTGTACTGCCATTTCCAACATGGCGATCAACATTTAAAAAGTCTTTTTGTTGAA ACCTTCTTTCATAAGGTTAGAAAGGGACTAATTTTCTACCCCCAAAGACAACCACCATCTTTTGATCTGATTCCCAATAGCTGGACTACTATTTTCCCCGGCCTTCATAGCA ATTTTCAACTTGAAAAACCCCTCCCCGAAGAAAAAGAATGTTAGGCTGACGGCATTACCCAGCCCATTGAGGCTC
479
MSSIGTGYDLSASTFSPDG FQVEYAM AVENSS AIGIRCKDG VFGVEK V SKLYEEGS KRLFrTO HVGM VAG ADARSLADIA EEASNFRSNFGYNIPLKHL ADRVAMYVHAYTLYSAVRPFGCSFMLGSYSVNDGAQLYMIDPSGVSYGYWGCAIGKARQAAKTEIEKLQMKEMTCRDIVKEVAKIIYIVHDEVKDKAFELELS VGELTNGR HEIVPKDIREEAEKYAKESLKEEDESDDDNM
480
GCACGATGAGCTCAAICGGCACTGGGTATGACCTGTCAGCCTCTACATTCTCTCCTGACGGAAGAGTTTTTCAAGTTGAATATGCTATGAAGGCTGTGGAAAATAGTAGTAC AGCTATTGGAATCAGATGCAAAGATGGTGTTGTCTTTGGGGTAGAAAAATTAGTCCTTTCTAAACTTTATGAAGAAGGTTCCAACAAAAGACTTTTTAATGTTGATCGGCAT GTTGGAATGGCAGTAGCAGGTTTGTTGGCAGATGCTCGTTCTTTAGCAGACATAGCAAGAGAAGAAGCTTCCAACTTCAGATCTAACTTTGGCTACAACATTCCACTAAAAC ATCTTGCAGACAGAGTGGCCATGTATGTGCATGCATATACACTCTACAGTGCTGTTAGACCTTTTGGCTGCAGTTTCATGTTAGGGTCTTACAGTGTGAATGACGGTGCGCA ACTCTACATGATTGACCCATCAGGTGTTTCATACGGTTATTGGGGCTGTGCCATCGGCAAAGCCAGGCAAGCTGCAAAGACGGAAATAGAGAAGCTTCAGATGAAAGAAATG ACCTGCCGTGATATCGTTAAAGAAGTTGCAAAAATAATTTACATAGTACATGACGAAGTTAAGGATAAAGCTTTTGAACTAGAACTCAGCTGGGTTGGTGAATTAACTAATG GAAGACATGAAATTGTTCCAAAAGATATAAGAGAAGAAGCAGAGAAATATGCTAAGGAATCTCTGAAGGAAGAAGATGAATCAGATGATGATAATATGTAACATTTACTCCA GCATCTATTGTATTTTAAATTTCTACTCCAGTCCAATGTAACTATTTAGCCCTG
481
MKLLWQAKMSSIQDWGEEVEEGAVYHVTLKRVQIQQAANKGARWLGVEGDQLPPGHTVSQYETCKIRTIKAGTLEKLVENLLTAFGDNDFTYISIFLSTYRGFASTKEVLEL
LLDRYGNLTSPNCEEDGSQSSSESKMVIRNAIASILRAWLDQCAEDFREPPHFPCLQKLLDYLTRMMPGSDPERRAQNLLEQFQKQEVETDNGLPNTISFSLEEEEELEGGE
SAEFTCFSEDLVAEQLTYMDAQLFKKWPHHCLGCIWSRRDKKENKHLAPTIRATISQFNTLTKCWSTILGGKELKTQQRAKIIEKWINIAHECRLLKNFSSLRAIVSALQ
SNSIYRLKKTWAAVPRDRMIMFEELSDIFSDHNNHLTSRELLMKEGTSKFANLDSSVKENQKRTQRRLQLQKDMGVMQG'TVPYLGTFLTDLT LDTALQDYIEGGLINFEKR
RREFEVIAQIKLLQSACNSYCMTPDQKFIQ FQRQQLLTEEESYALSCEIEAAADAETTSPKPRKSMVKRLSLLFLGSDMITSPTPTKEQPKSTASGSSGEEMDSVSVSSCE
SNHSEAEEG8ITPMDTPDEPQKKLSES8SSCSSIHSMDTNSSGMSSLINPLSSPPSCNNNPKIHKRSVSVTSITSTVLPPVYNQQNEDTCIIRISVEDNNGNMYKSIMLTSQ
DKTPAVIQRAMLKHNLDSDPAEEYELVQVISEDKELVIPDSANVFYAMNSQVNFDFILRKKNSMEEQVKLRSRTSLTLPRTAKRGCWSNRHSKITL
482
GTGGCCCGAGTCGCGCGCACCGGCGGCGGCGGGGGCAGCGCGGCGCGTGTCTGTGCGCTGCGGTCGCTCGGGACCGGGACCGGGGCGAGGCGCCGCGGGGCTGAGCCCAGCA
GACATTGCGTTGGCCTCCGAGCAGGGCGCATCATGCAGCGTTCGCGCACCGGAGAGAAAACTGAGAATGAAATTGCTTTGGCAAGCTAAAATGAGCTCGATTCAGGACTGGG
GTGAAGAGGTAGAGGAAGGAGCTGTTTACCATGTCACCCTCAAAAGAGTCCAGATTCAACAGGCTGCCAATAAAGGAGCAAGATGGCTAGGGGTTGAAGGGGACCAGCTGCC
TCCAGGACACACAGTCAGTCAATATGAAACCTGTAAGATCAGGACCATAAAAGCTGGCACCTTGGAGAAGCTTGTGGAGAACCTGCTGACAGCTTTTGGGGACAATGACTTT
ACCTATATCAGCATCTTTCTTTCAACGTACAGAGGCTTTGCCTCCACTAAAGAAGTGCIGGAACTACTGCTGGACAGGTAIGGAAACCTGACAAGCCCAAACTGTGAAGAAG
ATGGAAGCCAAAGTTCATCAGAGTCCAAAATGGTGATCAGGAATGCAATCGCTTCCATACTAAGGGCCTGGCTTGACCAGTGTGCAGAAGACTTCCGAGAGCCCCCTCACTT
CCCTTGCTTACAGAAACTGCTGGATTATCTCACACGGATGATGCCGGGCTCTGACCCAGAAAGAAGAGCACAAAATCTTCTTGAGCAGTTTCAGAAGCAAGAAGTGGAAACT
GACAATGGGCTTCCCAACACGATCTCCTTCAGCCTGGAAGAGGAAGAGGAACTGGAGGG'IGGAGAGTCAGCAGAATTCACGTGCTTCTCAGAAGATCTCGTGGCAGAGCAGC
TGACCTACATGGATGCACAACTCTTCAAGAAAGTAGTGCCTCACCACTGCCTGGGCTGCATTTGGTCTCGAAGGGATAAGAAGGAAAACAAACATTTGGCTCCTACGATCCG
TGCCACCATCTCTCAGTTTAATACCCTCACCAAATGTGTTGTCAGCACCATCCTGGGGGGCAAAGAACTCAAAACTCAGCAGAGAGCCAAAATCATTGAGAAGTGGATCAAC
ATCGCTCATGAATGTAGACTCCTGAAGAATTTTTCCTCCTTGAGGGCCATCGTTTCGGCACTGCAGTCTAATTCCATCTATCGGTTAAAAAAGACTTGGGCTGCCGTCCCAA
GGGACCGAATGCTGATGTTTGAAGAACTTTCAGATATCTTCTCAGACCATAATAACCATTTGACCAGCCGAGAACTACTGATGAAGGAAGGAACCTCAAAATTTGCAAACCT
GGACAGCAGTGTGAAAGAAAACCAGAAGCGTACCCAGAGGCGGCTGCAGCTCCAGAAGGACATGGGTGTGATGCAGGGAACTGTGCCCTACCTGGGCACCTTCCTGACTGAC
CTGACCATGCTTGACACTGCCCTTCAGGACTACATCGAGGGTGGACTGATAAACTTTGAGAAAAGGAGAAGGGAATTTGAAGTaATTGCCCAGATAAAGCTCTTACAGTCTG
CCTGCAACAGCTATTGCATGACCCCAGACCAAAAGTTCATCCAGTGGTTCCAGAGGCAGCAGCTCCTGACAGAGGAGGAGAGCTATGCCCTGTCATGTGAGATTGAAGCAGC
TGCTGACGCCAGCACCACCTCGCCCAAGCCTCGGAAGAGCATGGTGAAGAGACTCAGCCTACTGTTTCTAGGGTCTGACATGATCACCAGTCCCACTCCCACCAAAGAGCAG
CCCAAGTCCACTGCCAGCGGGAGCTCTGGTGAAAGCATGGACTCTGTCAGCGTGTCATCCTGCGAGTCGAACCACTCAGAGGCTGAGGAGGGCTCCATTACTCCCATGGACA
CCCCTGATGAGCCTCAAAAAAAGCTCTCTGAGTCCTCCTCATCCTGTTCTTCTATCCAT'ICCATGGACACAAATTCC'ICAGGGATGTCTTCCTTAATCAACCCCCTCTCCTC
CCCTCCGTCCTGCAACAACAACCCCAAAATCCACAAGCGCTCTGTCTCGGTGACGTCCATTACCTCGACTGTGCTGCCTCCTGTTTACAACCAACAGAATGAAGACACCTGC
ATAATCCGCATCAGTGTGGAAGACAATAACGGCAACATGTACAAGAGCATCATGTTGACGAGCCAGGATAAAACCCCCGCTGTGATCCAGAGAGCCATGCTGAAGCACAATC
TGGACTCAGACCCCGCCGAGGAGTACGAGCTGGTGCAGGTCATCTCGGAGGACAAAGAACTTGTGATTCCAGACTCAGCAAATGTCTTTTATGCCATGAACAGCCAAGTGAA
CTTTGACTTCATTTTGCGCAAAAAGAACTCCATGGAAGAACAAGTGAAACTGCGTAGCCGGACCAGCTTGACGTTGCCCAGGACAGCTAAACGGGGCTGCTGGAGTAACAGA
CACAGCAAAATCACCCTCTGAAGGGAGGGACCAGTGGCCCCTTGTTTGCCAAAGGCAGAGTGGGGCTGAGAAACAGGCTGCGGTGATTGCAATTACCATCCGGTGTTCGAGG
ATCATTGGTGAAGTCAGCAGATATTTATTGAGTTCCTGTGGTGTGCAAAGCATTATGATAGGCACCGTGGGGAAACTGGAAATGAATTTGACATGAAAAGGATGAACGATTC
ACTGATTCTCTTTGACTCATTTGAGACTAAAATGCAGAATTACCAACATTTAAAACATATATATGCACATGTATTTGGIATGCATGTGTATCTATATAAAAATATATAAGAG
GGACTTTATGGGATAGTATGGACTATGGAAAAACAAATTTGCACAATGGCCTGGGAAGTTGAGGTCACTTTTTACAGGGAAATAGAAGAAACTGAGAACCTAGTCTCGTATA
TTCTGAGTAAATGGAA'rCAGTCCTGGGAATAGAGAGTGTCCTTTGTGCCAGTATTACAAGAAGCCCAAACTTTATTTTTATAAAGGGAGAGGATGACTTTCTCAATCAAGrG
CCACCAGATAAAAACAACTGCAGAGGCTGGAACTGCCACAGGCTGTATGAAAGGCCACTTTGGAAAGGGTTTGGATGAGCTGGTGGCCTTCAACCTCTGCCTGCATCTGCCA
CTTTCTGCTACCCTAGGGAGGCCAGGAGGAGCTTCGGAGGACCATCGCCCCACTGGTCTAGCCATCATGACACCTCTGGAGGTGTCAAGCTCCTGAAACAAGCTCATTTCAG
TTTCTGGCAACCCCGTGTATTTCCGTTTTCCCCCTAAAGAACATATCATAATCATTGCACAAATAACCATGTTCTTTGGTAATGAAGCCAGAAAAGAAAGCGCAAAAGAATG
GTGACTCATTTGGACTCTTATCTGTCTTGGAATGTCACTGCTTCATTGCCTTCTCTGATTGCCTTTTGCATGTAAAACTATGTGTCTGGAGTCTTTTGCCATCTGGATCTTA
GTACCTCTTTATTATGTGCAATTTATTCCTCAGGTGTGGAAATTTCTACTGCAATTGACTACGTTTGATTATTTTGAGCTTGTGAAAGATTTCTGAACAGTGATTGTCCCGT
TAATAGCCCCTCAGAAGATGTTCCCTGCTGATAACAGCATCCTATTTTACTTACTTTTATAGCATTACTGTGCCTAGTCGTGGGGAAAGAGATGGGGCTGTATAGATTATCT
GAATCATTTGTCTAAGAGGTACATTCTTCCAGATGGAATCAATAACTTTTTTTTTTCCAGGTTCCCGTGCTTGCTATCACAGTATCATTGTTAAGTGACACTTTTGTCTCrC
ATAACACCATCACACTCTTCCTTCCAAGTCTGAGCTGTGCTGGGGTTTGAACTAAAAGCCATATGTGGAATATTGACATGTGTAAGAAGCACTTTCAGAATGTTGTCCTTTT
TAAGAAATGATTCTCAAAATACCAGTTTTTATTCCAAAAATTTAGAGAACAAACCCGGAATATGAAGTGCAGATTGTAACATGGAGCTATTTTTTTTTCC'IAATCCCATAAT
ACAGCTCCTAAAAGTTGTGTGGGATTTGCGTTGCATAAATAGCCATGTGAATTCCACAAGAAGCACCAGGGAAAGTTTAGAGATTTGCGGCAATGGACCGAAGAACGGGCCA
GGAAGTCCTCCAATTTCCTTTGGTCTTTCCAGGAGATTGGACTACACATTGTAAAGACTGACTGGGTTTCAACTAGTCAAAAAGCACTTTCTTCTGTTTTCAATCCCTGTTC
GATTTGTGCTTCTGTGCTTGTAGGAGAGATGGCCAGGGTGGCAGCCCTCATGCAGGTTGAAGTATATGTAGCCTCAGCCTGATATTCTTGGTGCGAAGGTAAAAAAAAAAAA
AATAAATAAAACCA'rTGGCCTGGTTGAGGGCGTGACCACCAAGACATATATGTTGTGCCCGTGTTCATCCTGTGTATTTATACTGTATATGTAGAGTCTAGATTTATATACT
GCAATGTAAAATATATATATATTTACCTTTTTTAAAGACAATGGAAATTCCAAGTAGC'IAAAACTTAGCTTCATTTATTTAATGCCACTTTAAATGTCTTAAATTTGTTTCC
TGGTGGACAGCCGGGTAATGCTTTTAGCTGCTCGCATGCTTGTCTTTCTGCATCTCCATCATCTGTTTACCTTTTGGTTAAACTAATAAACTAGTTTGGGACTTGGCTGGCA
TGTGCTGCCAGACCCAAAGGGAAAAAAAA
483
MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPSKDEGVLKEISITHHVKAGSEKADPSHFELLKVLGQGSFGKVFLVRKVTRPDSGHLYAMKVLKKATLKVRDRVRTKME
PJDII-ADVNHPFVVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYIAELALGLDHLHSLGI IYRDLKPENILLDEEGHIKLTDFGLSKEAIDHEKKAYSFCG
TVEYMAPEVVNRQGHEHEADVWSYGVLMPEMLTGSLPFQGKDRKETMTLILKAKLGMPQFLSTEAQSLLRALFKPJIPANRLGSGPrX3AEEIl RHVFYSTIDWNKLYRREITP
PPKPAVAQPDDTFYFDTEFTSRTPKDSPGI PPSAGAHQLFRGFSFVATGLMEDDGKPRAPQAPLHSWQQLHGKNLVFSDGYWKETIGVGSYSECKRCVHKATNMEYAVKV
IDKSKRDPSEEIEILLRYGQHPNIITLKDVYDDGKHVYLVTELMRGGELLDKILRQKFFSEREASFVLHTIGKTVEYLH8QGVVHRDLKPSNILYVDE8GNPECLRICDFGF
AKQLRAENGLL rPCYTANFVAPEVLKRQGYDEGCDI SLGILLYT LAGYTPFANGPSDTPEEILTRIGSGKFTLSGGNWNTVSETAKDLVSKMLHVDPHQRLTAKQVLQH
PWVTQKDKLPQSQLSKQDLQLVKGAMAATYSALNSSKPTPQLKPIESSILAQRRVRKLPSTTL
484
CGCGGCGCAGGGCCGCCGGAGAGCGCGGGTGACCTGGCGGCGGCAGATGCCGCTCGCCCAGCTCAAGGAGCCC GGCCGCTCATGGAGCTAGTGCCGCTGGACCCGGAGAAT GGACAGACCTCAGGGGAAGAAGCTGGACTTCAGCCGTCCAAGGATGAGGGGGTCCTCAAGGAGATCTGCATCACGCACCACGTCAAGGCTGGCTCTGAGAAGGCTGATCCAT CCCATTTCGAGCTCCTCAAGGT CTGGGCCAGGGATCCTTTGGCAAAGTCTTCCTGGTGCGGAAAGTCACCCGGCCTGACAGTGGGCACCTGTATGCTATGAAGGTGCTGAA GAAGGCAACGCTGAAAGTACGTGACCGCGTCCGGACCAAGATGGAGAGAGACATCCTGGCTGATGTAAATCACCCATTCGTGGTGAAGCTGCACTATGCCTTCCAGACCGAG GGCAAGCTCTATCTCATTCTGGACTTCCTGCGTGGTGGGGACCTCTTCACCCGGCTCTCAAAAGAGGTGATGTTCACGGAGGAGGATGTGAAGTTTTACCTGGCCGAGCTGG CTCTGGGCCTGGATCACCTGCACAGCCTGGGTATCATTTACAGAGACCTCAAGCCTGAGAACATCCTTCTGGA GAGGAGGGCCACATCAAACTCACTGACTTTGGCCTGAG CAAAGAGGCCATTGACCACGAGAAGAAGGCCTATTCTTTCTGCGGGACAGTGGAGTACATGGCCCCTGAGGTCGTCAACCGCCAGGGCCACTCCCATAGTGCGGACTGGTGG TCCTATGGGGTGT GATGTTTGAGATGCTGACGGGCTCCCTGCCCTTCCAGGGGAAGGACCGGAAGGAGACCATGACACTGATTCTGAAGGCGAAGCTAGGCATGCCCCAGT TTCTGAGCACTGAAGCCCAGAGCCTCTTGCGGGCCCTGTTCAAGCGGAATCCTGCCAACCGGCTCGGCTCCGGCCCTGATGGGGCAGAGGAAATCAAGCGGCATGTCTTCTA CTCCACCATTGACTGGAATAAGCTATACCGTCGTGAGATCACGCCACCCTTCAAGCCAGCAGTGGCTCAGCCTGATGACACCTTCTACTTTGACACCGAGTTCACGTCCCGC ACACCCAAGGATTCCCCAGGCATCCCCCCCAGCGCTGGGGCCCATCAGCTGTlCCGGGGCTTCAGCTTCGTGGCCACCσσCTTGATGGAAGACGACGGCAAGCCTCGTGCCC CGCAGGCACCCCTGCACTCGGTGGTACAGCAACTCCATGGGAAGAACCTGGTTTTTAGTGACGGCTACGTGGTAAAGGAGACAATTGGTGTGGGCTCCTACTCTGSGTGCAA GCGCTGTGTCCACAAGGCCACCAACATGGAGTA'IGCTGTCAAGGTCATTGATAAGAGCAAGCGGGATCCTTCAGAAGAGATTGAGATTCTTCTGCGGTATGGCCAGCACCCC AACATCATCACTCTGAAAGATGTGTATGATGATGGCAAACACGTGTACCTGGTGACAGAGCTGATGCGGGGTGGGGAGCTGCTGGACAAGATCCTGCGGCAGAAGTTCTTCT CAGAGCGGGAGGCCAGCTTTGTCCTGCACACCATTGGCAAAACTGTGGAGTATCTGCACTCACAGGGGGTTGTGCACAGGGACCTGAAGCCCAGCAACATCCTGTATGTGGA CGAGTCCGGGAATCCCGAGTGCCTGCGCATCTGTGACTTTGGTTTTGCCAAACAGCTGCGGGCTGAGAATGGGCTCCTCATGACACCTTGCTACACAGCCAACTTTGTGGCG CCTGAGGTGCTGAAGCGCCAGGGCTACGATGAAGGCTGCGACATCTGGAGCCTGGGCATTCTGCTGTACACCATGCTGGCAGGATATACTCCATTTGCCAACGGTCCCAGTG ACACACCAGAGGAAATCCTAACCCGGATCGGCAGTGGGAAGTTTACCCTCAGTGGGGGAAATTGGAACACAGTTTCAGAGACAGCCAAGGACCTGGTGTCCAAGATGCTACA CGTGGATCCCCACCAGCGCCTCACAGCTAAGCAGGTTCTGCAGCATCCATGGGTCACCCAGAAAGACAAGCTTCCCCAAAGCCAGCTGTCCCACCAGGACCTACAGCTTGTG AAGGGAGCCATGGCτσCCACGTACTCCGCACTCAACAGCTCCAAGCCCACCCCCCAGCTGAAGCCCATCGAGTCATCCATCCTGGCCCAGCGGCGAGTGAGGAAGTTGCCAT CCACCACCCTGTGAGGCACCAGGGCATTCGGGCCACAGGGCGGTGCTAGCTTGACACAGTCAGATGCTTCCAGAGGGAGCAGGCCGGAACCACAGGGCCAGAGGGAGCTGGA ACCGAGGGGCCGGGGAAGCTGCCAGCCCAGAACACCCCTAATGAGGGTGTGAGAAGTGCCTTCTCCTTCCCCAGGATGGACTCTTCTCGGCTCAGGCTCTGCTGGTGGAAAG CαATTCACTGTATAAACTTTTTTTATGAAAAAAATGGCATCAACCACCATGGA'TTTTTACAAGATCCATTTGCCTTTCTGGGAGCAGAAACAGCCATTGCGGCCCAGGAGGG GAACTGAGTCACGCTGGGGCTCTCTGAGACTCTTTAGAGCAGCTTTGGGATCCCACCCTGGGACCCCCACGATTGGCCACCTGTAGCCATCTGCACACACCTCCGAGACAGT CCAGTGTCACCTCTCTCAGAGCATCTGGCTGTTTAGCAGΔACTCATTCTATCCCCAATCAGCTCCTTTTCCGTTCTGTTCTGCTGGGAGTTCTAGAACCACTTCCTGCTACA GGAGGGGTCTCATGTCCTGCTGGCTTCCAGCTTCAGGCACCAGCATCCACCTTGCTCTGCCAGTGGATCCCTGCGGTCAGGCTGGGCAGCCCCAGAGAGAGGATGTGGAAAG CACTTTTTGGCTGACTTCATCTGGGGTTGGCAACAGGACAGAGTTCACAGGAGGCCAGTGGGCGGGCCATGAGGGACAGGGTCTTTTTTCATTTCTTCCTCAGCTGGTTACT CAGGGTTCATCTGTCCATGGCCTTTCTAATGGAATTC
485
MCGSERILQAGNILEIRVGQAGARRVATMTSPVLVDIREEVTCPICLELLTEPLEIDCGHSFCQACITPNGRESVIGQEGERECPVCQTSYQPGNFGPNRHLANIVRRLREV
VLGPGKQLKAVLCADHGEKLQLFCQEDGKVICWLCERSQEHRGHHTFLVEEVAQEYQEKFQESLKKLKNEEQEAEKLTAFIREKKTSWKNQMEPERCRIQTEFNQLRNILDR
VEQRELKKLEQEEKKGLRIIEEAENDLVHQTQSLRELISDLERRCQGSTMELLQDVSDVTERSEFWTLRKPEALPTKLRSMFRAPDLKRMLRVCRELTDVQSYWAIQGSLTR
RERRASGVRTRRSQGSSAMASKILLNVQEEV CPICLELLTEPLSLDCGHSLCRACITVSNKEAVTSMGGKSSCPVCGISYSFEHLQANQHLANIVERLKEVKLSPDNGKKR
DLCDHHGEKLLLFCKEDRKVICWLCERSQEHRGHHTVLTEEVFKECQEKLQAVLKRLKKEEEEAEKLEADIREEKTEWKYQVQTERQRIQTEFDQLREILNNEEQRELQRLE
EEEKKTLDKFAEAEDELVQQKQLVRELI8DVECRSQWSTMELLQDMSGIMKWSEIWRLKKProWSKKLKTVFHAPDLSPJ^LQMFRELTAVRCYWVDVTI^εVNLNLNLVLSΞ
DQRQVIEVPIWPFQCYNYGVLG8QYFSSGKHYWEVDVSKKTAWILGVYCRTYSRHMKYWRRCANRQNLYTKYRPLFGY VIGLQNKCKYGVFEESLS8DPEVLTL8MAVPP
CRVGVFLDYEAGIVSFFNVTSHGSLIYKF8KCCF8QFVYPYFNPWNCPAPMTLCPPSS
486
CTGCCTTTCTCGGAAGGAAGGAGCAGAGTCGTGCGTGGTTGAGTTTAGATAAAAGCCGAGTGAGCGCGCTCTGTTCCTTAAGATTAGTTTAAGGTGCCTTGGATTGCTCTGA
AGAGCTTTGACCACCTGATATTGCTTACATCTGGAACTTCTTGTCTTCTCATTCCCCAGATGTGCGGGTCAGAGAGGATTCTACAGGCAGGAAACATCTTAGAAATCAGGGT
TGGGCAGGCAGGAGCCAGGAGAGTAGCTACAATGACTTCACCAGTACTGGTGGACATACGAGAAGAGGTGACCTGCCCTATCTGCCTGGAGCTCCTAACAGAACCCCTGAGC
ATAGACTGTGGCCACAGCTTCTGCCAAGCCTGCATCACACCAAATGGCAGGGAATCAGTGATTGGTCAAGAAGGGGAAAGAAGCTGCCCTGTGTGCCAGACCAGCTACCAGC
CAGGGAACTTCGGGCCTAATCGGCATCTGGCCAACATAGTGAGGCGGCTCAGAGAGGTAGTGTTGGGCCCTGGGAAGCAGCTGAAAGCAGTTCTTTGTGCAGACCATGGAGA
AAAACTGCAGCTCTTCTGTCAGGAGGATGGGAAGGTCATTTGCTGGCTTTGTGAGCGGTCTCAGGAGCACCG'IGGTCACCACACGTTCCTCGTGGAGGAGGTTGCCCAGGAG
TACCAGGAGAAGTTTCAGGAGTCTCTAAAGAAGCTGAAGAACGAGGAGCAGGAAGCTGAGAAGCTAACAGCTTTTATCAGAGAGAAGAAGACATCCTGGAAGAATCAGATGG
AGCCTGAGAGATGCAGGATCCAGACAGAGTTTAATCAGCTGCGAAATATCCTAGACAGAGTGGAGCAACGGGAGCTGAAAAAGCTGGAACAGGAAGAGAAGAAGGGGCTACG
AATTATAGAAGAGGCTGAGAATGATCTGGTCCACCAGACCCAGTCGCTGCGAGAGCTCATCTCGGATCTGGAGCGTCGATGTCAGGGGTCAACAATGGAGCTGCTGCAGGAT
GTGAGTGATGTCACAGAAAGGAGTGAGTTCTGGACCCTGAGGAAGCCAGAAGCTCTCCCTACAAAGCTGAGAAGTATGTTCCGAGCCCCAGATCTGAAAAGGATGCTGCGAG
TGTGTAGAGAGCTGACAGATGTCCAAAGCTACTGGGCCATCCAGGGGTCTTTAACCAGAAGAGAGAGGAGAGCCTCAGGAGTTAGGACCAGAAGAAGCCAGGGAAGCAGTGC
AATGGCTTCAAAAATCTTGCTTAACGTACAAGAGGAGGTGACCTGTCCCATCTGCCTGGAGCTGTTGACAGAACCCTTGAGTCTAGACTGTGGCCACAGCCTCTGCCGAGCC
TGCATCACTGTGAGCAACAAGGAGGCAGTGACCAGCATGGGAGGAAAAAGCAGCTGTCCTGTGTGTGGTATCAGTTACTCATTTGAACATCTACAGGCTAATCAGCATCTGG
CCAACATAGTGGAGAGACTCAAGGAGGTCAAGTTGAGCCCAGACAATGGGAAGAAGAGAGATCTCTGTGATCATCATGGAGAGAAACTCCTACTCTTCTGTAAGGAGGATAG
GAAAGTCATTTGCTGGCTTTGTGAGCGGTCTCAGGAGCACCGTGGTCACCACACAGTCCTCACGGAGGAAGTATTCAAGGAATGTCAGGAGAAACTCCAGGCAGTCCTCAAG
AGGCTGAAGAAGGAAGAGGAGGAAGCTGAGAAGCTGGAAGCTGACATCAGAGAAGAGAAAACTTCCTGGAAGTATCAGGTACAAACTGAGAGACAAAGGATACAAACAGAAT
TTGATCAGCTTAGAAGCATCCTAAATAATGAGGAGCAGAGAGAGCTGCAAAGATTGGAAGAAGAAGAAAAGAAGACGCTGGATAAGTTTGCAGAGGCTGAGGATGAGCTAGT
TCAGCAGAAGCAGTTGGTGAGAGAGCTCATCTCAGATGTGGAGTGTCGGAGTCAGTGGTCAACAATGGAGCTGCTGCAGGACATGAGTGGAATCATGAAA'IGGAGTGAGATC
TGGAGGCTGAAAAAGCCAAAAATGGTTTCCAAGAAACTGAAGACTGTATTCCATGCTCCAGATCTGAGTAGGATGCTGCAAATGTTTAGAGAACTGACAGCTGTCCGGTGCT
ACTGGGTGGATGTCACACTGAATTCAGTCAACCTAAATTTGAATCTTGTCCTTTCAGAAGATCAGAGACAAGTGATATCTGTGCCAATTTGGCCTTTTCAGTGTTATAATTA
TGGTGTCTTGGGATCCCAATATTTCτCCTCTGGGAAACATTACTGGGAAGTGGACGTGTCCAAGAAAACTGCCTGGATCCTGGGGGTATACTGTAGAACATATTCCCGCCAT
ATGAAGTATGTTGTIAGAAGATGTGCAAATCGTCAAAATCTTTACACCAAATACAGACCTCTATTTGGCTACTGGGTIATAGGGTTACAGAATAAATGTAAGTATGGTGTCT
TTGAAGAGTCTTTGTCCTCTGATCCCGAGGTTTTGACTCTCTCCATGGCTGTGCCTCCCTGCCGTGTTGGGGTTTTCCTCGACTATGAAGCAGGCATTGTCTCATTTTTCAA
TGTCACAAGCCATGGCTCCCTCATTTACAAGTTCTCTAAATGTTGCTTTTCTCAGCCTGTTTATCCATATTTCAATCCTTGGAACTGTCCAGCTCCCATGACTCTATGCCCA
CCAAGCTCTTGAATTITCTCATTTCTTCACCTACAACCCTTTGTCTCGACTTATCTCCTGCAACTGACTCATCTGCAACATTCACACCATTGCTTCCTTGTGGTTTCCCTTC
TTTAGAACTTTTACTCATCCTTGAGATGTATGGTGTATTTGGCTTGAGTTATGAGAGATGCTTATTTATTCATTTACTCTTTTTCATATTTTCAGAGAAAGTTACCTAATCC
CTCCTAAAGACACAGCAGTATGGGTATAACATCCTTGCCTTCCCATTTATCCATGTTTCACTTTATCACTGATGTGAAGAGGCCCAAAGCCTGTTAGCCACCATCCATGCTA
CCTAGGTAGTCCATAGGAACCACCCCCATGACCACCACCAACATCAACTAAAGGTTCTTGGAGGGTATGTCΔGTGTGTTGCTCAGGATACCCCAGGTACATCAAGGAATCAA
GGAGAGGAAAATATGAGCAATATGTGTATTCAGAGTGAAGATTTTATGTCCAGAGTATTTGAGCTCAAACCTTGCCTGTTGTTTTCTAATCATGATGAATACTTTCTCAGTT
TCTTTTTCCTGAAATATAAATTGGGATTTAAGACTGTACCTAACTATTAAGATCACTGTGTAAAACTAAGTGTCTCTAAATGTAATGCATCGATTTAGTGTCTGGAACATAA
TAAATATTTGCTCTCATGATTGCTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
487
MAGAGGGNDIQWCFSQVKGAVDDDVAEADIISTVEFNHSGELLATGDKGGRWIFQQEQENKIQSHSRGEYNVY8TFQ8HEPEFDYLKSLEIEEK1NKIRWLPQKNAAQFLL
ETNDKTIKL KISERDKRPEGYNLKEEDGRYRDPTTVTTLRVPVFRPMDLMVEASPRRIFANAHTYHINSISINSDYETYLSADDLRINL HLEITDRSFNIVDIKPANMEE
LTEVITAAEFHPNSCNTFVYSSSKGTIRLCDMRASALCDRHSKLFEEPEDPSNRSFFSEIISSISDVKFSHSGRYNMTRDYLSVKIWDLNMENRPVETYQVHEYLRS LCSL
YEITOCIFDKFECCVmGSDSVVMTGSYNNFFRMFDRNTKRDITLEASREITOKPRTVLKPRKVCASGKRKroEIS\π:SLDFNKKILHTAVmPKENIIAVATTNNLYIFQDKVN
488
CCGCCGCCATCCGCCCTCTCTACCCCCCCATCCCCAGGTGAGGGGGGTGAGTTCAGGAAGCGGAGACCCCGAGGAACCCAGCAGGGTCACCATTTGCAGCGCAACATGGCAG GAGCTGGAGGAGGGAATGATATTCAGTGGTGTTTTICTCAGGTGAAAGGAGCAGTAGATGATGATGTAGCAGAAGCAGATATAATTTCTACAGTAGAATTTAATCATTCTGG AGAATTACTAGCAACAGGAGATAAAGGTGGTAGAGTTGTCATCTTTCAACAGGAGCAGGAGAACAAAATCCAGTCTCATAGCAGAGGAGAATATAATGTTTACAGCACCTTC CAGAGCCATGAACCAGAGTTTGACTACTTGAAAAGTTTAGAAATAGAAGAAAAGATCAATAAAATTAGGTGGTTACCCCAGAAAAATGCTGCTCAGTTTTTATTGTCTACCA ATGATAAAACAATAAAATTATGGAAAATCAGTGAAAGGGACAAAAGACCAGAAGGG'IATAACTTGAAAGAGGAGGATGGAAGGTATAGAGATCCTACTACAGTTACTACACT ACGAGTGCCAGTCTTTAGGCCTATGGATCTAATGGTTGAGGCCAGTCCACGAAGAATATTTGCCAATGCTCATACA'rATCACATCAACTCAATTTCTATTAATAGTGATTAT GAAACATATTTATCTGCAGATGATTTGCGGATTAATCTTTGGCATCTGGAAATTACAGACAGGAGTTTTAACATTGTGGATATCAAGCCTGCCAATATGGAAGAGCTAACAG AGGTGATTACAGCAGCAGAATTTCATCCAAACAGCTGTAACACATTTGTATACAGCAGCAGTAAAGGAACTATTCGGCTATGTGACATGAGGGCATCTGCCCTCTGTGATAG ACATTCTAAATTGTTTGAAGAACCTGAAGATCCCAGTAACAGGTCATTTTTTTCCGAAATCATCTCCTCTATTTCGGATGTAAAATTCAGCCATAGTGGTCGATATATGATG ACTAGAGACTATTTGTCAGTCAAAATTTGGGACTTAAATATGGAAAACAGGCCTGTGGAAACATACCAGGTGCATGAATACCTCAGAAGTAAACTCTGTTCACTGTATGAAA ATGACTGCATATTTGACAAATTTGAATGTTGTTGGAATGGATCTGACAGTGTTGTCATGACTGGATCTTACAATAATTTCTTCAGAATGTTTGACAGAAACACAAAGCGAGA CATAACCCTAGAAGCATCGCGGGAAAACAATAAGCCTCGCACAGTTCTGAAGCCTCGCAAAGTCTGTGCAAGTGGCAAGCGAAAGAAAGATGAAATAAGTGTTGACAGCCTA GACTTCAATAAGAAAATCCTTCACACAGCCTGGCACCCCAAGGAAAATATCATTGCCGTAGCTACTACAAACAATCTGTATATATTTCAAGACAAAGTGAATTAGGGTTGGC ATTCCTAGCAGAAGAACCCACTTCCTGCTTAGTTGAGATAGTTGAATCTAGCATTCGTTCCTATAAAAGAGAGAGGTCCATTGTGGCGCCCCTTTCCAGTGTTTGACAGTGT GCCATTCGACAACACATTGTTATAGCTACATGGAGAAAGCTCTGTGGATTCATCACTGTGGTGTTCTCCATGTCTGCTAGCCATTTAGGTAAGGGTAGGGCACTTTTAATTT AAATGACTTCTTGCACCATCTTGCCTAATGGACTAGATTGGACTGTATCAACATTGATTTACTCCACTTTTTATGCCTTCCATTGTGATGACGTCAAACACAGTGAAAGCCT TCAGTCATGCTATGGGATTTAATTGTGTATCCTCATTACTGTATCATTTGTGGGGTACACCCCTTCCCCCTTTTTTTAAATTAAATACAGCTCATTCTTACTGTGGCTTGTΔ GCATTCCTCCTCTTCTGGCCTCCTGGACTGCTCCCCTTCATCTCTTACCCTTGCCCCCTCCACCCGGTCTTGGTGGTGGTATATTAAAAAAAGAAAGAATGAAAGCACACAA AATGAGTCAGTTTGGGGTCAGTGGTATAAAGGGGGTATATGTTGCAAACAAATGTTTTAGTAACAGTTGGCTGTAATCACTCCTCGCCGTGTCTGGCACTGAAAATAAGGAA AAG
489
MRRPSL LKDI KCT LVFGVWILYILK NY TEECDMKK^fflYVDPD VKP iQ YAQQΛ^QKEC PKFAKTSMALLFEHRYSVDLLPF QK PKDSEAESK DPPFGFRKF8
SKVQTLLELLPEHDLPEHLKAKTCRRCVVIGSGGILHGLELGHTLNQFDWIRLNSAPVEGYSEHVGNKTTIRMTYPEGAPLSDLEYYSNDLFVAVLFKSVDFN LQAMVKK
ETLPFW\WLFF KQVAEKIPLQPKΗFRILNPVIIKETAFDILQYSEPQSRF GRDKNVPTIGVIAW/LATHLCDEVSLAGFGYDLNQPRTPLHYFDSQCMAAP1NFQTMHNVT
TETKFLLKLVKEGWKDLSGGIDREF
490
CTGAGCGGGGGAGCGGCGGCCCCCAGCTGAATGGGCGCGAGAGCGGCGCTGGGGGCGGGTGGGGGCGCGGGGTACCGGGCTGGCGGCCGGCCGGCGCCCCCTCATTAGTATG CGGACGAAGGCGGCGGGCTGCGCGGAGCGGCGTCCCCTGCAGCCGCGGACCGAGGCAGCGGCGGCACCTGCCGGCCGAGCAATGCCAAGTGAGTACACCTATGTGAAACTGA GAAGTGATTGCTCGAGGCCTTCCCTGCAATGGTACACCCGAGCTCAAAGCAAGATGAGAAGGCCCAGCTTGTTATTAAAAGACATCCTCAAATGTACATTGCTTGTGTTTGG AGTGTGGATCCTTTATATCCTCAAGTTAAATIATACTACTGAAGAATGTGACATGAAAAAAATGCATTATGTGGACCCTGACCGTGTAAAGAGAGCTCAGAAATATGCTCAG CAAGTCTTGCAGAAGGAATGTCGTCCCAAGTTTGCCAAGACATCAATGGCGCTGTTATTTGAGCACAGGTATAGCGTGGACTTACTCCCTTTTGTGCAGAAGGCCCCCAAAG ACAGTGAAGCTGAGTCCAAGTACGATCCTCCTTTTGGGTTCCGGAAGTTCTCCAGTAAAGTCCAGACCCTCTTGGAACTCTTGCCAGAGCACGACCTCCCTGAACACTTGAA AGCCAAGACCTGTCGGCGCTGTGTGGTTATTGGAAGCGGAGGAATACTGCACGGATTAGAACTGGGCCACACCCTGAACCAGTTCGATGTTGTGATAAGGTTAAACAGTGCA CCAGTTGAGGGATATTCAGAACATGTTGGAAATAAAACTACTATAAGGATGACTTATCCAGAGGGCGCACCACTGTCTGACCTTGAATATTATTCCAATGACTTATTTGTTG CTGTTTTATTTAAGAGTGTTGATTTCAACTGGCTTCAAGCAATGGTAAAAAAGGAAACCCTGCCATTCTGGGTACGACTCTTCTTTTGGAAGCAGGTGGCAGAAAAAATCCC ACTGCAGCCAAAACATTTCAGGATTTTGAATCCAGTTATCATCAAAGAGACTGCCTTTGACATCCTTCAGTACTCAGAGCCTCAGTCAAGGTTCTGGGGCCGAGATAAGAAC GTCCCCACAATCGGTGTCATTGCCGTTGTCTTAGCCACACATCTGTGCGATGAAGTCAGTTTGGCGGGTTTTGGATATGACCTCAATCAACCCAGAACACCTTTGCACTACT TCGACAGTCAATGCATGGCTGCTATGAACTTTCAGACCATGCATAATGTGACAACGGAAACCAAGTTCCTCTTAAAGCTGGTCAAAGAGGGAGTGGTGAAAGATCTCAGTGG AGGCATTGATCGTGAATTTTGAACACAGAAAACCTCAGTTGAAAATGCAACTCTAACTCTGAGAGCTGTTTTTGACAGCCTTCTTGATGTATTTCTCCATCCTGCAGATACT TTGAAGTGCAGCTCATGTTTTTAACTTTTAATTTAAAAACACAAAAAAAATTTTAGCTCTTCCCACTTTTTTTTTCCTATTTATTTGAGGTCAGTGTTTGTTTTTGCACACC ATTTTGTAAATGAAACTTAAGAATTGAATTGGAAAGACTTCTCAAAGAGAATTGTATGTAACGATGTTGTATTGATTTTTAAGAAAGTAATTTAATTTGTAAAACTTCTGCT CGTTTACACTGCACATTGAATACAGGTAACTAA'RTGGAAGGAGAGGGGAGGTCACTCTTTTGATGGTGGCCCTGAACCTCATTCTGGTTCCCTGCTGCGCTGCTTGGTGTGA CCCACGGAGGATCCACTCCCAGGATGACGTGCTCCGTAGCTCTGCTGCTGATACTGGGTCTGCGATGCAGCGGCGTGAGGCCTGGGCTGGTTGGAGAAGGTCACAACCCTTC TCTGTTGGTCTGCCTTCTGCTGAAAGACTCGAGAACCAACCAGGGAAGCTGTCCTGGAGGTCCCTGGTCGGAGAGGGACATAGAATCTGTGACCTCTGACAACTGTGAAGCC ACCCTGGGCTACAGAAACCACAGTCTTCCCAGCAATTATTACAATTCTTGAATTCCTΓGGGGATTTTTTACTGCCCTTTCAAAGCACTTAAGTGTTAGA'ICTAACGTGTTCC AGTGTCTGTCTGAGGTGACTTAAAAAATCAGAACAAAACTTCTATTATCCAGAGTCATGGGAGAGTACACCCTTTCCAGGAATAATGTTTTGGGAAACACTGAAATGAAATC TTCCCAGTATTATAAATTGTGTATTTAAAAAATΛAGAAACTTTTCTGAATGCCTACCTGGCGGTGTATACCAGGCAGTGTGCCAGTTTAAAAAGATGAAAAAGAATAAAAACT
TTTGAGG
491
MΞAPLDATALHALQEEQARLKMRLWDLQQLRKELGDSPKDKVPFSVPKIPLVFRGHTζJQDPEVPKSLVSNLRIHCPLLAGSALITFDDPKVAEQVLQQKEHTINMEECRLRVQ
VQPLELPMVTTIQVSSQLSGRRVLVTGFPASLRL8EEELLDKLEIFFGKTRNGGGDVDVRELLPG8VMLGFARDGVACRLCQIGQFTVPLGGQQVPLRVSPYVNGEIQKAEI
RSQPVPRSVLVLNIPDILDGPELHDVLEIHFQKPTRGGGGRGPDSRTPRTAGPSSLHL
492
GGCACGAGGCTGAGGTGTATTTCGGGTCTTGCTGGGGCTGAGAGAGACCACAGCCCTTTGGGGGGTACAAACAAGAGTTCAGTTGCTGTGAATTCTGCCACTGTGCCCAGCT
CTGAAGCCTCAGCTCTTGCCAAACAGACCCGAGACCCATGTCAGCCCCACTGGATGCCGCCCTCCACGCCCTTCAGGAGGAGCAGGCCAGACTCAAGATGAGGCTGTGGGAC
CTGCAGCAGCTGAGAAAGGAGCTCGGGGACTCCCCCAAAGACAAGGTCCCATTTTCAGTGCCCAAGATCCCCCTGGTATTCCGAGGACACACCCAGCAGGACCCGGAAGTGC
CTAAGTCTTTAGTTTCCAATTTGCGGATCCACTGCCCTCTGCTTGCGGGCTCTGCTCTGATCACCTTTGATGACCCCAAAGTGGCTGAGCAGGTGCTGCAACAAAAGGAGCA
CACGATCAACATGGAGGAGTGCCGGCTGCGGGTGCAGGTCCAGCCCTTGGAGCTGCCCATGGTCACCACCATCCAGGTGATGGTGTCCAGCCAGTTGAGTGGCCGGAGGGTG
TTGGTCACTGGATTTCCTGCCAGCCTCAGGCTGAGTGAGGAGGAGCTGCTGGACAAGCTAGAGATCTTCTTTGGCAAGACTAGGAACGGAGGTGGCGATGTGGACGTTCGGG
AGCTACTGCCAGGGAGTGTCATGCTGGGGTTTGCTAGGGATGGAGTGGCTCAGCGTCTGTGCCAAATCGGCCAGTTCACAGTGCCACTGGGTGGGCAGCAAGTCCCTCTGAG
AGTCTCTCCGTATGTGAATGGGGAGATCCAGAAGGCTGAGATCAGGTCGCAGCCAGT CCCCGCTCGGTACTGGTGCTCAACATTCCTGATATCTTGGATGGCCCGGAGCTG
CATGACGTCCTGGAGATCCACTTCCAGAAGCCCACCCGCGGGGGCGGGGAGGTAGAGGCCCTGACAGTCGTACCCCAAGGACAGCAGGGCCTAGCAGTCTTCACCTCTGAGT
CAGGCTAGGGGCCTCCCCTTCTCATCCTCCCCACCCCCCCGCCAAGGTTCTCACACTGGCCTGGGCTTGGGTGCCCATATAGGAGGTCTGTATGTTCACCAACAGTGCGGAG
Gα3TCACACATTGCAAAACACTGCCCAGAACAGTAAAAAGAGCCTGCATGCCAAAAAAAAAAAAAAAAAA
493
MWVLTPAAFAGKLLSVFRQPLSSLWRSLVPLFCWLRATFWLLATKRRKQQLVLRGPDETKEEEEDPPLPTTPTSVNYHFTRQCNYKCGFCFHTAKTSFVLPLEEAKRGLLLL
KEAG EKINFSGGEPFLQDRGEYLGKLVRFCKVELRLPSVSIVSNGSLIRERWFONYGEYLDILAISCDSFDEEVNVLIGRGQGKKNHVENLQKLRRWCRDYRVAFKINSVI
NRFNVEEDMTEQIKALNPVR KVFQCLLIEGENCGEDALREAERFVIGDEEFERFLERHKEVSCLVPESNQKMKDSYLILDEYMRFLNCRKGRKDPSKSILDVGVEEAIKFS
GFDEKMFLKRGGKYI SKADLKLDW
494
CAGGAAGGGCCATGAAGATTAATAAAGATTTGGACTCAGGGCAAATATTTACTTAGTAGCAATAACTCAAAGAATTACTGTTGAATAAATAAGCCAATTAAGCAGCCAATCA
CGTACTATGCGGATGCACACAAATGAAACCCTCACTTCAACCTGAAGACATTCGCACATGAGTTACGTAGAGGGACCTGCAGGAAGCGGTAGAGAAAACATAAGGCTTATGC
GTTTAATTTCCACACCAATTTCAGGATCTTTGTCACTGACAGCAGCACTAAGACTTGTTAACTTTATATAGTTAAGAAGAACAAGGCTGAGCGCGATGACTCACGCCTGTAA
GCCTAGAACTTTGGGAGGCCAAAGCAGGCAGACTGCTTGAGCCCAGGAGTTCCAGACCAGCCTGGGCAACATGGCAACACCCCATCTCTACAAAAAAATACAAGAATCAGCT
GGGCGTGGTGATGTGTTCCTGTAATCTCAGCTACTCGGGAGGCAGAGGCAGGAGGATTGCTTGAACCCGGGAGGCAGAGGTTGTAGTTAGCCGAGATC'rCGCCACTGCACTC
CAGTCTGGACGACAGAGTGAGACTCAGTCTCAAATAAATAAATAAATACATAAATATAAGGAAAAAAATAAAGCTGCTTTCTCCTCTTCCTCCTCITTGGTCTCATCTGGCT
CTGCTCCAGGCATCTGCCACAATGTGGGTGCTTACACCTGCTGCTTTTGCTGGGAAG TCTTGAGTGTGTTCΔGGCAACCTCTGAGCTCTCTGTGGAGGAGCCTGGTCCCGC
TGTTCTGCTGGCTGAGGGCAACCTTCTGGCTGCTAGCTACCAAGAGGAGAAAGCAGCAGCTGGTCCTGAGAGGGCCAGATGAGACCAAAGAGGAGGAAGAGGACCCTCCTCT
GCCCACCACCCCAACCAGCGTCAACTATCACTTCACTCGCCAGTGCAACTACAAATGCGGCTTCTGTTTCCACACAGCCAAAACATCCTTTGTGCTGCCCCTTGAGGAAGCA
AAGAGAGGATTGCTTTTGCTTAAGGAAGCTGGTA'IGGAGAAGATCAACTTTTCAGGTGGAGAGCCATTTCTTCAAGACCGGGGAGAATACCTGGGCAAGTTGGTGAGGTTCT
GCAAAGTAGAGTTGCGGCTGCCCAGCGTGAGCATCGTGAGCAATGGAAGCCTGATCCGGGAGAGGTGGTTCCAGAATTATGGTGAGTATTTGGACATTCTCGCTATCTCCTG
TGACAGCTTTGACGAGGAAGTCAATGTCCTTATTGGCCGTGGCCAAGGAAAGAAGAACCATGTGGAAAACCTTCAAAAGCTGAGGAGGTGGTGTAGGGATTATAGAATCCCT
TTCAAGATAAATTCTGTCATTAATCGTTTCAACGTGGAAGAGGACATGACGGAACAGATCAAAGCACTAAACCCTGTCCGCTGGAAAGTGTTCCAGTGCCTCTTAATTGAAG
GTGAGAATTGTGGAGAAGATGCTCTAAGAGAAGCAGAAAGATTTGTTATTGGTGATGAAGAATTTGAAAGATTCTTGGAGCGCCACAAAGAAGTGTCCTGCTTGGTGCCTGA
ATCTAACCAGAAGATGAAAGACTCCTACCTTATTCTGGATGAATATATGCGCTTTCTGAACTGTAGAAAGGGACGGAAGGACCCTTCCAAGTCCATCCTGGATGTTGGTGTA
GAAGAAGCTATAAAATTCAGTGGATTTGATGAAAAGATGTTTCTGAAGCGAGGAGGAAAATACATATGGAGTAAGGCTGATCTGAAGCTGGATTGGTAGAGCGGAAAGTGGA
ACGAGACTTCAACACACCAGTGGGAAAACTCCTAGAGTAACTGCCATTGTCTGCAATACTATCCCGTTGGTATTTCCCAGTGGCTGAAAACCTGATTTTCTGCTGCACX3TGG CATCTGATTACCTGTGGTCACTGAACACACGAATAACTTGGATAGCAAATCCTGAGACAATGGAAAACCATTAACTTTACTTCATTGGCTTATAACCTTGTTGTTATTGAAA CAGCACTTCTGTTTTTGAGTTTGTTTTAGCTAAAAAGAAGGAATACACACAGGAATAATGACCCCAAAAATGCTTAGATAAGGCCCCTATACACAGGACCTGACATTTAGCT CAATGATGCGTTTGTAAGAAATAAGCTCTAGTGATATCTGTGGGGGCAATATTTAATTTGGATTTGATTTTTTAAAACAATGTTTACTGCGATTTCTATAT'ITCCATTTΓGA AACTATTTCTTGTTCCAGGTTTGTTCATTTGACAGAGTCAGTATTTTTTGCCAAATA'ICCAGATAACCAGTTT'ICACATCTGAGACATTACAAAGTATCTGCCTCAATTATT TCTGCTGGTTATAATGCTTTTTTTTTTTTTTGCTTTTATGCCATTGCAGTCTTGTACTTTTTACTGTGATGTACAGAAATAGTCAACAGATGTTTCCAAGAACATATGAΓAT GATAATCCTACCAATTTTCAAGAAGTCTCTAGAAAGAGATAACACATGGAAAGACGGCGTGGTGCAGCCCAGCCCACGGTGCCTGTTCCATGAATGCTGGCTACCTATGTGT GTGGTACCTGTTGTGTCCCTTTCTCTTCAAAGATCCCTGAGCAAAACAAAGATACGCTTTCCATTTGATGATGGAGTTGACATGGAGGCAGTGCTTGCATTGCTTTGTTCGC CTATCATCTGGCCACATGAGGCTGTCAAGCAAAAGAATAGGAGTGTAGTTGAGTAGCTGGTTGGCCCTACATTTCTGAGAAGTGACGTTACACTGGGTTGGCATAAGATATC CTAAAATCACGCTGGAACCTTGGGCAAGGAAGAATGTGAGCAAGAGTAGAGAGAGTGCCTGGATTTCATGTCAGTGAAGCCATGTCACCATATCATATTTTTGAATGAACTC TGAGTCAGTTGAAATAGGGTACCATCTAGGTCAGTTTAAGAAGAGTCAGCTCAGAGAAAGCAAGCATAAGGGAAAATGTCACGTAAACTAGATCAGGGAACAAAATCCTCRC CTTGTGGAAATATCCCATGCAGTTTGTTGATACAACTTAGTATCTTATTGCCTAAAAAAAAATTTCTTATCAT'TGTTTCAAAAAAGCAAAATCATGGAAAATTTTTGTTGTC CAGGCAAATAAAAGGTCATTTTAATTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGCCA
495
MNQTAILICCLIFLTLSGIQGVPLSRTVRCTCISISNQPVNPR8LEKLEIIPASQFCPRVEIIATMKKKGEKRCLNPESKAIKNLLKAVSKEMSKR8P
496
GAGACATTCCTCAATTGCTTAGACATATTCTGAGCCTACAGCAGAGGAACCTCCAGTCTCAGCACCATGAATCAAACTGCGATTCTGATTTGCTGCCTTATCTTTCTGACΓC TAAGTGGCATTCAAGGAGTACCTCTCΤCTAGAACCGTACGCTGTACCTGCATCAGCATTAGTAATCAACCTGTTAATCCAAGGTCTTTAGAAAAACTTGAAATTATTCCTGC AGCCAATTTTGTCCACGTGTTGAGATCATTGCTACAATGAAAAAGAAGGGTGAGAAGAGATGTCTGAATCCAGAATCGAAGGCCATCAAGAATTTACTGAAAGCAGTTAGC AAGGAAATGTCTAAAAGATCTCCTTAAAACCAGAGGGGAGCAAAATCGATGCAGTGCTTCCAAGGATGGACCACACAGAGGCTGCCTCTCCCATCAC'TTCCCTACATGGAGT ATATGTCAAGCCATAATTGTTCTTAGTTTGCAGTTACACTAAAAGGTGACCAATGATGGTCACCAAATCAGCTGCTACTACTCCTGTAGGAAGGTTAATGT'ICATCATCCTA AGCTATTCAGTAATAACTCTACCCTGGCACTATAATGTAAGCTCTACTGAGGTGCTA'IGTTCTTAGTGGATGTTCTGACCCTGCTTCAAATATTTCCCTCACCTTTCCCAΓC
TTCCAAGGGTACTAAGGAATCTTTCTGCTTTGGGGTTTATCAGAATTCTCAGAATCTCAAATAACTAAAAGGTA'IGCAATCAAATCTGCTTTTTAAAGAATGCTCTTTACTT CATGGACTTCCACTGCCATCCTCCCAAGGGGCCCAAATTCTTTCAGTGGCTACCTACATACAATTCCAAACACATACAGGAAGGTAGAAATATCTGAAAATGTATGTGTAAG TATTCTTATTTAATGAAAGACTGTACAAAGTATAAGTCTTAGATGTATATATT'ICCTATATTGTTTTCAGTGTACATGGAATAACATGTAATTAAGTACTATGTATCAATGA GTAACAGGAAAATTITAAAAATACAGATAGATATATGCTCTGCATGTTACATAAGATAAATGTGCTGAATGGTTTTCAAATAAAAATGAGGTACTCTCCTGGAAATATTAAG AAAGACTATCTAAAIGTTGAAAGATCAAAAGGTTAATAAAGTAATTATAACT
497
MGRELDLAPYGTLRKSQSADSLNSISSVSNTFGQDFTLGQVEVSMEYDTASHTLNVAVMQGKDLLEREEASFESCFMRVSLLPDEQIVGISRIQRNAYSIFFDEKFSIPLDP
TALEEKSLRFSVFGIDEDER TVSTGVVELKLEVLDLPLQPFEGWLYLQDQNKAADAVGEILLELSYLPTAERLTVVVVKAKNLI TNDKTTADPFVKVYLLQDGRKMSKKKT
AVKRDDPNPVFNEAMIFSVPAIVLQDLSLRVTVAESSSDGRGDNVGHVIIGAVSQWHGNHTLEPDVGHAAQARVHVARCPAKLATRRASWAMELLEPGTHSALSDALSIAQL
EP
498
GAAGTTCTAGAAAATGTTAATTGGGGGAGCTGTGGCTGGCAGAGAAGGAAAAAGGAAGCTGAAGGGCACTTGGGCTCATAATGGTCTCTCCAACCCTGATCCTGTCCTTTAT
GGACATTTGGCAGCGCTGCTGCCTTGAGGTGCCTTGCAATGCTTTATCTTTTTGTTAAAGCCACCTCTGTTGCTTCAGCCAGCTTGAGCGGTTTTCTGTTACTTGCTAGTGG
TTGGGAAGGCTTAGCCGACGAAGGGAAAATGAGTCAGGTCCTGAAGGATGAGCAAGT'IACGGGAGTGGGCCGCATGGTGAGGGAGTGGACTTCCTGATGGGGTTAAGGGCGC
CTGAACACCTGGGAGGCAAGTTGAGGCCAAGACCTGGGGTGATGGAGAGGCAGGGTAGGCTACCCAGTGAGTAGGAGGCCGAAGGAACCACAGCAGGGCTCCAGATCTCCTG
GCCCAGAGGGGCTGGTACGGGAAGCCCAGAAGACACTCATCCCTAAGGGGAGCCTGAGACTGAGGAACTCTCATGCCCTGCGTCGGGCTCGTGGGCGAAGGGCCTTCCCAGG
GACTGCACCATGGCCTGTCCCCAGCCTTACCCAGGGGCCTCCCTCTCAGGTTCTGAAGGACCCAGGGGTCACAGCTGTGTGGGGTGCTCCACTGAACACTTCCTTCAAACTC
CTTCAGGCTGGAGTGCAGTGGCGCGATCTCAGCTCCATGGGAGAGAGTTTGAAAGGATGAAGAGTTTACATCCTCTGGAAAGAAGCAAATAGAAGGCATTCCAGGCAAAAGG
AACTGCATCGAGTAAAAGCATGGAGGCAAGAAAGGGCTTGGTGTGTTTGAGAAACAGTGAGTAGGGCATGGTGGTGGCAGAAGCTTAAAGTGTATGGCCCGTGGACAGTGAC
AGCCGGACAAGAAGCTGAAGTGACAGAACAAGTTGAACCAAAGGAATTCCAGACCTGGGAAAGTGGAGAAAGAATTTTGGGGTCAGAGCCGTTTAAGACTTTGCCTAGGGCC
TGGGTCTTCTTTCTCCTAAAGGCCTCAACCCACAGCACGCCACACAAATATGTCACATAACACACAAACAAACA'ICA'IATTTCACAGTCCAGGAAATGAAATGAAGACAAAA
GCGCCCCCTGTGGGTGAAGTCACAGTCACTGCAGCAGACATCATGGCTGTGGATGTGGCAGAATACCATCTGAGCGTCATCAAGAGCCCCCCTGGCTGGGAGGTGGGTGTCT
ATGCTGCAGGGGCCCTGGCCCTGCTGGGAATCGCAGCTGTGAGCCTGTGGAAGCTCTGGACGTCGGGGAGCTTCCCCAGCCCCTCTCCGTTCCCCAATTACGACTACAGGTA
CCTTCAGCAGAAGTACGGCGAGAGCTGCGCAGAGGCCAGGGAGAAGAGAGTGCCTGCCTGGAATGCCCAGCGGGCCAGCACGCGGGGACCACCCAGCCGCAAAGGCAGTCTC
AGCATTGAGGACACCTTTGAGAGCATCAGTGAACTGGGGCCTCTGGAGCTGATGGGCCGGGAGTTGGACCTGGCCCCCTATGGGACCCTCCGGAAGTCCCAGTCGGCCGACT
CCCTGAACTCCATCTCCTCCGTGAGCAACACCTTTGGGCAGGACTTCACACTGGGCCAGGTGGAGGTGAGCATGGAGTACGACACTGCCTCCCACACGCTGAACGTGGCGGT
GATGCAGGGCAAGGACCTCCTGGAGCGGGAGGAGGCCAGCTTCGAGTCCTGCTTCATGCGCGTCAGCCTGCTGCCGGACGAGCAGATCGTGGGCATTTCTCGGATCCAGAGA
AATGCCTACTCCATCTTCTTTGATGAGAAGTTCTCCATCCCCCTGGATCCCACAGCCCTGGAGGAGAAGAGCCTGCGGTTTTCTGTATTTGGCATCGATGAGGATGAGCGCA
ACGTCAGCACGGGGGTGGTGGAGCTGAAGCTTTCTGTGCTTGACCTCCCGCTGCAGCCCTTCAGTGGCTGGCTCTATTTACAGGACCAGAACAAGGCCGCCGATGCTGTGGG
GGAGATCCTGCTCTCCCTCAGCTACCTCCCCACAGCCGAGCGCCTCACCGTGGTCGTGGTTAAGGCCAAGAACCTCATCTGGACCAACGACAAGACCACAGCGGACCCCTTC
GTCAAGGTGTACCTGCTGCAGGATGGGAGGAAGATGAGCAAAAAGAAGACAGCCGTGAAGAGGGATGACCCCAACCCGGTGTTCAACGAAGCCATGATCTTCTCGGTGCCAG
CCATTGTGCTCCAGGACCTGTCTCTCCGCGTGACGGTGGCTGAGAGCAGCAGCGACGGCCGTGGGGACAACGTGGGCCATGTCATCATTGGGCCGTCAGCCAGTGGCATGGG
AACCACACATTGGAACCAGATGTTGGCCACGCTGCGCAGGCCCGTGTCCATGTGGCACGCTGTCCGGCGAAACTAGCAACCAGGGCGGGCCAGTTGGGCAATGGAGCTGCTG
GAGCCCGGTACCCACTCAGCTCTGTCTGATGCCCTCTCCATAGCCCAGCTGGAGCCGTGAACACTGGGGTCCCCTGGCAGAGTCCTCATGACCCATCCTGGTCTCTCTGTCC
AGATTGCAGCAGAGGAGTGGGCGTGGCTCTGTGTCCAGGGCCCCAGGGTCTGCTCCTGCTGAGGACCAGCTGTGGCTGGGCCAGGACAGAGGACTCAACCCTGCTCCTCCCG
GTAGGCCAGCTGCCGAGCTGGGCTATGTTCTGGAACCCAGTGAATCTTGGGGGCCAGGCACTGTGCTAGGCACCAGCAGGGGTAACACAAAGAAGACCCGGCCCTTAGGGCA
TCAGGAAGACTAGCTCCCCTGCCCCGGAGGATCTGCTCAGTGCTGATGGCAGCCCAGCTGTGTGGACTCAGGGGGCTCTGAGGGCTAGGGAAACAGGAAGGGCCTCTTTGAC
AAGGTAGGAGCTGTGCTTGGAGGGGCAGGAAAAGAACIGAGCATGTCGCAGGCAGCGGGCCCAGCCTGAGCAATGGCAGGATGTGAACTTCCCCATCGCAAATGCAGTTCTC
AGCCCACTGCAGTGGATACAAGGAAGGGCCTTTCTCGGGGCCGGAGAAGAGACCAAGAGACCAGGCCCGGGCAGCAGCCTACCGGCCACGTGGAACACTGGCTCCGGAGTTA
TTCTCTGTCAAATCTACTCCCCGGACCTCAACCATGGCAAGAACCAGAGGTCCAAAGAGGCCCAGACCCAGGTCCTTGTGCTCAGTCCTGCGCAAACCAGGCCCAGACCCTG
CAAGCATTTGTTGATGCCCTTGCAGGCCCACTGGGAGAAAGATGCCTCAGGCAGGTCTCAGCCTGGGGGTGGCAGGGGTGGGGCAGAGAGAATACTGACAGCAGAGGTCTTG
GTGGGCTGCACGTGCCTGCGAAGATGTGGTGGACAAGGAGGCTCTCGGGCTGGGCCTTGGAGGGGTGGCAGCGGAAGGACAGCCCAGGTGGCTGAGGCCTGATGGGAAGCCG
GGGAAGGCCAGGGTGGAAGGGCGGCTTGAGGGACGCCAGGAGAAGACTGAATGCCAGGCTAGGAAGGAGGCGGCTCTCGATCACGGGGTGGGTGCCCCCGACACCGGGTCTC
CTAGCTTGAGTTCCCTAGAAGCGAAATCTGAGAGGGGGATTCTGGGGCAAGTAGTTTCTTGCGGGTGAGTGTTCTCAGAGAAACTTACCAGATCAAGAAAGGGAGCTCAGGC
TGGATGGAGGAAGCCACGCAAGTGTGGCTTCAAGATCCATCGCCTTGGCCTGATCGCTGTGGGGGCAGGGGCCTGGAGTAGGAGGGGCACCCTGGGGGCTCCCACCCAGAAG
CAGAGGGGCTGGGCTGTTGCACCTCTACTGGCATCAGTCTTTGGTTACCCCCCAGCCCCAGTAGGAGGAGAGCAGGCAGAGCTTGTCATCCCCAGCCTGGTGTCCCGCAGTC
CCAGGAAGCCGCTTCTTGCCTTCATGGCTGAGTGCTGGGAAGGGCTGAGCTCACCCAGGCCAGCAGGTGGGGTATCATCTGCTCGGTGGGGCCACCCACAGGTGACAGCATG
GACCCTCAGGCTGGCTGCCCCTGTTCCTTGGTCCATAACTGGTGAGCTATGGAGACCCAGGCCAACAAATTATCCCCAGTGATATGGGGGGAGGAGGGGCTAGAACAAGGGC
CCAGGGGACTGGAGGCAGGATGGTGGCTTTCCCTACCTGACACAGCCATGGCCCAGCCCCAAGGCCAGGCTGTCTACCCTATGGCCACAGCAGGAGGTCAGCCCAGGGCCAG
GAGACACATGGCTGGACAAGGCTTTGCAGCCTGGGAGACCCCGACTTTCTCTAACCCAGTGGCTGTGCGGTGCAGGCCACTGACTCCCCCCCTGCCCTCTCCCCTCTCTCCC
TCCCCCTAACTGCATGACATGTTAACTGTGTGCCCAGGACAGCCGTGGTGGGAACCGGGTATGCCAACTGGAATGATTCTAGAACCAAAATAAAGTTGGGGCAGGAAGAGGG
GGCTTCCAGGGAGCCCTGCTCGGCCCTGAATCAC
499
MA>_vIEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQMQDKYSKSGIACFLKEDDSY DPNDEESMNSPCWQVK QLRQLVRKMILRTSEETISTVQEKQQNI8P LVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINS ES8R8GHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMK SARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG
500 CCTCACTGACTATAAAAGAATAGAGAAGGAAGGGCTTCAGTGACCGGCTGCCIGGCTGACTTACAGCAGTCAGACTCTGACAGGATCATGGCTATGATGGAGGTCCAGGGGG GACCCAGCCTGGGACAGACCTGCGTGCTGATCGTGATCTTCACAGTGCTCCTGCAGTCTCTCTGTGTGGCTGTAACTTACGTGTACTTTACCAACGAGCTGAAGCAGATGCA GGACAAGTACTCCAAAAGTGGCATTGCTTGTTTCTTAAAAGAAGATGACAGTTATTGGGACCCCAATGACGAAGAGAGTATGAACAGCCCCTGCTGGCAAGTCAAGTGGCAA CTCCGTCAGCTCGTTAGAAAGATGATTTTGAGAACCTCTGAGGAAACCATTTCTACAGTTCAAGAAAAGCAACAAAATATTTCTCCCCTAGTGAGAGAAAGAGGTCCTCAGA GAGTAGCAGCTCACATAACTGGGACCAGAGGAAGAAGCAACACATTGTCTTCTCCAAACTCCAAGAATGAAAAGGCTCTGGGCCGCAAAATAAACTCCTGGGAATCATCAAG GAGTGGGCATTCATTCCTGAGCAACTTGCACTTGAGGAATGGTGAACTGGTCATCCATGAAAAAGGGTTTTACTACATCTATTCCCAAACATACTTTCGATTTCAGGAGGAA ATAAAAGAAAACACAAAGAACGACAAACAAATGGTCCAATATATTTACAAATACACAAGTTATCCTGACCCTATATTGTTGATGAAAAGTGCTAGAAATAGTTGTTGGTCTA AAGATGCAGAAIATGGACTCTATTCCATCTATCAAGGGGGAATATTTGAGCTTAAGGAAAATGACAGAATTTTTGTTTCTGTAACAAATGAGCACTTGATAGACATGGACCA TGAAGCCAGTTTTTTCGGGGCCTTTTTAGTTGGCTAACTGACCTGGAAAGAAAAAGCAATAACCICAAAGTGACTATTCAGTTTTCAGGATGATACACTATGAAGATGTTTC AAAAAATCTGACCAAAACAAACAAACAGAAAACAGAAΛCAAAAAAACCTCTATGCAATCTGAGTAGAGCAGCCACAACCAAAAAATTCTACAACACACACTGTTCTGAAAG TGACTCACTTATCCCAAGAAAATGAAATTGCIGAAAGATCTTTCAGGACTCTACCTCATATCAGTTTGCTAGCAGAAATCTAGAAGACTGTCAGCTTCCAAACATTAATGCA ATGGTTAACATCTTCTGTCTTTATAATCTACTCCTTGTAAAGACTGTAGAAGAAAGCGCAACAATCCATCTCTCAAGTAGTGTATCACAGTAGTAGCCTCCAGGTTTCCTTA AGGGACAACATCCTTAAGTCAAAAGAGAGAAGAGGCACCACTAAAAGATCGCAGTTTGCCTGGTGCAGTGGCTCACACCTGTAATCCCAACATTTTGGGAACCCAAGGTGGG TAGATCACGAGATCAAGAGATCAAGACCATAGTGACCAACATAGTGAAACCCCATCTCTACTGAAAGTGCAAAAATTAGCTGGGTGTGTTGGCACATGCCTGTAGTCCCAGC TACTTGAGAGGCTGAGGCAGGAGAATCGTTTGAACCCGGGAGGCAGAGGTTGCAGTGTGGTGAGATCATGCCACTACACTCCAGCCTGGCGACAGAGCGAGACTTGGTTTCA AAAAAAAAAAAAAAAAAAAACTTCAGTAAGTACGTGTTATTTTTTTCAATAAAATTCTATTACAGTATGTCAAAAAAAAAAAAAAAAAA
501 ELGSCLEGGREAAEEEGEPEVKKRRLLCVRFASVAECDAAVAQCFLAENDWEMERALNSYFEPPVEESALERRPETISEPKTYVDLTNEETTDSTTSKISPSEDTQQENGS
MFSLIT NIDGLDLNNLSERARGVCSYLALYSPDVIFLQEVIPPYYSYLKKRSSNYEIITGHEEGYFTAIMLKKSRVKLKSQEIIPFPSTKMMRNLLCVHVNVSGNELCLMT
SHLEST GHAAERWQLK^rVLKKMQEAPESATVIFAGDTNL D EVTRCGGLP^πOVDVWEFLGKPKHC^
LGLEKLDCGRFPSDHWGLLCNLDIIL
502
GCAGAGGCGCAGGTAGATGGAGTTGGGGAGTTGCCTGGAGGGCGGGAGGGAGGCσσCGGAGGAAGAGGGCGAGCCTGAGGTGAAAAAGCGGCGACTTCTGTGTGTGAGGrTT
GCCTCGGTCGCAAGCTGCGATGCCGCAGTGGCTCAGTGCTTCCTGGCCGAGAACGACTGGGAGATGGAAAGGGCTCTGAACTCCTACTTCGAGCCTCCGGTGGAGGAGAGCG
CCTTGGAACGCCGACCTGAAACCATCTCTGAGCCCAAGACCTATGTTGACCTAACCAATGAAGAAACAACTGATTCCACCACTTCTAAAATCAGCCCATCTGAAGATACTCA
GCAAGAAAATGGCAGCATGTTCTCTCTCATTACCTGGAATATTGATGGATTAGATCTAAACAATCTGTCAGAGAGGGCTCGAGGGGTGTGTTCCTACTTAGCTTTGTACAGC
CCAGATGTGATATTTCTACAGGAAGTTATTCCCCCAIATTATAGCTACCTAAAGAAGAGATCAAGTAATTATGAGATTATTACAGGTCATGAAGAAGGATATTTCACAGCTA
TAATGTTGAAGAAATCAAGAGTGAAATTAAAAAGCCAAGAGATTATTCCTTTTCCAAGTACCAAAATGATGAGAAACCTTTTATGTGTGCATGTGAACGTGTCAGGAAATGA
GCTTTGCCTTATGACATCCCΔTTTGGAGAGCACCAGAGGGCATGCTGCGGAACGAATGAATCAGTTAAAAATGGTTTTAAAGAAAATGCAAGAGGCTCCAGAGTCAGCTACA
GTTATATTTGCAGGAGATACAAATCTAAGGGATCGAGAGGTTACCAGATGTGGTGGTTTACCCAACAACATTGTGGATGTCTGGGAGTTTTTGGGCAAACCTAAACATTGCC
AGTATACATGGGATACACAAATGAACTCTAATCTTGGAATAACTGCTGCTTGTAAACTTCGTTTTGATCGAATATTTTTCAGAGCAGCAGCAGAAGAGGGACACATTATTCC
CCGAAGTTTGGACCTTCTTGGATTAGAAAAACTGGACTGTGGTAGATTTCCTAGTGATCACTGGGGTCTTCTGTGCAACTTAGATATAATATTGTAAAATGCTTTTCAAGrG
TGGGTTTTGCCCTGATTGTTGCAAATACAATTTCCACCTTCTGGAAAGGTAGGTTTGCTGTGGAGGAAATAATGTACTAGATCATTGTCACAGAAAAACCAACTATGATTTA
TGGTTGTGTTTTCAGAATTCAACATTAAAGATTAATGTTTATTTAAACGAACACATTCCTGCATTCAGGATGTGAGGCCATTTAATAAAAAGGGCACAAAGCCTGTCAGAGT
TTTCAACGGTGCTTATAGCTGCCAGCTGGATTCCAAACAGGTACCCCATTGTCTCTGAGCTAATGTTTATATTTTTCCATTCAGGCACCGAAATAGTTAATATTTAAAATAA
GTCTTCAAAAGAAAACATAAGAGATTATTGAGTTCTTGGGACTGGATCCTTTATTTCATAAGTTCAGATCATCTTAAATGAAAATGCCATGATTATCTGCAGTTAAGTAGAT
GACAGCTATTCTACATCAGACTTGATTTTTGTCAGCTAATTACATAATTGGTAAGCTATAATTGAAACCTTATGGCTTAAAATTCCTTAACTCCTTTTTGATTCATGTTTGT
AGTCATGTTGTCAACAGAGGCAAAGTTAAGCTTGATGATGGTTAAAATCGGTTTGATAGCACCATGGGACATTTTTCTAACAAAAATAAATGCATGAAGAGACATAGCCTTT
TAGTTTTGCTAATTGTGAAATGGAAATGCTTTACAGGAAGTAAATGCAAATTACTTTTAAGTGTGCTTTAAAGAAAAATATTTTCCCCACAAGAGAAATTTAAATAAAGAAT
TTTATTTGTTTAAAA AAAAAAAAAAAAAAAA
503
MGCIKSKGKDSLSDDGVDLKTQPVRNTERTIYVRDPTSNKQQRPVPESQLLPGQRFQTKDPEEQGDIWALYPYDGIHPDDLSFKKGEKMKVLEEHGEWWKAKSLLTKKEGF IPSNYVAKLNTLETEEWFFKDITRKDAERQLLAPGNSAGAFLIRESΞTLKGSFSLSVRDFDPVHGDVIKHYKIRSLDNGGYYISPRITFPCISDMIKHYQKQADGLCRRLEK ACISPKPQKPVTOKDAWEIPRESIKLVKRLGAGQFGEVVmGYYNN8TKVAVKTLKPGTMSVQAFLEEANLMKTLQHDKLVRLYAVVTREEPIYI ITEYMAKG8LLDFLK8DEG GKVLLPKLIDFSAQIAEGMAYIERKNYIHRDLRAANVLVSESLMCKIADFGLARVIEDNEYTAREGAKFPIK TAPEAINFGCFTIK8DVWSFGILLYEIVTYGKIPYPGRT NADVMTALSQGYRMPRVENCPDELYDIMKMC KEKAEERPTFDYLQSVLDDFYTATEGQYQQQP
504
TCGGCCGAGCCCAGAGACAGCCAGTTCCTCTCCCGCCGCGCCGGGCCGCGTGCCGCTCGCTCCCCGGCCGTGGCGCCTCCGGGCCAGACGCGCTGCAGCCTCCAGCCCGCGG
CAAGCGGGCGGGGCGGCCGCGCCACCCCCGGCCCCGCGCCAGCAGCCCCTCGCCGCGCGTCCAGCGTTCCCGGCCAGCAGCCTCCCCATACGCAGTCCTGCTGGACCGCCCC
GTCGCGCCCCCCACrCTGAACTCAAGTCACCGTGGAGCTCCGCCGCCCCGAAACTTTCACGCGAGCGGGAAATATGGGATGTATAAA TCAAAAGGGAAAGACAGCTTGAGT
GACGATGGAGTAGATTTGAAGACTCAACCAGTACGTAA'IACTGAAAGAACTATTTATGTGAGAGATCCAACGTCCAATAAACAGCAAAGGCCAGTTCCAGAATCTCAGCTTr
TACCTGGACAGAGGTTTCAAACTAAAGATCCAGAGGAACAAGGAGACATTGTGGTAGCCTTGTACCCCTATGATGGCATCCACCCGGACGACTTGTCTTTCAAGAAAGGAGA
GAAGATGAAAGTCCTGGAGGAGCATGGAGAATGGTGGAAAGCAAAGTCCCTTTTAACAAAAAAAGAAGGCTTCATCCCCAGCAACTATGTGGCCAAACTCAACACCTTAGAA
ACAGAAGAGTGGTTTTTCAAGGATATAACCAGGAAGGACGCAGAAAGGCAGCTTTTGGCACCAGGAAATAGCGCTGGAGCTTTCCTTATTAGAGAAAGTGAAACATTAAAAG
GAAGCTTCTCTCTGTCTGTCAGAGACTTTGACCCTGTGCATGGTGATGTTATTAAGCACTACAAAATTAGAAGTCTGGATAATGGGGGCTATTACATCTCTCCACGAATCAC
TTTTCCCTGTATCAGCGACATGATTAAACATTACCAAAAGCAGGCAGATGGCTTGTGCAGAAGATTGGAGAAGGCTTGTATTAGTCCCAAGCCACAGAAGCCATGGGATAAA
GATGCCTGGGAGATCCCCCGGGAGTCCATCAAGTTGGTGAAAAGGCTTGGCGCTGGGCAGTTTGGGGAAGTCTGGATGGGTTACTATAACAACAGTACCAAGGTGGCTGTGA
AAACCCTGAAGCCAGGAACTATGTCTGTGCAAGCCT'rCCTGGAAGAAGCCAACCTCATGAAGACCCTGCAGCATGACAAGCTCGTGAGGCTCTACGCTGTGGTCACCAGGGA
GGAGCCCATTTACAaCATCACCGAGTACATGGCCAAGGGCAGTTTGCTGGATTTCCTGAAGAGCGATGAAGGTGGCAAAGTGCTGCTTCCAAAGCTCATTGACTTTTCTGCT
CAGATTGCAGAGGGAATGGCATACATCGAGCGGAAGAACTACATTCACCGGGACCTGCGAGCAGCTAATGTTCTGGTCTCCGAGTCACTAATGTGCAAAATTGCAGATTTTG
GCCTTGCTAGAGTAATTGAAGATAATGAGTACACAGCAAGGGAAGGTGCTAAGTTCCCTATTAAGTGGACGGCTCCAGAAGCAATCAACTTTGGATGTTTCACTATTAAGTC
TGATGTGTGGTCCTTTGGAATCCTCCTATACGAAATTGTCACCTATGGGAAAATTCCCTACCCAGGGAGAACTAATGCCGACGTGATGACCGCCCTGTCCCAGGGCTACAGG
ATGCCCCGTGTGGAGAACTGCCCAGATGAGCTCTATGACATTATGAAAATGTGCTGGAAAGAAAAGGCAGAAGAGAGACCAACGTTTGACTACTTACAGAGCGTCCTGGATG
ATTTCTACACAGCCACGGAAGGGCAATACCAGCAGCAGCCTTAGAGCACAGGGAGACCCGTCCATTTGGCAGGGGTGGCTGCCTCATTTAGAGAGGAAAAGTAACCATCACT
GGTTGCACTTATGATTTCATGTGCGGGGATCATCTGCCGTGCCTGGATCCTGAAATAGAGGCTAAATTACTCAGGAAGAACACCCTCTAAATGGGAAAGTATTCTGTACTCT
TAGATGGATTCTCCACTCAGTTGCAACTTGGACTTGTCCTCAGCAGCTGGTAATCTTGCTCTGCTTGACAACATCTGAGTGCAGCCGTTTGAGAAGAAAACATCTATTCTCT
CCAAAAATGCACCCAACTAGCTCTATGTTTACAAATGGACATAGGACTCAAAGTTTCAGAGACCATTGCAATGAATCCCCAATAATTGCAGAACTAAACTCATTTATAAAGC
TAAAATAACCGGATATATACATAGCATGACATTTCTTTGTGCTTTGGCTTACTTGTTT
505
MALKRIQKELSDLQRDPPAHCSAGPVGDDLFHWQATINGPPDSAYQGGVFFLTVHFPTDYPFKPPKIAFTTKIYHPNINSNGSICLDILRSQ 8PALTV8KVLLSICSLLCD
PNPDDPLVPDIAQIYK8DKEKYNRHAREWTQKYAM
506
ACACTCGCGCACACTCGGGCTCGGGCGCACACGGAGCAGGGACCGGCGCCCGGAGCGAGCCAGGGAGCGGCTAACCGGGGACCCACCGCGCGGAGCCAGCCTAGCTGCCAGC GAGCCCAACCCGCGACGACCCACGCCCCTGAGCCCCGCAGCCGACCCCTGCCGGCCGGTGTCCCCACCGCCATCCCTGACCCATGGCGCTGAAGAGGATTCAGAAAGAATTG AGTGATCTACAGCGCGATCCACCTGCTCACTGTTCAGCTGGACCTGTGGGAGATGACTTGTTCCACTGGCAAGCCACTATTATGGGGCCTCCTGATAGCGCATATCAAGGTG GAGTCTTCTTTCTCACTGTACATTTTCCGACAGATTATCCTTTTAAACCACCAAAGATTGCTTTCACAACAAAAATTTACCATCCAAACATAAACAGTAATGGAAGTATTTG TCTCGATATTCTGAGGTCACAATGGTCACCAGCTCTGACTGTATCAAAAGTTTTATTGTCCATATGTTCTCTACTTTGTGATCCTAATCCAGATGACCCCTTAGTACCAGAT ATTGCACAAATCTATAAATCAGACAAAGAAAAATACAACAGACATGCAAGAGAATGGACTCAGAAATATGCAATGTAAAAATCAAAAACATTTTCATATATACCAGAGTACT GTAAAATCTAGGTTTTTTTCAACATTAGCAGTAAATTGAGCACTGTTTACTGTTTCATTGTACCATGAAACCATTTGATTTTTACCCATTTTAAATGTGTTTCTGAAGCAAG ACAAAACAAACTTCCAAAAATACCCTTAAGACTGTGATGAGAGCATTTATCATTTTGTATGCATTGAGAAAGACATTTATTATGGTTTTTAAGATACTTGGACATCTGCATC TTCAGCTTACAAGATCTACAATGCAGCTGAAAAGCAACCAAATTATTTTTTGCTGAAACTAGATGTTTTTACATGAGAAATACTGTATGTGTTGTCTAAGATGTCAGTTTTA TAAATCTGTATTCAGATTTCATTCTTTGTTAGCTCACTTTATAATTTGTATTTTTTTACTGTATAGACTAAATATATTCTATTTACATGTATGTCAACTCATTACTTTTTTC CTGTGAACAGTATTGAAAAACCCCAACGGCTGATAATTAAGTGAATTAACTGTGTCTCCCTTGTCTTAGGATATTCTGTAGATTGATTGCAGATTTCTTAAATCTGAAATGA TCTTTACACTGTAATTCTCAGCATACTGATTATGGAGAAACACTTGTTTTGATTTTGTTATACTTGACTTAACTTTATTGCAATGTGAATTAATTGCACTGCTAAGTAGGAA GATGTGTAACTTTTATTTGTTGCTATTCACATTTGAATT'ITTTCCTGTATAGGCAATATTATATTGACACCTTTTACAGATCTTACTGTAGCTTTTTCCATATAAATAAAAT GCTTTTTCGGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
507
MG DLTVKMLAGNEFQVSLSSSMSVSELKAQITQNIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLIQTVAHLKQQVS GLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGGGTEPGGRS
508
CGGCTGAGAGGCAGCGAACTCATCTTTGCCAGTACAGGAGCTTGTGCCGTGGCCCACAGCCCACAGCCCACAGCCATGGGCTGGGACCTGACGGTGAAGATGCTGGCGGGCA
ACGAATTCCAGGTGTCCCTGAGCAGCTCCATGTCGGTGTCAGAGCTGAAGGCGCAGATCACCCAGAAGATTGGCGTGCACGCCTTCCAGCAGCGTCTGGCTGTCCACCCGAG
CGGTGTGGCGCTGCAGGACAGGGTCCCCCTTGCCAGCCAGGGCCTGGGCCCTGGCAGCACGGTCCTGCTGGTGGTGGACAAATGCGACGAACCTCTGAGCATCCTGGTGAGG
AATAACAAGGGCCGCAGCAGCACCTACGAGGTCCGGCTGACGCAGACCGTGGCCCACCTGAAGCAGCAAGTGAGCGGGCTGGAGGGTGTGCAGGACGACCTGTTCTGGCTGA
CCTTCGAGGGGAAGCCCCTGGAGGACCAGCTCCCGCTGGGGGAGTACGGCCTCAAGCCCCTGAGCACCGTGTTCATGAATCTGCGCCTGCGGGGAGGCGGCACAGAGCCTGG
CGGGCGGAGCTAAGGGCCTCCACCAGCATCCGAGCAGGATCAAGGGCCGGAAATAAAGGCTGTTGTAAGAGAAT
509 EAE L MAGAAG QGDEDL G MPEAPLDELVG YPrYNEEEEE RYYRRKR GVLKrVL ASAGGML YGVY GLLQMQLILHYDETYREVKYGN^lGLPDIDSK L
MGi ^TPIAALLYTPVLIRFFGTK MMFLAVGIYALFVSTNYWERYYTLVPSAVALGMAIVPL ASMGNYITRMAQKYHEYSHYKEQDGQGMKQRPPRGSHAPYLLVFQAIF
YSFFHLSFACAQLPMIYFLNHYLYDLNHTLYNVQSCGTN8HGIL8GFNKTVLRTLPRSGNLIWESVLMAVAFLAMLLVLGLCGAAYRPTEEIDLRSVG GNIFQLPFKHVR
DYRLRHLVPFFIYSGFEVLFACTGIALGYGVCSVGLERLAYLLVAYSLGASAASLLGLLGL LPRPVPLVAGAGVHLLLTFILFF APVPRVLQHSWILYVAAALWGVGSAL
NKTGLSTLLGILYEDKERQDFIFTIYHWWQAVAIFTVYLGSSLHMKAKLAVLLVTLVAAAVSYLRIEQKLRRGVAPRQPRIPRPQHKVRGYRYLEEDNSDESDAEGEHGDGA
EEEAPPAGPRPGPEPAGLGRRPCPYEQAQGGDGPEEQ
510
GACTCCGGGGCGACCGCCGCGAGTCCGCAGTAGTTCGGGCCATGGAGGCGGAGCCGCCGCTCTACCCGATGGCGGGGGCTGCGGGGCCGCAGGGCGACGAGGACCTGCTCGG GGTCCCGGACGGGCCCGAGGCCCCGCTGGACGAGCTGGTGGGCGCGTACCCCAACTACAACGAGGAGGAGGAGGAGCGCCGCTACTACCGCCGCAAGCGCCTGGGCGTGCTC AAGAACGTGCTGGCTGCCAGCGCCGGGGGCATGCTCACCTACGGCGTCTACCTGGGCCTCCTGCAGATGCAGCTGATCCTGCACTACGACGAGACCTACCGCGAGGTGAAGT ATGGCAACATGGGGCTGCCCGACATCGACAGCAAAATGCTGATGGGCATCAACGTGACTCCCATCGCCGCCCTGCTCTACACACCTGTGCTCATCAGGTTTTTTGGAACGAA GTGGATGATGTTCCTCGCTGTGGGCATCTACGCCCTCTTTGTCTCCACCAACTACTGGGAGCGCTACTACACGCTTGTGCCCTCGGCTGTGGCCCTGGGCATGGCCATCGTG CCTCTTTGGGCTTCCATGGGCAACTACATCACCAGGATGGCGCAGAAGTACCATGAGTACTCCCACTACAAGGAGCAGGATGGGCAGGGGATGAAGCAGCGGCCTCCGCGGG GCTCCCACGCGCCCTATCTCCTGGTCTTCCAAGCCATCTTCTACAGCTTCTTCCATCTGAGCTTCGCCTGCGCCCAGCTGCCCATGATTTATTTCCTGAACCACTACCTGTA TGACCTGAACCACACGCTGTACAATGTGCAGAGCTGCGGCACCAACAGCCACGGGATCCTCAGCGGCTTCAACAAGACGGTTCTGCGGACGCTCCCGCGGAGCGGAAACCTC ATTGTGGTGGAGAGCGTGCTCATGGCAGTGGCCTTCCTGGCCATGCTGCTGGTGCTGGGTTTGTGCGGAGCCGCTTACCGGCCCACGGAGGAGATCGATCTGCGCAGCGTGG GCTGGGGCAACATCTTCCAGCTGCCCTTCAAGCACGTGCGTGACTACCGCCTGCGCCACCTCGTGCCTTTCTTTATCTACAGCGGCTTCGAGGTGCTCTTTGCCTGCACTGG TATCGCCTTGGGCTATGGCGTGTGCTCGGTGGGGCTGGAGCGGCTGGCTTACCTCCTCGTGGCTTACAGCCTGGGCGCCTCAGCCGCCTCACTCCTGGGCCTGCTGGGCCTG TGGCTGCCACGCCCGGTGCCCCTGGTGGCCGGAGCAGGGGTGCACCTGCTGCTCACCTTCATCCTCTTTTTCTGGGCCCCTGTGCCTCGGGTCCTGCAACACAGCTGGATCC TCTATGTGGCAGCTGCCCTTTGGGGTGTGGGCAGTGCCCTGAACAAGACTGGACTCAGCACACTCCTGGGAATCTTGTACGAAGACAAGGAGAGACAGGACTTCATCTTCAC CATCTACCACTGGTGGCAGGCTGTGGCCATCTTCACCGTGTΔCCTGGGCTCGAGCCTGCACΔTGAAGGCTAAGCTGGCGGTGCTGCTGGTGACGCTGGTGGCGGCCGCGGTC TCCTACCTGCGGATTGAGCAGAAGCTGCGGCGGGGCGTGGCCCCGCGCCAGCCCCGCATCCCGCGGCCCCAGCACAAGGTGCGCGGTTACCGCTACTTGGAGGAGGACAACT CGGACGAGAGCGACGCGGAGGGCGAGCATGGGGACGGCGCGGAGGAGGAGGCGCCGCCCGCAGGGCCCAGGCCTGGCCCCGAGCCCGCTGGACTCGGCCGCCGGCCCTGCCC GTACGAACAGGCGCAGGGGGGAGACGGGCCGGAGGAGCAGTGAGGGGCCGCCTGGTCCCCGGACTCAGCCTCCCTCCTCGCCGGCCTCAGTTTACCACGTCTGAGGTCGGGG GGACCCCCTCCGAGTCCCGCGCTGTCTTCAAAGGCCCCTGTCTCCCCTCCCCGACGTTGGGGACGCCCCTCCCAGAGCCCAGGTCACCTCCGGGCTTCCGCAGCCCCCTCCA AGGCGGAGTGGAGCCTTGGGAACCCCTCGGCCAAGCACAGGGGTTCGAAAATACAGCTGAAACCCCGCGGGCCCTTAGCACGCGCCCCAGCGCCGGAGCACGGTCAGGGTCT TCTTGCGACCCGGCCCGCTCCAGATCCCCACAGCTTTCGGCCGCGGACCCGGGCCGCGTGTGAGCGCACTTTGCACCTCCTATCCCCAGGGTCCGCCGAGAGCCACGATTTT TTACAGAAAATGAGCAATAAAGAGATTTTGTACTGTCAAAAA
511
MAGIELERCQQQANEVTEIMRNNFGKVLERGVKLAELQQRSDQLLDMΞSTFNKTTQNLAQKKC ENIRYRICVGLVWGVLLIILIVLLWFLPQSSDSSSAPRTQDAGIAS
GPGN
512
GCGGCCGCTCCGCAGGCAGAGAAGCCGGGAGCGTTTGAGGCGGCGGCGGCACGAGCGATGGCAGGAATAGAGTTGGAGCGGTGCCAGCAGCAGGCGAACGAGGTGACGGAAA
TTATGCGTAACAACTTCGGςAAGGTCCTGGAGCGTGGTGTGAAGCTGGCCGAACTGCAGCAGCGTTCAGACCAACTCCTGGATATGAGCTCAACCTTCAACAAGACTACACA
GAACCTGGCCCAGAAGAAGTGCTGGGAGAACATCCGTTACCGGATCTGCGTGGGGCTGGTGGTGGTTGGTGTCCTGCTCATCATCCTGATTGTGCTGCTGGTCGTCTTTCTC
CCTCAGAGCAGTGACAGCAGTAGTGCCCCACGGACCCAGGATGCAGGCATTGCCTCAGGGCCTGGGAACTGACCCAGCTGGTCCTGAAGGAGAAGCCCAATGGCTGCACTGG
CCGATTCTGGTCTCCAAGGACCTTGGTGTTTGCTCTCCCTGACCCAGCCCAGTGAGTGCCAAAGGGCAGCCCCAACATGTGCACCCCTGCATTCCCGTCATGCACAGACTTG
CCCTTGAGCAGGCCGCTGTACTGGCCAGCTGGGCAACCCCCCTGGAGCTCATAAAAAT
513
MFNSMTPPPISSYGEPCCLRPLPSQGAPSVGTEGLSGPPFCHQANLMSGPHSYGPARETNSCTEGPLFSSPRSAVKLTKKRALSISPLSDASLDLQTVIRTSPSSLVAFINS
RCTSPGGSYGHLSIGTMSPSLGFPAQMNHQKGPSPSFGVQPCGPHDSARGGMIPHPQSRGPFPTCQLKSELDMLVGKCREEPLEGDMSSPNSTGIQDPLLGMLDGREDLERE
EKREPESVYETDCRWDGCSQEFDSQEQLVHHINSEHIHGERKEFVCHWGGCSRELRPFKAQYMLWHMRRHTGEKPHKCTFEGCRKSYSRLENLKTHLRSHTGEKPYMCEHE
GCSKAFSNASDRAKHQNRTHSNEKPYVCKLPGCTKRYTDPSSLRKHVKTVHGPDAHVTKRHRGDGPLPRAPSISTVEPKREREGGPIREESRLTVPEGAMKPQPSPGAQS8C
8SDHSPAGSAANTDSGVEMTGNAGGSTEDLSSLDEGPCIAGTGLSTLRRLENLRLDQLHQLRPIGTRGLKLPSLSHTGTTVSRRVGPPVSLERRSSSSSSISSAYTVSRRSS
LASPFPPGSPPENGASSLPGLMPAQHYLLRARYASARGGGTSPTAASSLDRIGGLPMPP R8RAEYPGYNPNAGVTRRASDPAQAADRPAPARVQRFKSLGCVHTPPTVAGG
GQNFDPYLPTSVYSPQPPSITENAAMDARGLQEEPEVGTSMVGSGLNPYMDFPPTDTLGYGGPEGAAAEPYGARGPGSLPLGPGPPTNYGPNPCPQQASYPDPTQETWGEFP
SHSGLYPGPKALGGTYSQCPRLEHYGQVQVKPEQGCPVGSDSTGLAPCLNAHPSEGPPHPQPLFSHYPQPSPPQYLQSGPYTQPPPDYLPSEPRPCLDFDSPTHSTGQLKAQ
LVCNYVQSQQELLWEGGGREDAPAQEPSYQSPKFLGGSQV8PSRAKAPVNTYGPGFGPNLPNHKSGSYPTPSPCHENFWGANRASHRAAAPPRLLPPLPTCYGPLKVGGTN
PSCGHPEVGRLGGGPALYPPPEGQVCNPLDSLDLDNTQLDFVAILDEPQGLSPPPSHDQRGSSGHTPPPSGPPNMAVGN SVLLRSLPGETEFLNSSA
514
CCCAGACTCCAGCCCTGGACCGCGCATCCCGAGCCCAGCGCCCAGACAGAGTGTCCCCACACCCTCCTCTGAGACGCCATGTTCAACTCGATGACCCCACCACCAATCAGTA
GCTATGGCGAGCCCTGCTGTCTCCGGCCCCTCCCCAGTCAGGGGGCCCCCAGTGTGGGGACAGAAGGACTGTCTGGCCCGCCCTTCTGCCACCAAGCTAACCTCATGTCCGG
CCCCCACAGTTATGGGCCAGCCAGAGAGACCAACAGCTGCACCGAGGGCCCACTCTTTTCTTCTCCCCGGAGTGCAGTCAAGTTGACCAAGAAGCGGGCACTGTCCATCTCA
CCTCTGTCGGATGCCAGCCTGGACCTGCAGACGGTTATCCGCACCTCACCCAGCTCCCTCGTAGCTTTCATCAACTCGCGATGCACATCTCCAGGAGGCTCCTACGGTCATC
TCTCCATTGGCACCATGAGCCCATCTCTGGGATTCCCAGCCCAGATGAATCACCAAAAAGGGCCCTCGCCTTCCTTTGGGGTCCAGCCTTGTGGTCCCCATGACTCTGCCCG
GGGTGGGATGATCCCACATCCTCAGTCCCGGGGACCCTTCCCAACTTGCCAGCTGAAGTCTGAGCTGGACATGCTGGTTGGCAAGTGCCGGGAGGAACCCTTGGAAGGTGAT
A GTCCAGCCCCAACTCCACAGGCATACAGGATCCCCTGTTGGGGATGCTGGATGGGCGGGAGGACCTCGAGAGAGAGGAGAAGCGTGAGCCTGAATCTGTGTATGAAACTG
ACTGCCGTTGGGATGGCTGCAGCCAGGAATTTGACTCCCAAGAGCAGCTGGTGCACCACATCAACAGCGAGCACATCCACGGGGAGCGGAAGGAGTTCGTGTGCCACTGGGG
GGGCTGCTCCAGGGAGCTGAGGCCCTTCAAAGCCCAGTACATGCTGGTGGTTCACATGCGCAGACACACTGGCGAGAAGCCACACAAGTGCACGTTTGAAGGGTGCCGGAAG
TCATACTCACGCCTCGAAAACCTGAAGACGCACCTGα3GTCACACACGGGTGAGAAGCCATACATGTGTGAGCACGAGGGCTGCAGTAAAGCCTTCAGCAATGCCAGTGACC GAGCCAAGCACCAGAATCGGACCCATTCCAATGAGAAGCCGTATGTATGTAAGCTCCCTGGCTGCACCAAACGCTATACAGATCCTAGCTCGCTGCGAAAACATGTCAAGAC AGTGCATGGTCCTGACGCCCATGTGACCAAACGGCACCGTGGGGATGGCCCCCTGCCTCGGGCACCATCCATTTCTACAGTGGAGCCCAAGAGGGAGCGGGAAGGAGGTCCC ATCAGGGAGGAAAGCAGACRGACTGTGCCAGAGGGTGCCATGAAGCCACAGCCAAGCCCTGGGGCCCAGTCATCCTGCAGCAGTGACCACTCCCCGGCAGGGAGTGCAGCCA ATACAGACAGTGGTGTGGAAATGACTGGCAATGCAGGGGGCAGCACTGAAGACCTCTCCAGCTTGGACGAGGGACCTTGCATTGCTGGCACTGGTCTGTCCACTCTTCGCCG CCTTGAGAACCTCAGGCTGGACCAGCTACATCAACTCCGGCCAATAGGGACCCGGGGTCTCAAACTGCCCAGCTTGTCCCACACCGGTACCACIGTGTCCCGCCGCGTGGGC CCCCCAGTCTCTCTTGAACGCCGCAGCAGCAGCTCCAGCAGCATCAGCTCTGCCTATACTGTCAGCCGCCGCTCCTCCCTGGCCTCTCCTTTCCCCCCTGGCTCCCCACCAG AGAATGGAGCATCCTCCCTGCCTGGCCTTATGCCTGCCCAGCACTACCTGCTTCGGGCAAGATATGCTTCAGCCAGAGGGGGTGGTACTTCGCCCACTGCAGCATCCAGCCT GGATCGGATAGGTGGTCTΓCCCATGCCTCCTTGGAGAAGCCGAGCCGAGTATCCAGGATACAACCCCAATGCAGGGGTCACCCGGAGGGCCAGTGACCCAGCCCAGGCTGCT GACCGTCCTGCTCCAGCTAGAGTCCAGAGGTTCAAGAGCCTGGGCTGTGTCCATACCCCACCCACTGTGGCAGGGGGAGGACAGAACTTTGATCCTTACCTCCCAACCTCTG TCTACTCACCACAGCCCCCCAGCATCACTGAGAATGCTGCCATGGATGCTAGAGGGCTACAGGAAGAGCCAGAAGTTGGGACCTCCATGGTGGGCAGTGGTCTGAACCCCTA TATGGACTTCCCACCTACTGATACTCTGGGATATGGGGGACCTGAAGGGGCAGCAGCTGAGCCTTATGGAGCGAGGGGTCCAGGCTCTCTGCCTCTTGGGCCTGGTCCACCC ACCAACTATGGCCCCAACCCCTGTCCCCAGCAGGCCTCATATCCTGACCCCACCCAAGAAACATGGGGTGAGTTCCCTTCCCACTCTGGGCTGTACCCAGGCCCCAAGGCTC TAGGTGGAACCTACAGCCAGTGTCCTCGACTTGAACATTATGGACAAGTGCAAGTCAAGCCAGAACAGGGGTGCCCAGTGGGGTCTGACTCCACAGGACTGGCACCCTGCCT CAATGCCCACCCCAGTGAGGGGCCCCCACATCCACAGCCTCTCTTTTCCCATTACCCCCAGCCCTCTCCTCCCCAATATCTCCAGTCAGGCCCCTATACCCAGCCACCCCCT GATTATCTTCCTTCAGAACCCAGGCCTTGCCTGGACTTTGATTCCCCCACCCATTCCACAGGGCAGCTCAAGGCTCAGCTTGTGTGTAATTATGTTCAATCTCAACAGGAGC TACTGTGGGAGGGTGGGGGCAGGGAAGATGCCCCCGCCCAGGAACCTTCCTACCAGAGTCCCAAGTTTCTGGGGGGTTCCCAGGTTAGCCCAAGCCGTGCTAAAGCTCCAGT GAACACATATGGACCTGGCTTTGGACCCAACTTGCCCAATCACAAGTCAGGTTCCTATCCCACCCCTTCACCATGCCATGAAAATTTTGTAGTGGGGGCAAATAGGGCTTCA CATAGGGCAGCAGCACCACCTCGACTTCTGCCCCCATTGCCCACTTGCTATGGGCCTCTCAAAGTGGGAGGCACAAACCCCAGCTGTGGTCATCCTGAGGTGGACAGGCTAG GAGGGGGTCCTGCCTTGTACCCTCCTCCCGAAGGACAGGTATGTAACCCCCTGGACTCTCTTGATCTTGACAACACTCAGCTGGACTTTGTGGCTATTCTGGATGAGCCCCA GGGGCTGAGTCCTCCTCCTTCCCATGATCAGCGGGGCAGCTCTGGACATACCCCACCTCCCTCTGGGCCCCCCAACATGGCTGTGGGCAACATGAGTGTCTTACTGAGATCC CRACCTGGGGAAACAGAATTCCTCAACTCTAGTGCCTAAAGAGTAGGGAATCTCATCCATCACAGATCGCATTTCCTAAGGGGTTTCTATCCTTCCAGAAAAATTGGGGGAG CTGCAGTCCCCTGCACAAGATGCCCCAGGGATGGGAGGTATGGGCTGGGGGCTATGTATAGTCTGTATACGTTTTGAGGAGAAATTTGATAATGACACTGTTTCCTGATAAT AAAGGAACTGCATCAG
515
KGEIEDYRLLTDILGIEDYNGDMDFKIAGTNKGITAIRF3ADIKLPGIPIKIVMEAIQQASVAKKEILQIMNKTISKPRASRKENGPVVETVQVPLSKRAKFVGPGGYNLKKLQ AEΓGVTISQVDEETFSVFAPTPSAMHEARDFITEICKDDQEQQLEFGAVYTATITEIRDTGVMVKLYPNMTAVLLHNTQLDQRKIKHPTALGLEVGQEIQVKYFGRDPADGR MRLSRKVLQSPATTWRTLNDRSSIVMGEPISQSSSNSQ
516
AAGGGTGAAATAGAAGATTATCGTTTGCTGACAGATATTTTGGGAATTGAAGATTACAATGGTGACATGGACTTCAAAATAGCTGGCACTAATAAAGGAATAACTGCATTAC AGGCTGATATTAAATTACCCGGAATACCAATAAAAATTGTGATGGAGGCTATTCAACAAGCTTCAGTGGCAAAAAAGGAGATATTACAGATCATGAACAAAACTATTTCAAA ACCTCGAGCATCTAGAAAAGAAAATGGACCTGTTGTAGAAACTGTTCAGGTTCCATTATCAAAACGAGCAAAATTTGTTGGACCTGGTGGCTATAACTTAAAAAAACTTCAG GCTGAAACAGGTGTAACTATTAGTCAGGTGGATGAAGAAACGTTTTCTGTATTTGCACCAACACCCAGTGCTATGCATGAGGCAAGAGACTTCATTACTGAAATCTGCAAGG ATGATCAGGAGCAGCAATTAGAATTTGGAGCAGTATATACCGCCACAATAACTGAAATCAGAGATACTGGTGTAATGGTAAAATTATATCCAAATATGACTGCGGTACTGCT TCATAACACACAACTTGATCAACGAAAGATTAAACATCCTACTGCCCTAGGATTAGAAGTTGGCCAAGAAATTCAGGTGAAATACTTTGGACGTGACCCAGCCGATGGAAGA ATGAGGCTTTCTCGAAAAGTGCTTCAGTCGCCAGCTACAACCGTGGTCAGAACTTTGAATGACAGAAGTAGTATTGTAATGGGAGAACCTATTTCACAGTCATCATCTAATT
TAAATACATTTTAATTATTTGTACTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
517 r^QTSNYSLVLSLQFLLLSYDLFVNSFSELLQKTPVIQLVLFIIQDIAVLFNIIIIFLMFFNTFVFQAGLVNLLFHKFKGTIILTAVYFALSIELHVWVM LRWKNSNSFIW
TDGLQMLFVFQRLAAVLYCYFYKRTAVRLGDPHFYQDSL LRKEFMQVRR
518
ACGATGTCGCATTGACAACCGACGTTGGAGTTTGGAGGTGCTTGCCTTAGAGCAAGGGAAACAGCTCTCATTCAAAGGAACTAGAAGCCTCTCCCTCAGTGGTAGGGAGACA
GCCAGGAGCGGTTTTCTGGGAACTGTGGGATGTGCCCTTGGGGGCCCGAGAAAACAGAAGGAAGATGCTCCAGACCAGTAACTACAGCCTGGTGCTCTCTCTGCAGTTCCTG
CTGCTGTCCTATGACCTCTTTGTCAATTCCTTCTCAGAACTGCTCCAAAAGACTCCTGTCATCCAGCTTGTGCTCTTCATCATCCAGGATATTGCAGTCCTCTTCAACATCA
TCATCATTTTCCTCATGTTCTTCAACACCTTCGTCTTCCAGGCTGGCCTGGTCAACCTCCTATTCCATAAGTTCAAAGGGACCATCATCCTGACAGCTGTGTACTTTGCCCT
CAGCATCTCCCTTCATGTCTGGGTCATGAACTTACGCTGGAAAAACTCCAACAGCTTCATATGGACAGATGGACTICAAATGCTGTTTGTATTCCAGAGACTAGCAGCAGTG
TTGTACTGCTACTTCTATAAACGGACAGCCGTAAGACTAGGCGATCCTCACTTCIACCAGGACTCTTTGTGGCTGCGCAAGGAGTTCATGCAAGTTCGAAGGTGACCTCTTG
TCACACTGATGGATACTTTTCCTTCCTGATAGAAGCCACATTTGCTGCTTTGCAGGGAGAGTTGGCCCTATGCATGGGCAAACAGCTGGACTTTCCAAGGAAGGTTCAGACT
AGCTGTGTTCAGCATTCAAGAAGGAAGATCCTCCCTCTTGCACAATTAGAGTGTCCCCATCGGTCTCCAGTGCGGCATCCCTTCCTTGCCTTCTACCTCTGTTCCACCCCCT
TTCCTTCCTTTCC CTCTGTACCATTCATTCTCCCTGACCGGCCTTTCTTGCCGAGGGTTCTGTGGCTCTTACCCTTGTGAAGCTTTTCCTTTAGCCTGGGACAGAAGGACC
TCCCAGCCCCCAAAGGATCTCCCAGTGACCAAAGGATGCGAAGAGXGATAGTTACGTGCTCCTGACTGATCACACCGCAGACATTTAGATTTTTATACCCAAGGCACTTTAA
AAAAATGTTTTATAAATAGAGAATAAATTGAATTCTTGTTCCTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
519
RGRGPEAAAQEEAEEVGRSGPGRRAAQRRSFGIjAMLLASAVVVWEWLNEHGR RPYSPAVSHHIEAVVRAGPRAGGEVVLGQVDSRLAPYI IDLQSMNQFRQDTGTLRPVRR NYYDPSSAPGKGW E ENDNGSWTPYDMEVGITIQHAYEKQHPWIDLTεiGFSYVIDFNTMGQINRQTQRQRRVRRRLDLIYPMVTGTLPKAQS PVSPGPATSPPMSPCS CPQCVLVMSVKAAVVNGSTGPLQLPVTRKNMPPPGVVKLPPLPGSGAKPLDSTGTIRGPLKTAPSQVIRRQASSMPTGTTMGSPASPPGPNSKTGRVALATLNRTNLQRLAI AQSRVLIASGVPTVPVKNLNGSSPVNPALAGITGILMSAAGLPVCLTRPPKLVLHPPPVSKSEIKS I PGVSNTSRK'ITKKQAKKGKTPEEVLKKYLQKVRHPPDEDCTICME RLTAPSGYKGPQPTVKPDLVGKLSRCGHVYHIYCLVAMYNNGNKDGSLQCPTCKTIYGVKTGTQPPGKMEYHLIPHSLPGHPDCKTIRI IYSIPPGICGPEHPNPGK8F8AR GFPRHCYLPDSEKGRKVLKLLLVAWDRRLIFAIGISSTTGESDTVIWNEVHHKTEFGSNLTGHGYPDANYLDNVLAELAAQGISEDSTAQEKD
520
GGCGCGGTCGAGGCCCGGAGGCGGCGGCGCAGGAGGAAGCGGAGGAGGTCGGGCGCTCGGGGCCCGGGAGGCGGGCCGCGCAGCGCCGCAGCCCCGGGCTCGCCATGCTCCT
GGCCTCGGCCGTGGTGGTCTGGGAATGGCTGAACGAGCACGGCCGCTGGCGTCCCTACAGCCCAGCGGTGAGCCACCACATCGAGGCGGTGGTCCGCGCCGGCCCCCGCGCG
GGGGGCAGCGTGGTGCTGGGCCAGGTGGACAGCCGTCTCGCGCCCTACATCATCGACCTGCAGTCCATGAACCAGTTCCGCCAAGACACGGGAACTCTCCGCCCAGTTCGCC
GCAACTACTACGACCCCTCCTCGGCCCCTGGGAAGGGCGTGGTGTGGGAGTGGGAGAACGACAATGGCTCCTGGACGCCCTACGACATGGAAGTGGGCATCACCATCCAGCA
TGCCTATGAGAAGCAGCACCCCTGGATCGACCTCACTTCCATTGGCTTTAGCTACGTAATTGACTTCAACACCATGGGCCAGATCAACCGTCAGACCCAGCGCCAACGCCGC
GTCCGCCGGCGCCTCGACCTCATCTACCCCATGGTCACAGGGACCTTGCCTAAGGCTCAGTCCTGGCCAGTCAGCCCTGGGCCAGCCACCTCGCCCCCCATGTCCCCCTGCT
CCTGTCCCCAGTGTGTCTTGGTGATGAGTGTTAAGGCAGCCGTGGTCAATGGCAGCACTGGGCCCCTACAGCTGCCAGTGACCCGCAAGAACATGCCGCCTCCTGGAGTGGT
CAAGCTACCCCCACTGCCAGGCTCTGGGGCCAAGCCACTGGACAGCACAGGCACCATTCGAGGCCCACTGAAGACCGCCCCATCGCAGGTGATCCGGAGACAAGCCTCCAGC
ATGCCCACTGGGACAACCATGGGCTCTCCTGCCAGTCCCCCAGGACCCAACAGCAAGACCGGAAGGGTGGCCCTGGCCACCTTGAATCGTACCAACCTGCAGCGACTGGCCA
TTGCCCAGTCCCGGGTGCT3ATCGCCTCTGGGGTCCCCACAGTCCCAGTGAAGAACCTAAATGGGTCCAGTCCTGTCAACCCTGCCTTGGCAGGAATCACTGGGATCCTCAT
GAGTGCAGCGGGGCTGCCTGTGTGTCTCACCAGGCCACCAAAGCTGGTCCTACACCCACCCCCCGTCAGCAAGAGTGAAATAAAATCCATCCCAGGGGTTTCCAACACAAGC
CX3CAAGACCACCAAAAAACAAGCCAAGAAAGGTAAAACCCCAGAGGAAGTGCTAAAAAAATATCTACAGAAAGTCCGGCACCCACCAGATGAGGACTGCACCATCTGTATGG
AACGCCTCACGGCCCCCTCAGGCTACAAGGGCCCGCAGCCTACGGTAAAACCTGACCTGGTAGGGAAGCTGTCCAGATGCGGCCACGTCTACCACATCTACTGCTTGGTTGC
CATGTACAACAATGGGAACAAGGATGGAAGTTTGCAGTGTCCAACCTGCAAGACCATTTATGGGGTGAAGACAGGCACCCAACCTCCAGGGAAGATGGAGTACCACCTCATC
CCCCACTCCTTGCCTGGCCACCCAGACTGCAAAACCATCCGGATCATCTACAGCATCCCCCCCGGCATTCAGGGACCGGAACACCCGAATCCTGGGAAGAGTTTCAGCGCCC
GAGGCTTCCCACGACACTGTTACCTTCCGGACAGCGAGAAAGGGAGAAAAGTTCTGAAGCTGCTGCTCGTGGCCTGGGATCGCCGCCTCATTTTTGCCATTGGCACCTCCAG
CACCACAGGCGAGTCAGACACCGTCATCTGGAATGAGGTCCACCACAAGACAGAGTTTGGCTCTAATCTCACTGGCCATGGCTACCCAGATGCCAATTACCTGGATAATGTG
CIGGCTGAACTGGCTGCCCAGGGCATCTC GAGGACAGCACTGCCCAGGAGAAGGACTGAGGCCAGAAAAGCTTTGAGGTGGGAGGGGCCATGGAGACTGCAGGACAG^
TGAGGAGAGTGAGTCAATGTAGAAGAAGTTGGTGTCCTGCCCTCCCAACTTTCTATCCTCCCCTCCTGCCCTGTGTCCATCCCTCATCCCTCCCAACCACAGTGGGAGCCAG ACΓGAATATAGCGACATCATTCATAAATCTCATCCAACACAAAGGGAGATGGGATGAGGGCCATCCTGGGTCTGTTCCCATGGAGTTTTTGGTGCTGGGIAGGCAGGAATCC CCΓCCCTACCCCACCTCCCAAGTAGGGGCATGGTCAGCACACCTAGGGTATGGGCAGTGCTTAGGCACTCCATATCCTGGCTTTGGGAAGCCGGGG'ITTCTTGCCTCAGCCG GCΓTCTTGCTACTTCCACTCTGCTTTGAGACTGGAGTTTCTGCTATTCTCCCTCTGCTGGAGGCAGGGAGCTCTCACTGTGCAAGGTTGGGGGGTGGGCAAAGGGGTGAATC ACΓAAACTGCTGTGACATCAGAAACTGATGCCTTGGTGTAGAGCAAGGAAGCACTTCTTCCCAAGAGGGTCGGAGAAGGAAAAGCCTCTGGGAGCACATTCTGCTGTCATCA CAGTCCTTGGCTTCTCTGGGCCCTCCTCTCCTCCTCACAGCTCTCACCTGTCCAAAGAGGCATCTGGTTCTCTCATGTGGATGGATGGACTCTGGGGTTCCTCTTTGGAGTG GCATCCCATGATGCTGTTTCTAGACCCTCTCTGATCAAACCAGAGCCTGCATCCCACTGAGCATCTGAACTGTCCTCAGGGAGAGGAGCCCACAGCCTTCTTCCCAACTCAT TCΓAGACCAGCTCAAAGATTCCATGAGTTTCATCGAGTCACTGTGAGTGGAGCCCATGCTGGGCTCTGTGCCCTCTGTGTCTGTGCATGCGCGTGTGTGTGTGGGCGTGTGT GCATTGCTGGGCCAGCTTGAAGGGAAGGCCCGTCATGTCCCTGCACTCTGTTTTGCAAGATGCCAAACCCCAGTTCTGATGGGGCTCCAACAGCCAGGCTGTGGTCCTTTGA CGRTCCTCACCTGTTGCCAACCTATCCCGTAGTGAACTGAAACCCCAATGAAGACAGAACTGTGCCTGGGGAGATGCAATGAGGTGAGGGCTGAACTCATCCTTTTATATTT
CTTTTCAAGATTGGATCAGAGCTCATCTCCATCCAGTCTTGTTTCTATGAAGGCTTCAATCTGTTTCCATGCAAATT'IGCTAATCAGAGCCCAGAGCTGCTGGGTCCCTCAT
CTCCCTCATCTATTATAGATTGACTTACAGCAGGGAGAGAATCTCTTTAGCTCATICCTAATGGGGTTGGGATCACAATATGGTCTGGTCCAATCTGCATCTTGTTGTGTCC CAAGACCCTATCTCCTCCCCAACATTCTTATTGCCTTTGGCTCCCAGTAAGGAACGAATTGGGGGCCAGGGAGGAGAACAGGGGGGATCAAGAAGGGAAACCCAATTCCCCC TTTGAAAGTGGGTTCTTTGAACTATGTGTTTGGGGGAAGTTCCTCTGGATACTAATTTGAATTTATATACCTCATGTTTTGGGGGTTTGACGTATATATATATATATATATA
TATATATGCATATATATTTCATAATATTTGGAAGGTTTXTGATGCTAGAAAAATGGAAACAAGAGAACCTTCAAAAATGGTACTTAGATGGGAAC'IGGAGGCCAATCTTTCA
TAAAGCCAGCCCCATAGCTGCTTGCTGTTAGGCCTCCAGCCATTTTGACATTGGGGTGGATAGTCGATTCACCTGCCTGTCAGTCGATTCACCTGCCTGTCACCCAGTTCTG TGGATGTGCTGGTGCTGAGCCTTTGCTCTCTTTCCAAATGGTTACAGGGATGTTGATCAGCTCCACCAGAGGGAGCTCTGATGGGAGGAATTGCTCTGCCATCCTTGTCCCT GTGTCTCCTGTCGGCAGGCAGCCATTGTATCTCACCAGCAGACCAGGAGACTGGTCCCAAGGTTACTGCACCACAGGGCAATTTCCTGCCATAGTTAGGAAGGAAACACCTG AACTAAATGGAAGAGACATCCCTGCGGTGTTTAATATCACACCCATGCCCTTTGTCAGGTTACCATGTACAGAGATTACTTGGAGAGCCTCATGCCGTCTCTACCTTCGCAC ACTGGTCAAGTATCTGCTGAGCTTCTTGGCCGCAAGGATGCAGAAATAGGCTGAGGGTCCATGGGAAGAAAGACACAATGAGGCAGTAGGAGGTGGGGAAGAAAAGAAGACA GACTTTCAAAATGGAATTAGGCACTGGGGAGAGATCAGTTTCCCCACATCAGGGAGAAGAAGGTATAGGTGGGGAAGGGGGTGGCCAGGAGCAGAAGGAAGAAGACTCAAGA TGGAAAGGGAGCCGCTGTGCCTGTGGCAATACCACTTGGAGAGGTCGACTTCATACCTTCAAGCCTTTTCCCCTGGGCTTTTGATTGTGTCTGTGCCCCCTTTCTTGTCCTC CTGCAGATGCCCAGTAGGGGCTACCTCATCCTCGTGCTGTTCTTGTGTGGCTTTCTGGGCAGTAGGGATCTTGAATITCCTTTCTAACACTGTGCCCGGCAAGGCGGGGAG CATTCCTCTGCCCTTTGTCTTGTGCCAACCTGGAAAGGTGCAGTCTAGATTTCAGTGAGAACCCTGCCAGCTGAGCCCTGTGCATCTACTACCTTGACACAGAGTGTTTTCC CACTAGAAGCTCTGCTCTGCTCTCCTGGCCCAAGTAGGGGATTCCATGCCTTCCCTTTCATGGTCTTAGCACCAGCAGCCTAGTTTCTCCCTTCCAGAGTCTCCAGGGATGA CAAATTGGATTGGAGACAAACCTCGTCAGATGCTCATCCCCTAAAAGGTTAATTGTGTATTTGTGGCTGCGTG'IGCCTTTGTGTTTTCATTCTCT'ICCCATTTTTGTACATT TTGGTCTTCTCTGTGGTTTTATACTTGGTCAAAAGTACTCGTCTTGGTATTGCACIGTTGTGTGCATGAGAAAACTGGGGGAAGGCTCACTGGTACAAGAAAGGACCCCTGA CCCCTTTCCTTCTCTGTGGTCCCCGGCATTAGATTGGGGGTTCTGGGAGAGGCAGGTGAATGTCCTAAGTGAATTGTTCTGTTTGTAACTGGAATGTTTTTGAAGTCTTTGG TGTTGCTCCGTGAAAGGACATCGCCACCTGGTGCTCATGAGGTGTCTTTGCAGAACAATAAATGGCAAATGAACAACCACAAAATTGTTACTCTTGTTGGCCTTCTGCTGTT TGTAGATTAGTGCACCTATCTGTGAGGGATTTGGGTTACCTCCCTGAGTCTGTAAGCAACCACAAGCCCTGCCACTGGGTGGGGGAAGTCCCTCCCCAACCACTTAAAAACA AATTTTCCACATATTACCCACCCACACATTTGACCTGGCTAGACTCTTTGTTTGCCTAAAGGAACAGACCACATTGCTGGGAAAATGAGTAAGTGAACGTGTGGGAGAAAAA CACTTTTAGAATCACGAATATTCACTTTTAAAGGTCTCTTTGCCTGGCTGCAATATAGTGTGTGTTTAAATTATTTACAGGCTGTTGTTTCTCAAATAAATGTTTAATATTA ATCATTCCCAAACTGACAAGAACACAAAAATAAAATGCAAATACAGAGCC
521
YKLLFNFVEQNMKIERLVEVKPSLVIDYLKTEKKLFWPKIKKVNVQVSFNPENKQKGILLTGSKTEVLKAVDIVKQVWDSVCVKSVHTDKPGAKQFFQDKARFYQSEIKRLF
GCYIELQENEVMKEGGSPAGQKCFSRTVLAPGVVLIVQQGDIARLPVDVVVNAENEDLKHYGGLAAALSKAAGPELQADCDQIVKREGRLLPGNATISKAGKLPYHHVIHAV
GPRWSGYEAPRCVYLLRRAVQLSLCLAEKYKYRSIAIPAISΞGVFGFPLGRCVETIVSAIKENFQFKKDGHCLKEIYLVDVSEKTVEAFAEAVKTVFKATLPDTAAPPGLPP
AAAGPGKTSWEKGSLVSPGGLQMLLVKEGVQNAKTDWVNSVPLDLVL8RGPLSKSLLEKAGPELQEELDTVGQGVAVSMGTVLKTSSWNLDCRYVLHWAPEWRNG8TSSL
KIMEDIIRECMEITESLSLKSIAFPAIGTGNLGFPKNIFAELIISEVFKFSSKNQLKTLQEVHFLLHPSDHENIQAFSDEFARRANGNLVSDKIPKAKDTQGFYGTVSSPDS
GVYEMKIGSIIFQVASGDITKEEADVIVNSTSNSFNLKAGVSKAILECAGQNVERECSQQAQQRKNDYIITGGGFLRCKNIIHVIGGNDVKSSVSSVLQECEKKNYSSICLP
AIGTGNAKQHPDKVAEAIIDAIEDFVQKGSAQSVKKVK\A/IFLPQVLDVFYANMKKREGTQLSSQQS\/MSKLASFLGFSKQSPQKKNHLVLEKKTESATFRVCGENVTCVEY
AISWLQDLIEKEQCPYTSEDECIKDFDEKEYQELNELQKKLNINISLDHKRPLIKVLGISRDVMQARDEIEAMIKRVRLAKEQESRADCISEFIEWQYNDNNTSHCFNKMTN
LKLEDARREKKKTVDVKINHPJIYTVNLNTYTATDTKGH8LSVQRLTKSKVDIPAHWSDMKQQNFCVVELLPSDPEYNTVASKFNQTCSHFRIEKVSLLLECSFWMVEISSVM
VLYKIHFHSLPITFF
522
TATAAATTGCTTTTTAACTTCGTTGAACAAAACATGAAAATAGAGAGACTGGTTGAAGTAAAGCCTTCCTTAGTTAT'rGACTATTTAAAGACAGAAAAGAAGCTATTCTGGC CAAAGATAAAGAAGGTAAATGTGCAGGTAAGTTTCAATCCTGAGAACAAACAAAAAGGCATTTTACTAACTGGCTCAAAGACCGAAGTACTGAAGGCAGTGGACATTGTCAA GCAAGTCTGGGATTCAGTCTGTGTTAAAAGTGTCCATACTGATAAGCCAGGAGCCAAGCAGTTCTTCCAGGATAAAGCACGGTTTTATCAAAGTGAGATCAAACGGTTGTTT GGTTGTTACATTGAACTACAGGAGAATGAAGTAATGAAGGAGGGAGGCAGCCCCGCTGGGCAGAAGTGCTTCTCTCGGACAGTCTTGGCCCCTGGCGTTGTGCTGATTGTGC AGCAGGGTGACTTGGCACGGCTTCCTGTCGATGTGGTGGTGAATGCATCTAATGAGGACCTTAAGCATTATGGTGGCCTGGCCGCTGCGCTCTCAAAAGCAGCTGGCCCTGA GCTCCAGGCCGACTGTGACCAGATAGTGAAGAGAGAGGGCAGACTCCTACCGGGCAATGCCACCATCTCCAAGGCAGGAAAGCTGCCCTACCACCACGTGATCCATGCAGTG GGGCCCCGCTGGAGCGGATATGAGGCCCCGAGGTGTGTGTACCTATTAAGGAGAGCTGTGCAACTCAGTCTCTGTCTAGCCGAAAAATACAAGTACCGATCCATAGCCATCC CAGCTATTAGTTCTGGAGTCTTTGGCTTTCCCTTAGGCCGATGCGTGGAGACCATTGTTTCTGCCATCAAGGAAAACTTCCAATTCAAGAAGGATGGACACTGCTTGAAAGA AATCTACCTTGTGGATGTATCTGAGAAGACTGTTGAGGCCTTTGCAGAAGCTGTGAAAACTGTATTTAAAGCCACCCTGCCAGATACAGCTGCCCCGCCAGGTTTACCACCA GCAGCAGCGGGGCCTGGGAAAACATCATGGGAAAAAGGAAGCCTGGTGTCCCCGGGAGGCCTGCAGATGCTGTTGGTGAAAGAGGGTGTGCAGAATGCTAAGACCGATGTTG TTGTCAACTCCGTTCCCTTGGATCTCGTGCTTAGTAGAGGGCCTCTTTCTAAGTCCCTCTTGGAAAAAGCTGGACCAGAGCTCCAGGAGGAATTGGACACAGTTGGACAAGG GGTGGCTGTCAGCATGGGCACAGTGCTCAAAACCAGCAGCTGGAATCTGGACTGTCGCTATGTGCTTCACGTGGTAGCTCCGGAGTGGAGAAATGGTAGCACATCTTCACTC AAGATAATGGAAGACATAATCAGAGAATGTATGGAGATCACTGAGAGCTTGTCCTTAAAATCAATTGCATTTCCAGCAATAGGAACAGGAAACTTGGGATTTCCTAAAAACA TATTCGCTGAATTAATCATTTCAGAGGTGTTCAAATTTAGTAGCAAGAATCAGCTGAAAACTTTACAAGAGGTTCACTTTCTGCTGCACCCGAGTGATCATGAAAATATTCA GGCATTTTCAGATGAATTTGCCAGAAGGGCTAATGGAAATCTCGTCAGTGACAAAATTCCGAAGGCTAAAGATACACAAGGTTTTTATGGGACTGTTTCTAGCCCTGATTCA GGTGTGTATGAAATGAAGATTGGCTCCATCATCTTCCAGGTGGCTTCTGGAGATATCACGAAAGAAGAGGCAGATGTGATTGTAAATTCAACATCAAACTCATTCAATCTCA AAGCAGGGGTCTCCAAAGCAATTTTAGAATGTGCTGGACAAAATGTAGAAAGGGAATGTTCTCAGCAAGCTCAGCAGCGCAAAAATGATTATATAATCACCGGAGGTGGATT TTTGAGGTGCAAGAATATCATTCATGTAATTGGTGGAAATGATGTCAAGAGTTCAGTTTCCTCTGTTTTGCAGGAGTGTGAAAAAAAAAATTACTCATCCATTTGCCTCCCA GCCATTGGGACAGGAAATGCCAAACAACACCCAGATAAGGTTGCTGAAGCCATAATTGATGCCATTGAAGACTTTGTCCAGAAAGGATCAGCCCAGTCTGTGAAAAAAGTTA AAGTTGTTATCTTTCTGCCTCAAGTACTGGATGTGTTTTATGCCAACATGAAGAAAAGAGAAGGGACTCAGCTTTCTTCCCAACAGTCTGTGATG'ICTAAACTTGCATCATT TTTGGGCTTTTCAAAGCAATCTCCCCAAAAAAAGAATCATTTGGTTTTGGAAAAGAAAACAGAATCAGCAACTTTTCGGGTGTGTGGTGAAAATGTCACGTGTGTGGAATAC GCTATCTCCTGGCTACAAGACCTGATTGAAAAAGAACAGTGTCCTTACACCAGTGAAGATGAGTGCATCAAAGACTTTGATGAAAAGGAGTATCAGGAGTTGAATGAGCTGC AGAAGAAGTTAAATATTAACATTTCCCTGGACCATAAGAGACCTTTGATTAAGGTTTTGGGAATTAGCAGAGATGTGATGCAGGCTAGAGATGAAATTGAGGCGATGATCAA GAGAGTTCGATTGGCCAAAGAACAGGAATCCCGGGCAGATTGTATCAGTGAGTTTATAGAATGGCAGTATAATGACAATAACACTTCTCATTGTTTTAACAAAATGACCAAT CTGAAATTAGAGGATGCAAGGAGAGAAAAGAAAAAAACAGTTGATGTCAAAATTAATCATCGGCACTACACAGTGAACTTGAACACATACACTGCCACAGACACAAAGGGCC ACAGTTTATCTGTTCAGCGCCTCACGAAATCCAAAGTTGACATCCCTGCACACTGGAGTGATATGAAGCAGCAGAATTTCTGTGTGGTGGAGCTG TGCCTAGTGATCCTGA GTACAACACGGTGGCAAGCAAGTTTAATCAGACCTGCTCACACTTCAGAATAGAGAAGGTAAGCCTTCTGCTAGAATGCAGTTTCTGGATGGTGGAAATAAGTTCTGTCATG GTCCTATATAAAATCCATTTTCATTCACTTCCTATCACATTTTTTTAAACCCAGAATTAGAATTTGTATGGTAATTAGTAGTTCTAGATTCTACTCATGTGACCATAATTAC TGAGGCATTAAGATTCT'IGTGTCAGTGATTACAATATTTGATTGTAATATGATAGAACACTAAAGACATATATTTACTTTGTGAAGCAAGCTAATACAAATTCAAAGATATG GCTTTAAAATTGGATTTGATAGCTAGCAAATTCCACAGAGAGCCATGCAGAGGCTCCTTAGATCAGGACCATGTTACTCTGCCCCATTATTCACAGATCAACAGTGCTTCCT TGATAAAGCCAGCAGGCCTTTTCTCGTTTATCATAATTATTTTGGGCAGGTGAATGTGATGATTCGTGCCTGTAGTCCCAGCTATTGGGAGGCTGAGGTGGAAGGATTGCAT GAGCCCAGGAGTTTGACGCCAGTCTGGGTAACATAGTGAGATCCTGCTCTCAAATAAAAACAACCAATTATTTTGGCATCTTCTTCCATTTTTAAACATTTTTGATATTGCT
AATTCTAGCTTTATTCACGCCATTTATGCTTAAACGGTCTTTTGTCTCTGTACCTCACCAGGGAATATATTTACCCTTCTTGGATTCAACTATTAGTTCAATGTCGATAGCT CCCAAATCAACATTACCAACCTGGGTCTTTGACTCAAGCTCTAGAACATACTCCCAGTGGCCTAAAAAAATCTCCACTTGAGGCTGGGCACAGTGGCTCACGCCTGTAATCC CAGCACTTTGGGAGGCCGAGGTGGGTGGATCACGAGGTCAGGGGTTCAAGACCATCCTGGTGAAGATGGTGAAACCACGTCTCTACTAAAACTACAAAAATTAGCCGGGCAT GTTGGCAGGTGCCTATAATCCCACCTACTTGGGAGGCTGAGGCAGGATAATTGCTTGAACATGGGCGGCAGAGATTGCAGTGAGCCAAGATCACGCCACTGCACTCCAGCCT GGTCGACAGAGTGAGACTCCGTCTCAAAAAAAAAAATCTCCACTTGAATATCTAACTGCAAAATCAACTTCTCTAAAATCTAATGCATCATACGTAAGTAATTCTCTTTCCC TTTCCTTCCTCATTTCTGTTTTTGGTTCTACCACTTTCTGAGTAAAGCCGGAGATCTTTGATCCACCATAAGTCTGCCAGTAAGACCTACATTTTCTTTGCAAATTTTTCTT ACTCTCTATTTGAACTGCCAACACTGTTTATTCATGTTGTTAAGTACATCATAATTTAAAAAGATTCAAAGTGCCCTACAAAGATATAAACTATACCTTCAGATAAAATAAA TATACAAAGAAAAATGGTTAAAGAGAAAAGAATGGCAGGGAAAATAAGATAATACAGACGAACTGCTAGTTCTCAAAAATATATAACATGAGGTTACCAATTTGTCCCTGAG CTTCCTAGTAGACAAAGCAAGAAGTAAACATTCAGGTACAAGACTCATAATGTCCGTAAATCAAAAAGCAAACCATTTGATAAGGAGGCTCACAGCTCCTCACAATACTGAG
AACTGGTTGAACAAAACCGATGCCTGATTGAATGAAAACAATTCTATGAGGCACCAAGACAATATGATTCAAGTATGCAGCTCTATGATGGTCTATTTCTGAGATAACAAGT AAGTCTCACTCCAAGTACCAATTACTACTAACTGGTAGTGGCTGATTGGCACATTGTGATGAGATGCTAAGTTTAGATTGAGCAGGAATGAATGTTCTGCTTGACCAGCAAT ATCTACAGTGGGCCCTGTGGATGCCTGCTGTGTATTGGCAGACCCTGGCCAGAGAATTGATTTCAACACTTTTTTGCAGTGAAACCTTTTTTTTCAATAAAATCTTATGTGA AATCCCAGTGTATGAACCAGATAAAAGCAGAGGTGTGGGTAGTACTTAAGGTGCCTCCATGGAGGTCCCTAGAATTGTG
523
MPGEEEERAFLVAREELASALRRDSGQAFSLEQLRPLIjASSLPLAARYLQLDAARLVRCNAHGEPRNYLNTLPTPS DGPDKQSLVRRLLAVYALPSWGRAELALSLLQETP
RNYELGDWEAVRHΞQDRAFLRRLLAQECAVCGWALPHNRMQALTSCECTICPDCFRQHFTIALKEKHITDMVCPACGRPDLTDDTQLLSYFSTLDIQLRESLEPDAYALFH
KKLTEGVLMRDPKFLWCVQCSFGFIYEREQLEATCPQCHQTFCVRCKRQWEDFQN KRMNDPEYQAQGLAMYLQENGIDCPKCKFSYALARGGCMHFHCTQCRHQFCSGCYN
AFYAKNKCPEPNCRVKKSLHGHHPRDCLFYLRDWTALRLQKLLQDNKVMFNTEPPAGARAVPGGGCRVIEQKEVPNGLRDEACGKETPAGYAGLCQAHYKEYLVSLINAHSL
DPATLYEVEELETATERYLHVRPQPLAGEDPPAYQARLLQKLTEEI PLGQE I PRRRK
524
AGTACTTCCTGTTCTCGGCTAACCCTGGCGCTGGGCCGGGGGCTGGAGAGTGACCGTGGTCTGAGTGACCTGGGACGGCTGCGTGGGCCGGGGTGGGCCTCAAAGCCGGGCA CCAGACGGGAGGGGCGGCGCTCGGGCCGCGCGCTGCCCGCGCCGGGTCCTGGCGGGCGGCGAGGCTGGGGCTGACTCCTGCCTCAGGATGCCGGGGGAGGAAGAGGAGCGGG CCTTCCTGGTGGCCCGCGAGGAGCTGGCGAGCGCCCTGAGGΔGGGATTCCGGGCAGGCGTTTTCCCTGGAGCAGCTCCGGCCGCTACTAGCCAGCTCTCTGCCGCTAGCCGC CCGCTACCTGCAGCTGGACGCCGCACGCCTTGTCCGCTGCAACGCTCATGGGGAGCCCCGAAACTACCTCAACACCCTGCCCACCCCTTCCTGGGATGGGCCAGACAAGCAG AGCCTGGTCAGGCGGCTTTTGGCAGTCTACGCACTCCCCAGCTGGGGCCGGGCAGAGCTGGCACTGTCACTGCTGCAGGAGACACCCAGGAACTATGAGTTGGGGGATGTGG TAGAAGCTGTGAGGCACAGCCAGGACCGGGCCTTCCIGCGCCGCTTGCTTGCCCAGGAGTGTGCCGTGTGTGGCTGGGCCCTGCCCCACAACCGGATGCAGGCCCTGACTTC CTGTGAGTGCACCATCTGTCCTGACTGCTTCCGCβAGCACTTCACCATCGCCTTGAAGGAGAAGCACATCACAGACATGGTGTGCCCTGCCTGTGGCCGCCCCGACCTCACC GATGACACACAGTTGCTCAGCTACTTCTCTACCCTTGACATCCAGCTTCGCGAGAGCCTAGAGCCAGATGCCTATGCGTTGTTCCATAAGAAGCTGACCGAGGGTGTGCTGA TGCGGGACCCCAAGTTCTTGTGGTGTGTCCAGTGCTCCTTTGGCTTCATATATGAGCGTGAGCAGCTGGAGGCAACTTGTCCCCAGTGTCACCAGACCTTCTGTGTGCGCTG CAAGCGCCAGTGGGAGGACTTCCAGAACTGGAAACGCATGAACGACCCAGAATACCAGGCCCAGGGCCTAGCAATGTATCTTCAGGAAAACGGCATTGACTGCCCCAAATGC AAGTTCTCGTACGCCCTGGCCCGAGGAGGCTGCATGCACTTTCACTGTACCCAGTGCCGCCACCAGTTCTGCAGCGGCTGCTACAATGCCTTTTACGCCAAGAATAAATGTC CAGAGCCTAACTGCAGGGTGAAAAAGTCCCTGCACGGCCACCACCCTCGAGACTGCCTCTTCTACCTGCGGGACTGGACTGCTCTCCGGCTTCAGAAGCTGCTACAGGACAA TAACGTCΔTGTTTAATACAGAGCCTCCAGCTGGGGCCCGGGCAGTCCCTGGAGGCGGCTGCCGAGTGATAGAGCAGAAGGAGGTTCCCAATGGGCTCAGGGACGAAGCTTGT GGCAAGGAAACTCCAGCTGGCTATGCCGGCCTGTGCCAGGCACACTACAAAGAGTATCTTGTGAGCCTCATCAATGCCCACTCGCTGGACCCAGCCACCTTGTATGAGGTGG AAGAGCTGGAGACGGCCACTGAGCGCTACCTGCACGTACGCCCCCAGCCTTTGGCTGGAGAGGATCCCCCTGCTTACCAGGCCCGCTTGTTACAGAAGCTGACAGAAGAGAT ACCCTTGGGACAGAGTATCCCCCGCAGGCGGAAGTAGCTGAGGGCGAGGGTCCCGATGAGGGTCCCATGGCCTGCTCCCTCAGGAACAGCTCCAGCACCAATAAAGAGGCAT CTTACCACCCAG
525
MAAQYGSM8FNP8TPGA8YGPGRQEPRNSQLRIVLVGKTGAGKSATGNSILGRKVFHSGTAAKSITKKCEKRSSS KETELVWDTPGIFDTEVPNAETSKEIIRCILLTSP GPHALLLWPLGRYTEEEHKATEKILKMFGERARSFMILIFTRKDDLGDTNLHDYLREAPEDIQDLMDIFGDRYCALNNKATGAEQEAQRAQLLGLIQRWRENKEGCYTNR MYQRAEEEIQKQTQAMQELHRVELEREKARIREEYEEKIRKLEDKVEQEKRKKQMEKKLAEQEAHYAVRQQRARTEVESKDGILELIMTALQIASFILLRLFAED
S26
AGAGAGGGGTGCAAGATCCTGATTTTTCAGGAGTTCAAGCGACAATGGCAGCCCAATACGGCAGTATGAGCTTCAACCCCAGCACACCAGGGGCCAGTTATGGGCCTGGAAG GCAAGAGCCCAGAAATTCCCAATTGAGAATTGTGTTAGTGGGTAAAACCGGAGCAGGAAAAAGTGCAACAGGAAACAGCATCCTTGGCCGGAAAGTGTTTCATTC GGCACT GCAGCAAAATCCATTACCAAGAAGTGTGAGAAACGCAGCAGCTCATGGAAGGAAACAGAACTTGTCGTAGTTGACACACCAGGCATTTTCGACACAGAGGTGCCCAATGCTG AAACGTCCAAGGAGATTATTCGCTGCATTCTTCTGACCTCCCCAGGGCCTCATGCTCTGCTTCTGGTGGTTCCACTGGGCCGTTACACTGAGGAAGAGCACAAAGCCACAGA GAAGATCCTGAAAATGTTTGGAGAGAGGGCTAGAAGTTTCATGATTCTCATATTCACCCGGAAAGATGACTTAGGTGACACCAATTTGCATGACTACTTAAGGGAAGCTCCA GAAGACATTCAAGACTTGATGGACATTTTCGGTGACCGCTACTGTGCGTTAAACAACAAGGCAACAGGCGCTGAGCAGGAGGCCCAGAGGGCACAGTTGCTGGGCCTGATCC AGCGCGTGGTGAGGGAGAACAAGGAAGGCTGCTACACTAATAGGATGTACCAAAGGGCGGAGGAGGAGATCCAGAAGCAAACACAAGCAATGCAAGAACTCCACAGAGTGGA GCTGGAGAGAGAGAAAGCGCGGATAAGAGAGGAGTATGAAGAGAAAATCAGAAAGCTGGAAGATAAAGTGGAGCAGGAAAAGAGAAAGAAGCAAATGGAGAAGAAACTAGCA GAACAGGAGGCTCACTATGCTGTAAGGCAGCAAAGGGCAAGAACGGAAGTGGAGAGTAAGGATGGGATACTTGAATTAATCATGACAGCGTTACAGATTGCTTCCTTTATTT TGTTACGTCTGTTCGCGGAAGATTAAACTTAATGAAAATCTGTTTGTATTTTCTGCATATTCTCTGGCAACCTTGCCCCATACTTACTTATTTAGCATAGTCGAGTGCTCTA GTTTCTGTCTCTCAGGCACTCGTAACTAAGGACCACCATTGGCCATTGGTAGATGTTTGATTGACTTAACAAGAGAGGGACAAATTTTCAATTTGTGAAACTCCAAAGCAGA AAGTATTGGTGCITGCTACCTTGTGAATTCTTCCTTAGACATGCAGAGAAAATGTATGCAAGAGACCAAAAAGATGGCTCCAAGCTATGTCATGTTACCTGTAATAAAATCT TTTCTTCTAGATTCTCTCTATGTTGGCAGATAATCTCCCCTTGTAGCTTCCACTCACTTATTCTTGCATTCAGAGTCACAATGATCATCTTACCCATGTGGTTTTTGAGAAA GAAAGATCAATTCTTTGTTTGCAGTGGGTAATCTTAGAGATGGAGATGATTGTAGAATTATTCCTAGATGAGTGTCAATTTATTTAATTCCATTGTCATATAAGGAGTCAAA TTGTTTCTTATCATTTGTTCATTGAAGAACAGAGACCTGTCTGGAAAATCGATCTCTACAAATTCAATTAAATAATGATCCCCAAATGCTGAAAAAGTGAAATACAGCAATT CAACAGATAATAGAGCAATGTTTAGTATATTCAGCTGTATCTGTAGAAACTCTTTGACGAACCTCAATTTAACCAATTTGATGAATACCCAGTTCTCTTCTTTTCTAGAGAA AGATAGTTGCAACCTCACCTCCCTCACTCAACACTTTGAATACTTATTGTTTGGCAGGTCATCCACACACTTCTGCCCCCACTGCATTGAATTTTTTGCTTATGTTGTTTAT AATAAAACTTTTCAATTATCTC
527
MGTYSTILIKTEVIECGNYCGVRIIHSLIAEFSLEELKKSYHLNKSQIMLDMLTENLFFDTGMGKSKFLQDMHTLLLTRHRDEHEGETGN FSPFIEALHKDEGNEAVEAVL LESIHRFNPNAFICQALARHFYIKKKDFGNALNWAKQAKIIEPDNSYISDTLGQVYKSKIRWWIEENGGNGNISVDDLIALLDLAEHASSAFKESQQQSEDREYEVKERLYP KSKRRYDTYNIAGYQGEIEVGLYTIQILQLIPFFDNKNELSKRYNJVNFVSGSSDIPGDPNNEYKLALKNYIPYLTKLKFSLKK8FDFFDEYFVLLKPRNNIKQNEEAKTRRK VAGYFKKYVDIFCLLEESQNNTGLGSKFSEPLQVERCRRNLVALKADKFSGLLEYLIKSQEDAISTMKCIVNEYTFLLEQCTVKIQSKEKLNFILANIILSCIQPTSRLVKP VEKLKDQLREVLQPIGLTYQFSEPYFLASLLFWPENQQLDQHSEQMKEYAQALKNSFKGQYKHMHRTKQPIAYFFLGKGKRLERLVHKGKIDQCFKKTPDINSL QSGDVWK EEKVQELLLRLQGRAENNCLYIEYGINEKITIPITPAFLGQLRSGRSIEKVSFYLGFSIGGPLAYDIEIV
528
AGTGAATGAATATGCCTTCCTACTGCAGCAAAACTCAAAAAAGCCCATGACAAATGAGAAACAAAATTCCATTTGGCCAACATTATTCTGAGTGTCTAAAGCCCAACTCCAA
GTTAATTCAACCACTTACCACGCTAAAAAAACAACTCCGAGAGGTCTTGCAATTGTAGGACTAAGTCATCAATATCCAGGTCCTTATTTCTTGGCCTGCCTCCTGTTCTGGC
CAGAAAATCAAGAGCTAGATCAAGATTCCAAACTAATAGAAAAGTATGTTTCATCCTTAAATAGATCCTTCAGGGGACAGTACAAGCGCATGTGCAGGTCCAAGCAGGCAAG
CACACTTTTCTATCTGGGCAAAAGGAAGGGTCTAAACAGTATTGTTCACAAGGCCAAAATAGAGCAGTACTTTGATAAAGCACAAAATACAAATTCCCTCTGGCACAGTGGG
GATGTGTGGAAAAAAAATGAAGTCAAAGACCTCCTGCGTCGTCTAACTGGTCAGGCTGAAGGCAAGCTAATCTCTGTAGAATATGGAACAGAGGACAAAAATTAAAAATACC
AGTAATATCTGTTTATTCAGGTCCACTCAGAAGTGGTAGGAACATAGAAAGAGTGTCTTTCTACCTAGGATTTTCCATTGAAGGCCCTCTGGGCATTATGATATACGAAGTr
ATTTACGACAATTACATCACCTGGTAGGTTCAAATACGGTTTATTCATATCTTAATGAGTTATTCTCTCTCTCTATACTCATGGCATTTTCCTACCATTATTGGTTAACCTC
TAATAACGATTAGGTTGCTCCCTGATGATTACAGCCTTTAAGATATGAATTGCTACGGAAGTTGGCAAGGGGTCAACCTTAGGTCAAATGTTTCGCTCAAATAAAGAGTAGA
TCTCGGCCACATCTCTGGCAATTGGATCACACAACAGGGCTAAACGGCACACACCATAGAAAGTAAACAGCATGATAAAAATATACATATGTACTATA
529
MNKFPRRIPQKSCPRII ; SCQEVSPEVADAICQAIVLSAEGPtIAVLLVTQLGRFTDEDC<3VVRRLQEVFGVGVLGHTILVFTRKEDLAGSSLEDYVRETNNQALAWLDVTL
ARRHCGFNNRAQGEEQEAQLRELMEKVEAIMWENEGDYYSNKAYQYTQQNFRLKELQERQVSQGQGSEDVPGEES LEGLSQIQKESEEAHRCLLGKADL
530 GAAAACATTTTGCTGAAAATATAAGCAAACATCGGCCTTGTCCTCCTTGTGTTCATACACTGTGGAAGCTTTTCTCTGCCTCCTCCGTGAGAGTGCGTGGCCGGGAGACCAG AAACGTGGTCCTTTCTCTTGCCTGTGAGCTGGTGCAGAGATGGAGGAAGAAGAATATGAACAAATTCCCCAGGAGAATCCCCCAGAAGAGCTGTCCCAGGATCCTGTGCTGG AGCTGTCAGGAGGTCTCGCCAGAGGTGGCAGACGCTATCTGCCAAGCCATCGTCTTATCCGCCCCAGGGCCCCACGCCGTGCTCCTGGTGACACAACTGGGCCGGTTCACGG ATGAGGATCAGCAGGTGGTCAGGCGCCTGCAGGAGGTCTTTGGAGTGGGGGTTCTGGGTCACACCATCCTGGTGTTCACCCGGAAGGAAGACCTGGCTGGCAGCTCCCTGGA AGACTATGTGCGAGAGACCAACAACCAGGCCCTTGCCTGGCTGGATGTGACCCTTGCACGGCGCCATTGCGGCTTCAACAACAGGGCACAGGGGGAGGAGCAGGAGGCCCAA CTGCGAGAGCTCATGGAGAAAGTTGAAGCCATTATGTGGGAAAACGAAGGAGATTATTACAGCAACAAGGCTTACCAATATACCCAGCAAAACTTTCGGCTGAAAGAACTAC AGGAAAGGCAAGTAAGCCAGGGCCAAGGCTCTGAGGACGTGCCTGGTGAGGAGTCTTGGCTGGAAGGACTGTCCCAGATCCAGAAGGAATCTGAGGAAGCCCACAGATGCCT GCΓGGGGAAGGCTGACCTTTGAGCCTGTGCTGGACTTGAGCCAAGGACACCATCAGCCTTTGCACCCCCCTGTGTCCAGCCCTCTGTTTCTCTTTCCATCCCATGGAGTGCT TCCCAGTCTCCAGGTCATGACGTCTGGTGTAGGAAGAGGGGCATGGGGCTTGAGGACAGGGTCCAGCATGCCCAGATCACATTCCAGTTCCTTCATTCCTTCTTCCAGAACA TCTGGGTCCTCCCTCCTCTGTGCCCCAACAGCACGCTGTCTTCCTATTGGACCTTCTATCTCATTGGCATTGCCTTTCATGAGTTACTTGTCTATACTCTGATAGAACCAAA GTTTCTTGAGGGCAGGCCTGTATCTTTTACTTCTGTG1AACTTCCACAGCTTTTGACTGCATTGGAGTCATGCAGTCACGTTTGGTGCGGCAACTCCATGCAAGCTGTTGAC CAGATGACTTCTCATCTCTCCCCACACCATGATGGTTTAAGGTGCCTGTTGTGTCTGGTGGAGACAGTGCTGGGAGATGATCAGAAATCTCAGGGCACAGCC'ICAGGTCTAC CTGGACACTCATCCACTGTTGGAGATGCTCAACAGCTAGACACAGATGCTCACAGCCGACCTGTGGCCTCTTGCTCTGAAGCCATCCCCCATCTTCCCTAGACACAGCAGAC ATCTGAGAAAGCTTCAGCATTTCTCTTGCTAACAGA'ITCAGAAAAGTGTCTCAAAGCAGAGCACAGAGTTATTTGGTGTTTGCTGAAGACAGCCTTTGTGCCACAATCACTT ATTAAATAAGCGAICAATTTCCCATTGAACTGAACATGCAACATTTATCATACATTCAGCTCTCATTCACACTCCTTAAGATTTGGTCAGAATTTTTATTTCTGTTCATGTC TTCTACTTTTCTACTCCTGTATGAATAAAATATTGATTTGATTACAGTGGCTTTGACTATAATGTGGGAGCCAATTTTTGCCTCAGTCTTCATTTTTATATTTACCTTGTTA TTCTCAGGCATTTTTTTCTTCTATGTGAGAGTTAAAATCATTCTGTAATTTCCCCCCAAAATCATATTGGTATTCTAGT'IGGCAATGTCTTACATTTATGTTAAGTTTGAGG GAATTGGTAGTTCAAGTATAAGTTAATTAAGGCCATTTTATTTCTAAGTGAACAGACTTGAAACTCCAGAGCTACTGAAGTAAAAGTTAGAATCATTTGCATTTTCATTCAG
ATAGGAGATAATTTTGTAAATTTTGATGCTATTATTTTAACTCTATTAGCTTAAGTAATGTCATAATAGAAAACACAAGCATTTGACCAAATGAGATCCATTCAGCGACTAA CTGGCAAGGCACTCAAAACATGTCATTCATTAAATGTTGTTTTTATTTACCTCAAA7AAAAAAAAAAAAAAAAAAAA
531
MHSQMATQHRCGRGNGLILLKAIKEKRISQCPGCKRAL
532
GGCACGAGGGGGCCCAGCCTCAGCATACCCACCGAGCAGCTGCCAGCCTGGGCTGAGGGTGGGCATGAGGCAGGAGTCAGCACTTGGACCTAGGGATGTGAGGTTTTCTGTG CCCCAAGTTTGTGGGAAGGTGGGCACTACTGCTGGGCCCACAGACACAGCCAGCTGGCAAAAGGGAGGTCTAGCCCAGCAGAGAGATGAGGACATTTTGCTTCTCCTTCATG CCCACAGCATGAGCTGAGCTTCTGCTTTGCTGGAAATGAAATAAACTTGGTATGAATTGTGCCAAGGCCTCCCCAGTTGTCATCCTGCCTCTTGTTGCCCTCCCTGTCCTrG CCCCCCACCCCACACCCATGCCCCTGTTTCCTTACAGATTTTGATATTGTTCTAATGTGTAATAGAACCAGCCGAGTCCCCTTTTATCAGAAGGGTCTGAAAAGCAGCAGCA CAGAGTAGGTGAACACAGGCCTGCAAGTGCGACCACCTCAGACCCAGTACGTGTGCCCACAGTGGACACACTCACACCTCCAACACACCCACGCGCAGGCATGTGTACACGC ATGTACACACGCATGCATGCACAGCCAGATGGCCACTCAGCACAGATGTGGCAGAGGGAATGGTCTGATCCTGCTGAAAGCCATTAAGGAGAAACGAATTTCCCAGTGCCCG GGCTGCAAGAGAGCCTTATAGGGGCCCTGTTTCCTGGGCATGCGCTTCCTCTGCCAGCCAACCCCCACTTGCCCAAGTCACTGGTGCAATAACTTTTCTGCCTTCCTCAGAG CAGAGAAATTGGGAATTGTGTTAGGTGGGTGTGGGCAGCTCTGCTGAGCCAAGCAGACACGGATGTCCCCTCTTCTGGGAGGAGGGTAGTGCTCCCAGGCCTCAGGAGTCCA GACAGAGACCCCCAAAGCCTGACTGCCAACAGAAACCCTCTCCTAGTGAGGGGCAGGTGGGTGTGCCCCAGGTCCCCACACCCACAGGGAGGCTTCACACACTGCCCAGTAC CGGGGATGCCAGGAGGCAGGCCCCTCTGCTGCTGCCACTGCTGCCAACACTGCCCAGCTTGTGAGGCCAGGAGGAGCCCCTGTCCCACTCGGTGCTGCTGCTCTTCTGACCC CTGCTGTGAGGAATGGGATTCTTGGTCGAAAAAATTGGTTTTCCTTTTTTGTATAAATGAAAAGAATCCAGGAGAAGCTGCCACCCTCCCCTCCCAGCGTGATGCGCTACCT TGCTTCGGCGTCTTGTCGCCCTTTCCGCCTTTGGTCCAGGGACAGCCCAGCAGATCCTCCTGGTTCTGACCTGGGGGGTGTTTGCATCACCCCCTTTTACTTGTATTAAAAA AAAATGATGGGTTGAAAATGTACTGAGGATTAAAAATGTACTTTTTTATAAATAAAGTGTTTAAAACAAAAAAAAAAAAAAAAAA
534
TTTCCTAAGCATTGAAATGGCAAGTGCAACCAAAAGTAGGTATATTCGTGACTTCTTGTTTAGGTCTCTGGGCCAGGAAATTCATACTGTTACATGGATAAGGTTGGGATTG
GGGAGAGGGAACAGTTGGGACTAGAAGCAAAAGTGATTCTGGGACTAAAATAGGAAGCAGATGTCCTTTCCCAATGTGTGTTGCTGTCTTCACCTGAATGCATTTGTGTAAA
AATAGCGGAGGGACAATGTGAACATTTGTATTTGGAAGCTATGAATTTACTCTGAAGTTTGCAGTTGTTTCCAATTTGTGAGCTCTAAGAGTTTCTGCCTGTAAGAACTACT
CTCCTTTTATTTTGATTTTTAAAAACCTGTCTGAATTTCACACTCTTAGAGCCTGGAAGAGCCCTGAAAAGACACAAGTCTTGCCTGGCTACTGCTTTTTAACTTTGAGGGC
TCTATGTTGACAGACTGTTATCTCCTCTGGGTGACCTCAAACATCTGAAAAGAAAGATGTTGCCTGTGCCAATTCCACTTTTTCCAGCTGCCCCTTGATGAACACTCCCTTA
TACCAGACCACTCTAGGACTTCTGACTGGTGTCATCAAGTCCTCAGAAAATATTTTAAGTTATTTTAAGTTATTAAGGAAGGGATGATTTGGAGACAAGGAGTAATGAAAGA
TGGGTAAAAACTGGAAAAGATTCTGGTGCTAAGTACTACCCCTTCATCTTCCATGGATGGTCATTACCTTTCCTGTCCTCCTGTTCTATGAACACACACACACACACACACA
CCCCACATTTCAATAAG1CTTCATTGTTCTGGGTCCTTACCTTTCCTGTCCTCCTGTTATATGAACACACACACACACACACACACACACACACACGCACACACATACCACA
TTTCAATAAGTCTTCATTGTTCTGGGTCCTTACCTTTCCTGTCCTCCTGTTATATGAACACACACACACACACACACACACACGCACACCACATTTCAATGTCTGCATGGTT
CTGGGGGTAACAAAGGCAAGAAGTTAAAGTAAGACCACATTTGAGTATTACTTACTCTGTAGAATCAAAACAGAGTAGTTAACACCAATTATGCAAACTACTTTTTTTTCCA
GCAGAAAGGGAGCTGACATGATCAAATCCATGTTTTCAAATGAACTGAAAAAGGCATCCAGCACCACTTATAACACATTTATTTCAGTTCCAGGCTGACAGCCCTGGGGCAT
CTAGCAGGATGCATAATTGTCATCTGGTGAGAGTTGGGACTTTGCTCAATTTTAATACCAATCTCTCCTGATTGTAATTACCTCCACTACTTTCATGATCCCCCTACAATAT
TTTTTTAAATGATATATTTATTCACTGAATCAAATGTCATTAATGAGTTATCTTCTGTGGAGGATGACTGTTCTCTTTGTTAATGTTCACAATCAAGATCTTGGGCTGAGAA
GAGGCCCTTCACCCAAGGAGTTTGAAGTATCACAGCGTGTGGGAAGGTGGGAACCAGGATACCCATTCATTTCCAACCGAGACACAGAGAAGTGAGTCACAGAATTTGAGCC
TGCTCTCTTGACTGCCCAGCCAGAGACACTGATTTCTGTAACCTCTTCACTTGATCCTGCCTCTTAAGCATTAAAACATTCTCCTAAACCTCTGAGTGTTTTGTGGGTTCTG
GGTGTTTTGTACATTTTAGCCAAGCTAACCACTTGTCTGCAAGTACTGACTTTCCTATGAATTCTTTGAAGATTATTGAGTCAGAAAGGAAAAATATAGCCCCAAATTCCCA
GGCTTTTAATGCATTACATTAACTGCCTATTGAAATGAGAAGTTCTTCACAAACTTGTATACCCACTAACAAGATTGCACATAAACATGCATTAAAGTATATACTAAG
536
GTAATTATAAACACAATTTATAATTTTATTTAGCAGCTTTGATTTTATATATATAGTTTCTTGATTCCTAATATTAACAAAATTGCATGTTATTTATCCTCCAAAATGTATA TAATAGATTCAGAGlAACAATATTAACATATATTATTATTCTATATTAATACTATTTGTAAATTAATTTTATTTTTAA'1'rTTTTATTTATTTTTAATTTAGTTTCATACTTT AGGGCATATCCACTAAAAATGCATAGACAAGTGACTGTGTTTTAAAAATACTTGAAGTAATTCTCCTCTGTGTGTTTAGGACACCAACACAATTAGTTTCATTTATTTCATT TAGCTTTTGCTTTGGATATATAGTTACGCACCTCATAACATTGNTTCAGTCAATAATGGACCACAATGAACCACGTATGCACCAGTGGTTCCATAAGGTTGTAATGGAGCTG GACAATTTCTATCACCTAGTGACACT
538
ACATTTTTTTTTTTTTTTTTTTTTTAGGTTTGGAGTATGGCGTGGTTGTTGAGGTGACATTTATTATTGAGAGACAATGAAGAATGGTGTCTTGTTGCTTCATCACAGCTAC TGAACTCACAGACTGCCTGCTTGCCAGAGCCTTTGACTCCTCAGGGGGTGGAGCAAAAGATTTCTTTCCTGGATGGAGCAGTCAGTCTATGGTCAGTGTAAGAGTTGCTGTA GCAACCTCACAGCTGTGCTCTGTCTAGCAGAAACTTGGTATGATTTCACGGATTTTGTTCACTTAAGTAAAAAACAGATTTGTTTGGCTTTTATGTAATTAGAAATTGAAAT AATGGAATTGGAATTTTCTAGCCAAGGCAGGTCTCAATTTTGATGAAACTGAAGCCAGAAAGTTCCAGTGTTTGAAGCAGCAGGTAT
540
TTGGTAAAATTGAAGACTGAACTCGTGTTCAAATGCTTTCATGAACCGGGTTGGAGACGGTAGGAAAGCAACAAAACGGTGGGAACCGGGTGACTAAGGGCCTGGGTGCAAG GACTGGGGAAAGGTCATGGATAATAGATGGGGGGGTTTTCCCCCCTTTAGAAATGTGGGATATTAAGTGATATAAACACrTCTTTAAACTCCGAAAATCTTCGGAGAAATCA CAAAATTCACGGTATGCTCGGGAACGATCGGAGATTCCCTAGGTAGATGCTGGAATAGCCTAGACTTCACCAAGTGGGGGTGACACCAAAATCAGAGTCAGTTGGACCCAGA CATCAGCCACACTCGGGCGTCTGGACAAATGGTTCGGCCTGGTGGGACATTAATTTCAACGCTCTAACGTATATATCACCATCATCCCCATGGTGGCACTTCAACACAATAC CAAATTCAGGGTCCTCTCAAAGTCAAACAATTCTAACCACGTGTAACCAACAGTTCCGGGCGTCACTCCCCTGGTATTAACCCATCTGTGTTCGGCCCGCATCTGGAGGGTC ACTCAGGGGTGCCAACACACTCTGGTAATTCCCCTGGAACAAAGTGTGATTATACTTCGCCACTTAAGTCACAAGTAACCCTAACATACGCGACCACAACAAGCACAGGACA AATCAACCAGCACAAACACTACTCTGGTGGCGCGGACCCACCGCCCCTCTTGAAAAAACCCCTTCATAAACATCGCTGCTGGGGGGCGGGCCC
542
TTTTGAAAATTATGATATTTGTTATTTATTTAGCTGAGGCTAAAATAGGTATTTTAGTAAAACCAATGAGAACATTTAGAGTCCAATCCATGGTTGTCCCGTTGTATGACGA
TGTGGCCATGATCATGGGAGAGATTCATGATTGATGGTGACAAAGATTCTTTGCTTGCTGTAACTGCTTGGTCAGACTTTGGAATCTTCTGCTAGGCCCACCTGTGCACTTC TTTGTAAAATGTGCTGTGGGAATGGGGGATTCTGTGTCAGAGCTGGGGGGTCGGGTCCGGTGAGATGGGGATGCGGATTTAGATAATAGGGATGGGAAGTTCCGCGTGTGCG GCGGATATAAGGTCGGTGTACACTTGGTCGTTCAAGTGAGGCGGGGTCCACACTCGGTGGCCCGGTGA
544
GCGACCGCCCCCGCAAGATCTCGGCTCCCAGAGGAAGCACCCGCTCCCAGGAG'r'rGTGGGATCGGTCTTGAGGGTCTGGGCAGCCGAGTGGGAGCAGAAACCACACTGGTCC
TCCCACCCGCGCANCTCTCAGGGCCGGGGCGAGCGCGCCNGCGGGGTTTTTGCTAGCCTTTGCTGTGTCCTGGCCTCAACGGCGCCGCGCGGGAAAANTTTGNAGGGCAGGC
GGCGGGAAGTTATTTAAGCACTGGCTCGAANTGAGGACAGAGAACTGGNCAGGGGGTTACNCAGGGCCAATTCTTGGGCCATTCCGCCCCAAGGAACATGGAGCTGTCCCCA
AGCTTTCTTGAGCCCCGCCGGGAAACGCTTTCTCGGCTAATCTTTCTGNCAACTTTTACAAAGCTGCCTNCTCCNCATTTANATCTCTGAAAACANATCCTGGGCGTCCGGA
GN
546
TTCCAGGCCCGAGTGCTGGGCCACCACCACCAGGCCCAGGAGACCCGCTATGAGGTGCGCATCCAGCTCGTCTACAAGAACCGCTCGCCACTGCGGGCACGCGAGTACGTGT GGGCGCCAGGCCACTGCCCCTGCCCGATGCTGGCACCCCACCGGGACTACCTGATGGCTGTCCAGCGTCTTGTCAGCCCCGACGGCACACAGGACCAGCTGCTGCTGCCCCA CGCCGGCTACGCCCGGCCCTGGAGCCCTGCGGAGGACAGCCGCATACGCCTGACTGCCCGGCGCTGTCCTGGCTGAGCCCCTGCAGGAGCCCCGGCCACACACAGCAAGAAA GATACATCTGACCAGCCTCAACGTCAACGTATTTCCCCTCTCACCCTGGCTTCCAGGCAGCTCTGAAATA
548
AAAATGGAATCAGTGACTTTTATTTCTCATAACAGAGGTCAGAATAGAGAAAATGTGATGAAAGCACAAAATTTAACAAAGAAAAGGGGAGCAGCCACCCACCATCAAGGTG AGGACAGAATGTCTGTGTTCACGTAGGTCAATGGTAGCAGGTGGCAGATGGCAGCTGTTATCCGAAGCCCTGGACTCTTAAAGCTGAGGAAAAAGTTTTGTTCTGTTTAGGT GATTATGATAGTAGACCAGTCGAGGTTATTTGGAITTGGTTCACACCTGTGTAACGTTTCATTTATCAGTAGCTGAGTCTGAAAGATTTAAAGTACAGCAAAATTCCAGATG AACCAGAACACTGCTTTATGTTTTATCATATTTAGG
550
TTTTGCTCTTCTGAGCTGTTTACAACTGACCACTGTGTTCCACAGATGTATTTTTCAATAGCTTTTTGTTACTTAGTTTTCCATGATGCCTGTTATTTTTCTCTTGTAAATT
TAAATGAGCTGACTTTAAGGATCTTGGGAAAACCCATGGCATAATTACAATTTTCTTTTTAATCGACTTTTCATTACTTTTGGGAGTCTGTTGGTAACTAAAGATGTCAACA
AAGAATAAATTGGAGAAGTTACCTGTCCCCACTATAGCAGTAAACAAAACAGATGAAAAACACCTTGCTGTTAACTCAATGGTTGATCTAATTGTGAAATCGTTCACCTTGT
TAAACATCTAAGTAAGTCTGTAGTCGCTCTGCAAACAGCCATTATATTTATTTACTCTAGAAGAAACTGTAGAGTAGTAATTCGTGCTAATGAGAAAAACAAAATACCATGT
TCAAAACAGATGTATTTGAAAACTTAATGACATTGTTCCAAAAACTAGAGCATGTA'IGTATGCTGTGCATCATCTCAGCAGACCTAAAATATCCCCAAGTTGTCC
552
TTTTTAGATTAAAACATGAGAAATGACTTTTTATTTGCACTTATGCTTAATTACCTTTATTCATTTTGGAACATGCAGGAAATGATGCGGTGGTAACTTGCTGGGTAGTGAC
TAGGACGGTATTTACTGTCCTAGGGATGGTGGGATCCAGTGGACCAGAATCGTCAGCACCTCACCATGTACGCTGCTGTCCTCTCTCTGTGACTGTTTTGTGAGAGAGGAAG
GGAAGGGAAGGGGAAGGGAGGGGAGGGGGAAGGGAGAGGTGGGGAGGGGGACGGGAGGGAGGAAACAGAGCAACTCACCATTGCACCTCCCATGCTGGCCACAACATCTGTT
TATGGTGGGCCTACTGTGGGTTGCTTGGAGACTGCATGACATGTTCATACCGGCCCTCAAGATGCCATCAATAGGGGAGCCAGATAAATAAGCAAATAA'ITAGCATGCATGA
GCTGCTATTCGCTGCTTTAAAGGCTGCTTCTCTTACCIGGTATCTATTTCTTGTAGGAAAATGATCCATCTCTAAAGAATTTCTGAAAGAAAACGAACATGGTGGGACCCTC
CTGGCGC
554
GGGATACTTTATATTCTTTATTATTTTTATGTACAACCAACTCTAGTGAAGAACCIAAAAAGCTACAGACTAAATTTTTATAAAATCTCAGGACCTAATTATAAGAGCCCAA ACAACGGTTTAGTATCATTTAGCAAGCGGGGATTTTTCTCCCTCCAAAAACCGTTAATTTTGAAAAATATGGTTAAGTTTAAAAAGTTGCNATGTGTAAACGGNAGTTCCAT GGGNTGTGAAAACGGTTATAGNTACCTTCCTTAAAAAA
556
TTACGATGATGGCAAAATTAAAAGTTTAATTTTAAAAAGACGGTGGCAGCTTCTCTATCTGGATGTGTGTGTGAGTCATTTTTGCCGTCTCACGCCACGGCCCCΔCCACAGG CAGGCGACAGGTGGCTCCGTGGAGCTCCCGGGATGTGCTGGGGCCGCAGTCCGTGGTGGCCGCACGCAGACTGTTGGGTGGGCCGAGCAGCTGTCCTGAGGACACGGCAGGA ATTCGCGTGTGAACTCCCATTCCGGGTGCCGGCGAGGGACTCCGTGCCTGAGAGTTAGCAGG
558
TTTTTTTTGTTTTTGAGATGGAGTCTGGATCTGTCACGCAGGCTGGAGTGCAGTCGCGCGATCTCAGCTCACTGCAACCTATGCCTCCCAGGTCAAGCGATTCTCCTGCCTC
GGCCTCCCAAGGAAC'IGGAACCACAGGCGCGCGCCACTGCGCCCAAGGATTT'ICACTTTTAACTGTACAGTGAAGCACAGACTTCTGAGCCAGACTGCTTGGTCTGAACTCT
GGTGTCACCACTTAGTAAGTTCTGGTTTGAATG'IACTCACTGAGTGGTCTTCATAAATTACCTCTCTGCACTTGAGTCTCCTGTCTGTAAAATGGGGATAATAATCATTACA
ACGAAGCCTCATAGGATTCTGGTGGAGACCAAATGCATTAATACATATGCAAAGCGTTTGGAACAGCTGGCATATATAAGTGCCATATATCTATTATTAAAAATTC
560
GGTAGAACAATTTATΪTTCCTTTGGGTATATACCTAGTAATGGGATTGCTGGGTTGAACGGTAGTTCAGCTCTTAGTTCTTTGAGAACTCTCCAAATTACTTTCCACGGTGG CAGGACAAATTTACATTCTCACCAACAGTGTGTAAGTGTTCCCTTTTCTCTGCAGCCTCGCCAACATCTGTTATTTTTTGACTTTTTAACAAAAGCCATTCTGACTGGTGTG AGATGTTATCTCATTGTGGCTTTGATTTGCATTTCTCTGATGATTAGTGATGATGAACATTTTTTCATAAGTTTGTTGGCTGCTTGTATGCCTTCTTCTGAGAAGTGTCTGT TCATATCTTTCGCCTACTTTTTAACGGGGTTATTTGT
562
GAAGATTAGAGTTTTGATTTATTGAGATGGAAAAGGCTGTGGGAGCAAATGGGAGCAAAAGGTTTGAAGGGGGAGGATTAGGAATTTGCTTTTGGACATGCTACGTTTGAAC GCATTAGGCATCCACGIGCAGATATTGAGTCAGCAGTTGGGGATGTATGGGTCTGAAGTTCAGAGGAGAGTTCAGGCTGGAAAGAATATATTCGGAGTTGTAAACGTGAGGC CAGGCAGGATCACGAGGAAGTGAGTGTCAGTAGAGAAGAATGTGCATAGCCTTAGNACTTGAGTGAATAGGCTCNACTGTNTGGAAGT
564
TTTGCTTTTTGTTGTTGTTAGCTCATCAGCTATCATTAGTATCAGTGTATTTTATGTGTGGCCCAAAGCAATTCTTCCAAAGTGGCCCAGGGAAGCCAAAAGACTGGACATT CCTGATCTACACTATCTCGTTTTGTTCATTAGTTTCACAGACATTAGGTTAACTCTCCAATTAGACTTTAGGCAGCCTGTCCCTCAACTATTTATAATAATTCAAAGTATAC GTACTCATTGAAACCACCGCCTGCCAGAAAGGGAACTATAACGTTTTCAGGCAGGCCTAAGATGAGAAAGAAGCTGT'rAAGCCAAAATAGCTGATATCTATTCAGGCAAGGG GGTGGGGAGCAGAAAAAACAGGAGTGACATTTACACCGACTCTGTGCAGGTATTGTCTAAAGGGGCTTTCACAGCCACGACCTCGCTGAATCACCACAACCATCCTCTGAGA GGGGTGTATCTCCATTTTATAGATGAGAAAACACACACACATGCTATGGATCATTTTTAAAAACTAATGCAATGAACAAGCCTCCTTTCAGTATATATTCTG
566
GGTGTACAAATAGACAAGTAGTTTAATAAAGCAGAACAAAGAGTCTAGAAACAGACTCACAGATATATGGTCAATTTTCAACAAAGGTGCAAACTGGACATCATCAAAATTA
ACCTCTCTCTGCTCTTTGAAAGACGCTGTTGGCTGGGCACAGTGGCTCACGACTATAATGCCAGCACTTTGGGAGACTGAGATGGGTAGATTGCTTGTGCCCAGCAGCTCGA
GACCAGCCTGGGCAACATGGCATAACCCCATCTCTACAAAAANTTAGGCTGGGCATGGTGGCACACGCCTGTGGGTCCTGGGGAGGCTGAGGGTGGGGAGGGATAGCCTGAA
CCCCGGGGA

Claims

1. A substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257,
259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348,
350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
2. A polypeptide according to claim 1, wherein said biological activity is a hypoxia- regulated activity.
3. A polypeptide according to claim 2, wherein the expression of the polypeptide is hypoxia-induced.
4. A polypeptide according to claim 3, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265 or 267; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380 or 382, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
5. A polypeptide according to claim 3, wherein the expression of the polypeptide is hypoxia-repressed.
6. A polypeptide according to claim 5, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos:
515, 517, 519, 521, 523, 525, 527, 529 or 531; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii).
7. A polypeptide which is a functional equivalent according to part iv) of any one of claims 1-6, is homologous to the amino acid sequence as recited in any one of SEQ ID
Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531; or is homologous to the amino acid sequence encoded by a nucleic acid as recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334,
336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, and has equivalent biological activity to that possessed by the full length polypeptide of i) or ii).
8. A fragment or functional equivalent according to any one of claims 1-7, which has greater than 50% sequence identity with the amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531 or with the amino acid sequence that is encoded by a nucleic acid as recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334,
336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or with fragments thereof, preferably greater than 60%, 70%, 80%, 90%, 95%, 98% or 99% sequence identity.
9. A fragment as recited in any one of claims 1-8, having an antigenic determinant in common with a polypeptide according to part i) of any one of claims 1-8, which consists of 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more) amino acid residues from the amino acid sequence as recited in any one of SEQ ID Nos: 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 515, 517, 519, 521, 523, 525, 527, 529 or 531 or the amino acid sequence encoded by a nucleic acid as recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566.
10. A purified and isolated nucleic acid molecule that encodes a polypeptide according to any one of claims 1-9.
11. A purified nucleic acid molecule according to claim 10, which consists of the nucleic acid sequence as recited in any one of SEQ ID Nos.: 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276,
278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 or 566, or is a redundant equivalent or fragment thereof.
12. A purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule according to claim 10 or claim 11.
13. A vector comprising a nucleic acid molecule as recited in any one of claims 10-12.
14. A delivery vehicle comprising a nucleic acid according to any one of claims 10-12, or a vector according to claim 13.
15. A host cell transformed with a vector according to claim 13.
16. An antagonist ligand which binds specifically to, and which inhibits the hypoxia- induced activity of, a polypeptide according to any one of claims 1-9.
17. An agonist ligand which binds specifically to, and which activates the hypoxia-induced activity of, a polypeptide according to any one of claims 1-9 to augment or potentiate a hypoxia-induced activity.
18. A ligand according to claim 16 or 17, which is an antibody.
19. A ligand according to claim 16 or 17, which is a peptide, a peptidomimetic, or a drug molecule, such as a small natural or synthetic organic molecule of up to 2000Da, preferably 800Da or less.
20. A pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide according to any one of claims 1-9, a nucleic acid molecule according to any one of claims 10-12, a vector according to claim 13 or a ligand according to any one of claims 16-19, in conjunction with a pharmaceutically-acceptable carrier.
21. A vaccine composition comprising a polypeptide according to any one of claims 1-9, a nucleic acid molecule according to any one of claims 10-12, a vector according to claim 13 or a ligand according to claim 16-19.
22. A polypeptide according to any one of claims 1-9, a nucleic acid molecule according to any one of claims 10-12, a vector according to claim 13 or a ligand according to claim 16-19, for use in therapy or diagnosis of disease.
23. A polypeptide, nucleic acid molecule, vector or ligand as recited in claim 22, wherein said disease is a hypoxia-regulated condition.
24. A polypeptide, nucleic acid molecule, vector or ligand as recited in claim 22, wherein said hypoxia-regulated condition is tumourigenesis, angiogenesis, apoptosis, inflammation, erythropoiesis, the biological response to hypoxia conditions (including processes such as glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport or nitric oxide synthesis).
25. A substantially purified polypeptide, which polypeptide: i) comprises the amino acid sequence as recited in any one of SEQ ID Nos: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43,
45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83,
85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117,
119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147,
149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207,
209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237,
239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267,
383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411,
413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471,
473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501,
503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529 or 531; ii) has an amino acid sequence encoded by a nucleic acid sequence recited in any one of SEQ ID Nos: 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318,
320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564 and 566, or encoded by a gene identified from an EST recited in any one of these SEQ ID Nos; iii) is a fragment of a polypeptide according to i) or ii), provided that said fragment retains a biological activity possessed by the full length polypeptide of i) or ii), or has an antigenic determinant in common with the polypeptide of i) or ii); or iv) is a functional equivalent of a polypeptide of i), ii) or (iii); for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology, including cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation, erythropoiesis, or the biological response to hypoxia conditions, including processes such as glycolysis, gluconeogenesis, glucose transportation, catecholamine synthesis, iron transport and nitric oxide synthesis.
26. A purified and isolated nucleic acid molecule that encodes a polypeptide as recited in claim 25, for use in the diagnosis or therapy of for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
27. A purified nucleic acid molecule as recited in claim 26, which consists of the nucleic acid sequence as recited in any one of SEQ ID Nos.: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,
22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210,
212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380,
382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, or 566, or which is a redundant equivalent or fragment thereof, for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis. 28. A purified nucleic acid molecule which hydridizes under high stringency conditions with a nucleic acid molecule as recited in claim 26 or claim 27, for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
29. A vector comprising a nucleic acid molecule as recited in any one of claims 26-28, for use in the diagnosis or therapy of a disease or abnormal physiological condition that is affected by hypoxia, such as cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
30. A ligand which binds specifically to, and which preferably inhibits the hypoxia- induced activity of, a polypeptide as recited in claim 25, for use in the diagnosis or therapy of tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology.
31. A pharmaceutical composition suitable for modulating hypoxia and/or ischaemia, comprising a therapeutically-effective amount of a polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26- 28, a vector according to claim 13 or 29 or a ligand according to claim 16-19 or 30, in conjunction with a pharmaceutically-acceptable carrier.
32. A pharmaceutical composition according to claim 31, wherein said pharmaceutically- acceptable carrier is a liposome.
33. A vaccine composition comprising a polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26-28, or a vector according to claim 13 or 29.
34. A method of treating a disease in a patient in need of such treatment by administering to a patient a therapeutically effective amount of a polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26- 28, a vector according to claim 13 or 29 or a ligand according to claim 16-19 or 30.
35. A method of regulating tumourigenesis, angiogenesis, apoptosis, the biological response to hypoxia conditions, or a hypoxic-associated pathology in a patient in need of such treatment by administering to a patient a therapeutically effective amount of a a polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26-28, a vector according to claim 13 or 29 or a ligand according to claim 16-19 or 30 or a pharmaceutical composition according to claim 31 or 32. 36. A method according to claim 35, wherein, for diseases in which the expression of the natural gene or the activity of the polypeptide is lower in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, ligand, compound or composition administered to the patient is an agonist. 37. A method according to claim 35, wherein, for diseases in which the expression of the natural gene or activity of the polypeptide is higher in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an antagonist. 38. A polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26-28, a vector according to claim 13 or 29 or a ligand according to claim 16-19 or 30 or a pharmaceutical composition according to claim 31 or 32, for use in the manufacture of a medicament for the treatment of a hypoxia-regulated condition. 39. A method of monitoring the therapeutic treatment of a disease or physiological condition in a patient, comprising monitoring over a period of time the level of expression or activity of a polypeptide according to any one of claims 1-9 or 25, a nucleic acid molecule according to any one of claims 10-12 or 26-28, in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease.
40. A method of providing a hypoxia regulating gene, an apoptotic or an angiogenesis regulating gene by administering directly to a patient in need of such therapy an expressible vector comprising expression control sequences operably linked to one or more of the nucleic acid molecules recited in claims 10-12 or 26-28.
41. A method of diagnosing a hypoxia-regulated condition in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to any one of claims 1-9 or 25, or assessing the activity of such a polypeptide, in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of the hypoxia-related condition.
42. A method according to claim 41 that is carried out in vitro. 43. A method according to claim 41 or claim 42, which comprises the steps of: (a) contacting a ligand according to claim 16-19 or 30 with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex.
44. A method according to claim 41 or claim 42, comprising the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule according to any one of claims 10-12 or 26-28 and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of the hypoxia- related condition. 45. A method according to claim 41 or claim 42, comprising the steps of: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid primer under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule according to any one of claims 10-12 or 26-28 and the primer; b) contacting a control sample with said primer under the same conditions used in step a); c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; wherein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the amplified nucleic acid in the control sample is indicative of the hypoxia-related condition.
46. A method according to claim 51 or claim 52, comprising the steps of: a) obtaining a tissue sample from a patient being tested for the hypoxia-related condition; b) isolating a nucleic acid molecule according to any one of claims 10-12 or 26-28 from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation which is associated with the hypoxia-related condition in the nucleic acid molecule as an indication of the hypoxia-related condition.
47. The method of claim 46, further comprising amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product.
48. A method according to any one of claims 39-47, wherein said disease is cancer, ischaemic conditions, reperfusion injury, retinopathy, neonatal stress, preeclapmsia, atherosclerosis, inflammatory conditions, wound healing, tumourigenesis, angiogenesis, apoptosis, inflammation or erythropoiesis.
49. A method according to claim 48, wherein said hypoxia or ischaemia-related tissue damage is due to a disorder of the cerebral, coronary or peripheral circulation.
50. A method according to any one of claims 39, and 44-49, wherein the tissue is a cancer tissue.
51. A method for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a polypeptide according to any one of claims 1-9 or 25, or a nucleic acid molecule according to any one of claims 10-12 or
26-28 with one or more compounds suspected of possessing binding affinity for said polypeptide or nucleic acid molecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide.
52. A compound identified by a method according to claim 51. 53. A compound according to claim 52, which is a natural or modified substrate, an enzyme, a receptor, a small organic molecule, such as a small natural or synthetic organic molecule of up to 2000Da, preferably 800Da or less, a peptidomimetic, an inorganic molecule, a peptide, a polypeptide, an antibody, or a structural or functional mimetics of any of these compounds. 54. A kit useful for diagnosing disease comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to any one of claims 10-12 or 26-28; a second container containing primers useful for amplifying said nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease. 55. The kit of claim 54, further comprising a third container holding an agent for digesting unhybridised RNA.
56. An array of at least two nucleic acid molecules, wherein each of said nucleic acid molecules either corresponds to the sequence of, is complementary to the sequence of, or hybridises specifically to a nucleic acid molecule according to any one of claims 10- 12 or 26-28.
57. An array according to claim 56, which contains nucleic acid molecules that either correspond to the sequence of, are complementary to the sequence of, or hybridise specifically to at least 1-283 of the nucleic acid molecules implicated in a hypoxia- regulated condition as recited in claims 10-12 or 26-28. 58. An array according to any claim 56 or claim 57, wherein said nucleic acid molecules consist of between twelve and two thousand nucleotides.
59. An array of antibodies, comprising at least two different antibody species, wherein each antibody species is immunospecific with a polypeptide implicated in a hypoxia- regulated condition as recited in any one of claims 1-9 or 25.
60. An array of polypeptides, comprising at least two polypeptide species as recited in any one of claims 1-9 or 25, wherein each polypeptide species is implicated in a hypoxia- regulated condition, or is a functional equivalent variant or fragment thereof.
61. A kit comprising an array of nucleic acid molecules according to any one of claims 56- 58.
62. A kit comprising one or more antibodies that bind to a polypeptide as recited in any one of claims 1-9 or 25; and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide.
63. A transgenic or knockout non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to any one of claims 1-9 or
25. 64. A method for screening for a compound effective to treat disease, by contacting a non- human transgenic animal according to claim 63 with a candidate compound and determining the effect of the compound on the disease of the animal.
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