US20030096769A1 - Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders - Google Patents

Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders Download PDF

Info

Publication number
US20030096769A1
US20030096769A1 US09/791,196 US79119601A US2003096769A1 US 20030096769 A1 US20030096769 A1 US 20030096769A1 US 79119601 A US79119601 A US 79119601A US 2003096769 A1 US2003096769 A1 US 2003096769A1
Authority
US
United States
Prior art keywords
igf
nucleic acid
igfbp
acid molecule
molecule
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/791,196
Inventor
George Werther
Christopher Wraight
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Murdoch Childrens Research Institute
Original Assignee
Royal Childrens Hospital Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Royal Childrens Hospital Research Foundation filed Critical Royal Childrens Hospital Research Foundation
Priority to US09/791,196 priority Critical patent/US20030096769A1/en
Publication of US20030096769A1 publication Critical patent/US20030096769A1/en
Assigned to MURDOCH CHILDREN'S RESEARCH INSTITUTE reassignment MURDOCH CHILDREN'S RESEARCH INSTITUTE RELATIONSHIP AGREEMENT; ASSET AND LIABILITY TRANSFER AGREEMENT Assignors: ROYAL CHILDREN'S HOSPITAL RESEARCH FOUNDATION
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same.
  • the present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells.
  • the present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.
  • Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population.
  • the condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis.
  • IGFs insulin-like growth factors
  • IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as “progression factors” promoting “competent” cells through DNA synthesis.
  • the IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues (1).
  • GH growth hormone
  • IGFBPs IGF binding proteins
  • Skin comprising epidermis and underlying dermis, has GH receptors on dermal fiboblasts (4). Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6 (5) which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis.
  • the major epidermal cell type, the keratinocyte does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I (6).
  • IGF-I and other growth promoting molecules are responsible for or at least participate in a range of skin cell activities.
  • the inventors have established that abberations in the normal functioning of these molecules or abberations in their interaction with their receptors is an important factor in proliferative and/or inflammatory skin disorders. It is proposed, therefore, to target these molecules or other molecules which facilitate their functioning or interaction with their receptors to thereby ameliorate the effects of abberant activity during or leading to skin disease conditions.
  • one aspect of the present invention contemplates a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation.
  • Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and may be mediated by any number of molecules such as but not limited to IGF-I, keratinocyte growth factor (KGF), transforming growth factor- ⁇ (TGF ⁇ ), tumour necrosis factor- ⁇ (TNF ⁇ ), interleukin-1, -4, -6 and 8 (IL-1, IL-4, IL-6 and IL-8, respectively), basic fibroblast growth factor (bFGF) or a combination of one or more of the above.
  • IGF-I keratinocyte growth factor
  • TGF ⁇ transforming growth factor- ⁇
  • TGF ⁇ tumour necrosis factor- ⁇
  • TNF ⁇ tumour necrosis factor- ⁇
  • IL-1, -4, -6 and 8 interleukin-1, -4, -6 and 8
  • bFGF basic fibroblast growth factor
  • the present invention is particularly described and exemplified with reference to IGF-I and its receptor (IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, since targeting these molecules according to the methods contemplated herein provides the best results to date. This is done, however, with the understanding that the present invention extends to any growth factor or cytokine-like molecule, a receptor thereof or a facilitating molecule like the IGFBPs involved in skin cell proliferation such as those molecules contemplated above and/or their receptors and/or facilitating molecules therefor.
  • a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.
  • the present invention is particularly described by psoriasis as the proliferative skin disorder.
  • the subject invention extends to a range of proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of the skin.
  • proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of
  • the present invention is directed to a method for ameliorating the effects of psoriasis, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation.
  • the present invention extends to any mammal such as but not limited to humans, livestock animals (e.g. horses, sheep, cows, goats, pigs, donkeys), laboratory test animals (e.g. rabbits, mice, guinea pigs), companion animals (e.g. cats, dogs) and captive wild animals.
  • livestock animals e.g. horses, sheep, cows, goats, pigs, donkeys
  • laboratory test animals e.g. rabbits, mice, guinea pigs
  • companion animals e.g. cats, dogs
  • captive wild animals e.g., cows, cows, goats, pigs, donkeys
  • the instant invention is particularly directed to proliferative and/or inflammatory skin disorders such as psoriasis in humans.
  • nucleic acid molecule targets IGF-I interaction with its receptor.
  • nucleic acid molecule is an antagonist of IGF-I interaction with its receptor.
  • nucleic acid molecule antagonist is an antisense molecule to the IGF-I receptor, to IGF-I itself or to a molecule capable of facilitating IGF-I interaction with its receptor such as but not limited to an IGFBP.
  • the preferred molecules are IGFBP-2, -3, -4, -5 and -6.
  • the most preferred molecules are IGFBP-2 and IGFBP-3.
  • nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in FIGS. 1 (SEQ ID NO. 1) and 2 (SEQ ID NO. 2), respectively.
  • a nucleic acid molecule comprising at least about ten nucleotides capable of hybridising to, forming a heterodouplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to a genomic form of SEQ ID NO. 1 and/or SEQ ID NO. 2 and which thereby reduces or inhibits translation of said mRNA molecule.
  • the nucleic acid molecule is at least about 15 nucleotides in length and more preferably at least about 20-25 nucleotides in length.
  • the instant invention extends to any length nucleic acid molecule including a molecule of 100-200 nucleotides in length to correspond to the full length of or near full length of the subject genes.
  • the nucleotide sequence of the antisense molecules may correspond exactly to a region or portion of SEQ ID NO. 1 or SEQ ID NO. 2 or may differ by one or more nucleotide substitutions, deletions and/or additions. It is a requirement, however, that the nucleic acid molecule interact with an mRNA molecule to thereby reduce its translation into active protein.
  • Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 are those capable of interacting with sequences selected from the lists in Examples 6 and 7, respectively.
  • the nucleic acid molecules in the form of an antisense molecule may be linear or covalently closed circular and single stranded or partially double stranded.
  • a double stranded molecule may form a triplex with target mRNA or a target gene.
  • the molecule may also be protected from, for example, nucleases, by any number of means such as using a nonionic backbone or a phosphorothioate linkage.
  • a convenient nonionic backbone contemplated herein is ethylphosphotriester linkage or a 2′-O-methylribosyl derivative.
  • oligonucleotide analogues are conveniently described in Ts'O et al (7).
  • the antisense molecules of the present invention may target the IGF-I gene itself or its receptor or a multivalent antisense molecule may be constructed or separate molecules administered which target at least two or an IGFBP, IGF-I and/or IGF-I-receptor.
  • suitable antisense molecules capable of targetting the IGF-I receptor are those capable of interacting with sequences selected from the list in Example 8.
  • One particularly useful antisense molecule is 5′-ATCTCTCCGCTTCCTTTC-3′ (SEQ ID NO. 10).
  • a particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from two or more of an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3.
  • the nucleic acid molecule is topically applied in aqueous solution or in conjunction with a cream, ointment, oil or other suitable carrier and/or diluent.
  • a single application may be sufficient depending on the severity or exigencies of the condition although more commonly, multiple applications are required ranging from hourly, multi-hourly, daily, multi-daily, weekly or monthly, or in some other suitable time interval.
  • the treatment might comprise solely the application of the nucleic acid molecule or this may be applied in conjunction with other treatments for the skin proliferation and/or inflammatory disorder being treated or for other associated conditions including microbial infection, bleeding and the formation of a variety of rashes.
  • the subject invention extends to the nucleic acid molecule as, or incorporating, a ribozyme including a minizyme to, for example, IGF-I, its receptor or to molecules such as IGFBPs and in particular IGFBP-2 and -3.
  • Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach (8) and in International Patent Application No. WO 89/05852.
  • the present invention extends to ribozymes which target mRNA specified by genes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2 and/or IGFBP-3.
  • a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to SEQ ID NO. 1 or SEQ ID NO. 2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation.
  • Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3.
  • a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration.
  • nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.
  • the efficacy of the nucleic acid molecules of the present invention can be conveniently tested and screened using an in vitro system comprising a basal keratinocyte cell line.
  • a particularly useful system comprises the HaCaT cell line described by Boukamp et al (9).
  • IGF-I is added to an oligonucleotide treated HaCaT cell line.
  • growth of oligonucleotide treated HaCaT cells is observed on a feeder layer of irradiated 3T3 fibroblasts.
  • antisense oligonucleotides to IGFBP-3 for example, inhibit production of IGFBP-3 by HaCaT cells.
  • nude mouse/human skin graft model 15; 16
  • flaky skin 17; 18
  • nude mouse model microdermatome biopsies of psoriasis lesions are taken under local anaesthetic from volunteers then transplanted to congenital athymic (nude) mice.
  • These transplanted human skin grafts maintain the characteristic hyperproliferating epidermis for 6-8 weeks. They are an established model for testing the efficacy of topically applied therapies for psoriasis.
  • the flaky skin” mouse model the fsn/fsn mutation produces mice with skin resembling human psoriasis. This mouse, or another mutant mouse with a similar phenotype is a further in vivo model to test the efficacy of topically applied therapies for psoriasis.
  • nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents.
  • the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for co-suppression of one or more of these targets.
  • the composition may comprise a single species of a nuleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.
  • the nucleic acid molecules may be administered in dispersions prepared in creams, ointments, oil or other suitable carrier and/or diluent such as glycerol, liquid polyethylene glycols and/or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersion.
  • the form is preferably sterile although this is not an absolute requirement and is stable under the conditions of manufacture and storage.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants.
  • microorganism can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal and the like.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Topical solutions arc prepared by incorporating the nucleic acid molecule compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by where necessary filter sterilization.
  • pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the nucleic acid molecules of the present invention are stored in freeze-dried form and are reconstituted prior to use.
  • Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders mediated by a growth factor.
  • the proliferative and/or inflammatory skin disorder is generally psoriasis and the nucleic acid molecule targets IGF-I, the IGF-I receptor and/or an IGFBP such as IGFBP-2 and/or IGFBP-3.
  • Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis.
  • FIG. 1 is a representation of the nucleotide sequence of IGFBP-2.
  • IGFBP-2 insulin-like growth factor binding protein
  • KEYWORDS insulin-like growth factor binding protein.
  • SOURCE human ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
  • IGFBP-2 insulin-like growth factor binding protein
  • FIG. 2 is a representation of the nucleotide sequence of IGFBP-3.
  • ORGANISM Homo sapiens Eukaryota; Animalia; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
  • FIG. 3 is a representation of the nucleotide sequence of IGF-l-receptor.
  • SOURCE human ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
  • REFERENCE 1 bases 1 to 4989
  • AUTHORS Ullrich,A., Gray,A., Tam,A.W., Yang-Feng,T., Tsubokawa,M., Collins,C., Henzel,W., Bon,T.L., Kathuria,S., Chen,E., Jakobs,S., Francke , U., Ramachandran, J. and Fujita-Yamaguchi, Y. TITLE Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural dererminants that define functional specificity JOURNAL EMBO J.
  • FIG. 4A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 and BP3S) at 0.5 ⁇ M and 5 ⁇ M; * no oligonucleotide added.
  • BP3AS2, BP3AS3 and BP3S phosphorothioate oligonucleotides
  • FIG. 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (FIG. 4A), showing relative band intensities of IGFBP-3 and the 24 kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides; * no oligonucleotide added.
  • FIG. 5A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5 ⁇ M compared with several control oligonucleotides at 0.5 ⁇ M.
  • oligonucleotide BP3AS2NS oligonucleotide BP3AS4
  • oligonucleotide BP3AS4NS oligonucleotide BP3AS4NS
  • untreated no oligonucleotide added.
  • FIG. 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (FIG. 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in FIG. 5A, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide.
  • FIG. 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor.
  • IGFR.AS antisense
  • IGFR.S sense.
  • FIG. 7 is a graphical representation showing inhibition of IGFBP-3 production in culture medium following initial treatment with antisense oligonucleotides once daily over a 2 day period.
  • FIG. 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.
  • the differentiated human keratinocyte cell line, HaCaT (9) was used in the in vitro assay.
  • Cells at passage numbers 33 to 36 were maintained as monolayer cultures in 5% v/v CO 2 at 37° C. in Keratinocyte-SFM (Gibco) containing EGF and bovine pituitary extract as supplied.
  • Media containing foetal calf serum were avoided because of the high content of IGF-I binding proteins in serum.
  • Feeder layer plates of lethally irradiated 3T3 fibroblasts were prepared exactly as described by Rheinwald and Green (10).
  • IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in 0.5 ml fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours.
  • [ 3 H]-Thymidine (0.1 ⁇ Ci/well) was then added and the cells incubated for a further 3 hours. The medium was then aspirated and the cells washed once with ice-cold PBS and twice with ice-cold 10% v/v TCA.
  • TCA-precipitated monolayers were then solubilized with 0.25M NaOH (200 ⁇ l/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).
  • HaCaT conditioned medium 250 ⁇ l was concentrated by adding 750 ⁇ l cold ethanol, incubating at ⁇ 20° C. for 2 hours and centrifuging at 16,000 g for 20 min at 4° C. The resulting pellet was air dried, resuspended thoroughly in non-reducing Laemmli sample buffer, heated to 90° C. for 5 minutes and separated on 12% w/v SDS-PAGE according to the method of Laemmli (1970). Separated proteins were electrophoretically transferred to nitrocellulose membrane (0.45 mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25 mM Tris, 192 mM glycine and 20% v/v methanol.
  • IGFBPs were then visualised by the procedure of Hossenlopp et al (11), using [ 125 I]-IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.
  • Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Sydney, South Australia, Australia. The following antisense sequences were used: BP3AS2, 5′-GCG CCC GCT GCA TGA CGC CTG CAA C-3′ (SEQ ID NO. 4), a 25mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, 5′-CGG GCG GCT CAC CTG GAG CTG GCG-3′ (SEQ ID NO. 5), a 24 mer complementary to the exon 1/intron 1 splice site; BP3AS4, 5′-AGG CGG CTG ACG GCA CTA-3′ (SEQ ID NO.
  • BP3AS4 was found to be ineffective at inhibiting IGFBP-3 synthesis, it was used as a control.
  • the following additional control oligonucleotide sequences were used: BP3S, 5′-CAG GCG TCA TGC AGC GGG C-3′ (SEQ ID NO. 7), an 18 mer sense control sequence equivalent to the start codon region; BP3AS2NS, 5′-CGG AGA TGC CGC ATG CCA GCG CAG G-3′ (SEQ ID NO.
  • oligonucleotides were based on the human IGFBP-3 cDNA sequence of Spratt et al (12).
  • HaCaT cells secrete mainly IGFBP-3 (>95%), with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 ( ⁇ 5%).
  • Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA.
  • a sense oligonucleotide corresponding to the start site was used. As shown in FIGS.
  • BP3AS2 inhibition by this oligonucleotide at 0.5 ⁇ M was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5 ⁇ M.
  • BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of BP3AS2.
  • control oligonucleotides caused no reduction in IGFBP-3 levels at 0.5 ⁇ M, compared to untreated cells.
  • this control oligonucleotide, BP3AS2NS like BP3AS2 itself, has the highest potential T m of the three control oligonucleotides used in this experiment, enhancing the probability of non-specific base pairing with ron-target mRNAs.
  • the lack of inhibition of IGFBP4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.
  • Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: ATTCGGGGCGAGGGA AAGAAGCGGAGGAGG CCCGCTCGCAGGGCC TTCGGGGCGAGGGAG AGAAGCGGAGGAGGC CCGCTCGCAGGGCCG TCGGGGCGAGGGAGG GAAGCGGAGGAGGCG CGCTCGCAGGGCCGT CGGGGCGAGGGAGGA AAGCGGAGGAGGCGG GCTCGCAGGGCCGTG GGGGCGAGGGAGGAG AGCGGAGGAGGCGGC CTCGCAGGGCCGTGC GGGCGAGGGAGGAGG GCGGAGGAGGCGGCT TCGCAGGGCCGTGCA GGCGAGGGAGGAGGA CGGAGGAGGCGGCTC CGCAGGGCCGTGCAC GCGAGGGAGGAGGAA GGAGGAGGCGGCTCC GCAGGGCCGTGCACC CGAGGGAGGAGGAAG GAGGAGGCGGCTCCC CA
  • Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: CTCAGCGCCCAGCCG CCACAGCTTCGCGCC ATCCCTGCGCGCCCA TCAGCCCAGCCGC CACAGCTTCGCGCCG TCCCTGCGCCCAG CAGCGCCCAGCCGCT ACAGCTTCGCGCCGT CCCTGCGCGCCCAGC AGCCCAGCCGCTT CAGCTTCGCGCCGTG CCTGCGCCCAGCC GCGCCCAGCCGCTTC AGCTTCGCGCCGTGT CTGCGCCCAGCCT CGCCCAGCCGCTTCC GCTTCGCGCCGTGTA TGCGCCCAGCCTG GCCCAGCCGCTTCCT CTTCGCCGTGTA TGCGCCCAGCCTG GCCCAGCCGCTTCCT CTTCGCCGTGTAC GCGCGCCCAGCCTGC CCCAGCCGCTTCCTG TTCGCGCCGTGTACT CGCGCCCAGCCTGCC CCAGCCGCTTC
  • Antisense oligonucleotides to IGF-I may selected from molecules capable of interacting with one or the following sense oligonucleotides: TTTTTTTTTTTTTTG TCATCCCAAATAAAA GGCTCCGGAGGAGGG TTTTTTTTTGA CATCCCAAATAAAAG GCTCCGGAGGAGGGT TTTTTTTTTTGAG ATCCCAAATAAAAGG CTCCGGAGGAGGGTC TTTTTTTTTTTGAGA TCCCAAATAAAAGGA TCCGGAGGAGGGTCC TTTTTTTTTTGAGAA CCCAAATAAAAGGAA CCGGAGGAGGGTCCC TTTTTTTTTGAGAAA CCAAATAAAAGGAAT CGGAGGAGGGTCCCC TTTTTTTTGAGAAAG CAAATAAAAGGAATG GGAGGAGGGTCCCCG TTTTTTTGAAAGGAAGGAAGG AAATAAAAGGAATGA GAGGAGGGTCCCCGA TTTTTTGAGAAAGGG AATAAAAGGAATG GGAGGAGGGTCCCCG TTT
  • Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR.AS (antisense: 5′-ATCTCTCCGCTTCCTTT-3′; [SEQ ID NO. 10]; ref 13) and IGFR.S (sense control: 5′-GAAAGGAAGCGGAGAGAT-3′; [SEQ ID NO. 11]; Ref 13) IGF-I binding to the cell monolayers was then measured as 125 I-IGF-I.
  • IGFR.AS antisense: 5′-ATCTCTCCGCTTCCTTT-3′; [SEQ ID NO. 10]; ref 13
  • IGFR.S sense control: 5′-GAAAGGAAGCGGAGAGAT-3′; [SEQ ID NO. 11]; Ref 13
  • HaCaT cells were initially plated in DMEM with 10% v/v serum, then AS oligo experiments were performed in complete “Keratinocyte-SFM” (Gibco) to exclude the influence of exogenous IGFBPs.
  • Oligos were synthesised as phosphorothioate (nuclease-resistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, 5′-GCGCCCGCTGCATGACGCCTCAAC-3′ (IGFBP-3 start codon); control AS2NS, 5′-CGGAGATGCCGCATGCCAGCGCAGG-3′; AS4, 5′-AGGCGGCTGACGGCACTA-3′; AS4NS, 5′-GACAGCGTCGGAGCGATC-3′; IGFRAS, 5′-ATCTCTCCGCTTCCTTTC-3′; IGFRS, 5′-GAAAGGAAGCGGAGAGAT-3′.
  • Oligos to IGFBP-3 were based on the published sequence of Spratt et al [12]. AS oligos were added to HaCaT monolayers in 0.5 ml medium in 24-well plates at the concentrations and addition frequencies indicated. IGFBP-3 measured in cell-conditioned medium using a dot-blot assay, adapted from the Western ligand blot method of Hossenlopp et al [11], in which 100 ⁇ l of conditioned medium was applied to nitrocellulose filters with a vacuum dot-blot apparatus. After drying the membranes at 37° C., relative amounts of IGFBP are determined by 125 I-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in FIG.
  • Ribozymes are constructed with a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA which, in this case, encodes IGFBP-2. Activity of ribozymes is measurable on, for example, Northern blots or using animal models such as in the nude mouse model ( 15 ; 16 ) or the “flaky skin” mouse model ( 17 ; 18 ).
  • Example 11 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11.
  • Example 11 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.
  • Example 11 The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11

Abstract

The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.

Description

  • The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis. [0001]
  • Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide sequences referred to in the specification are defined following the bibliography. [0002]
  • Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers. [0003]
  • Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population. The condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis. [0004]
  • One important group of growth factors are the dermally-derived insulin-like growth factors (IGFs) which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as “progression factors” promoting “competent” cells through DNA synthesis. The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues (1). [0005]
  • Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability (2). Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed (3). There is some evidence, however, that certain IGFBPs are involved in targeting IGF-I to its cell surface receptor. [0006]
  • Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fiboblasts (4). Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6 (5) which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I (6). [0007]
  • It is apparent, therefore, that IGF-I and other growth promoting molecules, are responsible for or at least participate in a range of skin cell activities. In accordance with the present invention, the inventors have established that abberations in the normal functioning of these molecules or abberations in their interaction with their receptors is an important factor in proliferative and/or inflammatory skin disorders. It is proposed, therefore, to target these molecules or other molecules which facilitate their functioning or interaction with their receptors to thereby ameliorate the effects of abberant activity during or leading to skin disease conditions. [0008]
  • Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation. Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and may be mediated by any number of molecules such as but not limited to IGF-I, keratinocyte growth factor (KGF), transforming growth factor-α (TGFα), tumour necrosis factor-α (TNFα), interleukin-1, -4, -6 and 8 (IL-1, IL-4, IL-6 and IL-8, respectively), basic fibroblast growth factor (bFGF) or a combination of one or more of the above. The present invention is particularly described and exemplified with reference to IGF-I and its receptor (IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, since targeting these molecules according to the methods contemplated herein provides the best results to date. This is done, however, with the understanding that the present invention extends to any growth factor or cytokine-like molecule, a receptor thereof or a facilitating molecule like the IGFBPs involved in skin cell proliferation such as those molecules contemplated above and/or their receptors and/or facilitating molecules therefor. [0009]
  • According to this preferred embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation. [0010]
  • The present invention is particularly described by psoriasis as the proliferative skin disorder. However, the subject invention extends to a range of proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of the skin. [0011]
  • In a preferred embodiment, therefore, the present invention is directed to a method for ameliorating the effects of psoriasis, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation. [0012]
  • The present invention extends to any mammal such as but not limited to humans, livestock animals (e.g. horses, sheep, cows, goats, pigs, donkeys), laboratory test animals (e.g. rabbits, mice, guinea pigs), companion animals (e.g. cats, dogs) and captive wild animals. However, the instant invention is particularly directed to proliferative and/or inflammatory skin disorders such as psoriasis in humans. [0013]
  • The aspects of the subject invention instantly contemplated are particularly directed to the topical application of one or more suitable nucleic molecules capable of inhibiting, reducing or otherwise interfering with IGF-mediated cell proliferation and/or inflammation. More particularly, the nucleic acid molecule targets IGF-I interaction with its receptor. Conveniently, therefore, the nucleic acid molecule is an antagonist of IGF-I interaction with its receptor. Most conveniently, the nucleic acid molecule antagonist is an antisense molecule to the IGF-I receptor, to IGF-I itself or to a molecule capable of facilitating IGF-I interaction with its receptor such as but not limited to an IGFBP. [0014]
  • Insofar as the invention relates to IGFBPs, the preferred molecules are IGFBP-2, -3, -4, -5 and -6. The most preferred molecules are IGFBP-2 and IGFBP-3. [0015]
  • The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in FIGS. [0016] 1 (SEQ ID NO. 1) and 2 (SEQ ID NO. 2), respectively. According to a particularly preferred aspect of the present invention, there is provided a nucleic acid molecule comprising at least about ten nucleotides capable of hybridising to, forming a heterodouplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to a genomic form of SEQ ID NO. 1 and/or SEQ ID NO. 2 and which thereby reduces or inhibits translation of said mRNA molecule. Preferably, the nucleic acid molecule is at least about 15 nucleotides in length and more preferably at least about 20-25 nucleotides in length. However, the instant invention extends to any length nucleic acid molecule including a molecule of 100-200 nucleotides in length to correspond to the full length of or near full length of the subject genes.
  • The nucleotide sequence of the antisense molecules may correspond exactly to a region or portion of SEQ ID NO. 1 or SEQ ID NO. 2 or may differ by one or more nucleotide substitutions, deletions and/or additions. It is a requirement, however, that the nucleic acid molecule interact with an mRNA molecule to thereby reduce its translation into active protein. [0017]
  • Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 are those capable of interacting with sequences selected from the lists in Examples 6 and 7, respectively. [0018]
  • The nucleic acid molecules in the form of an antisense molecule may be linear or covalently closed circular and single stranded or partially double stranded. A double stranded molecule may form a triplex with target mRNA or a target gene. The molecule may also be protected from, for example, nucleases, by any number of means such as using a nonionic backbone or a phosphorothioate linkage. A convenient nonionic backbone contemplated herein is ethylphosphotriester linkage or a 2′-O-methylribosyl derivative. [0019]
  • Examples of suitable oligonucleotide analogues are conveniently described in Ts'O et al (7). [0020]
  • Alternatively, the antisense molecules of the present invention may target the IGF-I gene itself or its receptor or a multivalent antisense molecule may be constructed or separate molecules administered which target at least two or an IGFBP, IGF-I and/or IGF-I-receptor. Examples of suitable antisense molecules capable of targetting the IGF-I receptor are those capable of interacting with sequences selected from the list in Example 8. One particularly useful antisense molecule is 5′-ATCTCTCCGCTTCCTTTC-3′ (SEQ ID NO. 10). A particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from two or more of an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3. [0021]
  • In accordance with one aspect of the present invention the nucleic acid molecule is topically applied in aqueous solution or in conjunction with a cream, ointment, oil or other suitable carrier and/or diluent. A single application may be sufficient depending on the severity or exigencies of the condition although more commonly, multiple applications are required ranging from hourly, multi-hourly, daily, multi-daily, weekly or monthly, or in some other suitable time interval. The treatment might comprise solely the application of the nucleic acid molecule or this may be applied in conjunction with other treatments for the skin proliferation and/or inflammatory disorder being treated or for other associated conditions including microbial infection, bleeding and the formation of a variety of rashes. [0022]
  • As an alternative to or in conjunction with antisense therapy, the subject invention extends to the nucleic acid molecule as, or incorporating, a ribozyme including a minizyme to, for example, IGF-I, its receptor or to molecules such as IGFBPs and in particular IGFBP-2 and -3. Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach (8) and in International Patent Application No. WO 89/05852. The present invention extends to ribozymes which target mRNA specified by genes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2 and/or IGFBP-3. [0023]
  • According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to SEQ ID NO. 1 or SEQ ID NO. 2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation. [0024]
  • Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3. In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone. [0025]
  • The efficacy of the nucleic acid molecules of the present invention can be conveniently tested and screened using an in vitro system comprising a basal keratinocyte cell line. A particularly useful system comprises the HaCaT cell line described by Boukamp et al (9). In one assay, IGF-I is added to an oligonucleotide treated HaCaT cell line. Alternatively, growth of oligonucleotide treated HaCaT cells is observed on a feeder layer of irradiated 3T3 fibroblasts. Using such in vitro assays, it is observed that antisense oligonucleotides to IGFBP-3, for example, inhibit production of IGFBP-3 by HaCaT cells. Other suitable animal models include the nude mouse/human skin graft model (15; 16) and the “flaky skin” mouse model (17; 18). In the nude mouse model, microdermatome biopsies of psoriasis lesions are taken under local anaesthetic from volunteers then transplanted to congenital athymic (nude) mice. These transplanted human skin grafts maintain the characteristic hyperproliferating epidermis for 6-8 weeks. They are an established model for testing the efficacy of topically applied therapies for psoriasis. In the “flaky skin” mouse model, the fsn/fsn mutation produces mice with skin resembling human psoriasis. This mouse, or another mutant mouse with a similar phenotype is a further in vivo model to test the efficacy of topically applied therapies for psoriasis. [0026]
  • Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents. Preferably, the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for co-suppression of one or more of these targets. The composition may comprise a single species of a nuleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3. [0027]
  • The nucleic acid molecules may be administered in dispersions prepared in creams, ointments, oil or other suitable carrier and/or diluent such as glycerol, liquid polyethylene glycols and/or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. [0028]
  • The pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersion. In all cases, the form is preferably sterile although this is not an absolute requirement and is stable under the conditions of manufacture and storage. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants. The prevention of the action of microorganism can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. [0029]
  • Topical solutions arc prepared by incorporating the nucleic acid molecule compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by where necessary filter sterilization. [0030]
  • As used herein “pharmaceutically acceptable carriers and/or diluents” include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Conveniently, the nucleic acid molecules of the present invention are stored in freeze-dried form and are reconstituted prior to use. [0031]
  • Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders mediated by a growth factor. The proliferative and/or inflammatory skin disorder is generally psoriasis and the nucleic acid molecule targets IGF-I, the IGF-I receptor and/or an IGFBP such as IGFBP-2 and/or IGFBP-3. [0032]
  • Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis. [0033]
  • The present invention is further described by the following non-limiting Figures and/or Examples. [0034]
  • In the Figures: [0035]
  • FIG. 1 is a representation of the nucleotide sequence of IGFBP-2. [0036]
    LOCUS HSIGFBP2   1433 bp  RNA     PRI    31-JAN-1990
    DEFINITION Human mRNA for insulin-like growth factor binding protein (IGFBP-2)
    ACCESSION X16302
    KEYWORDS insulin-like growth factor binding protein.
    SOURCE human
    ORGANISM Homo sapiens
    Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia;
    Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
    REFERENCE 1 (bases 1 to 1433)
    AUTHORS Binkert,C., Landwehr,J., Mary,J.L., Schwander,J. and Heinrich,G.
    TITLE Cloning, sequence analysis and expression of a cDNA encoding a
    novel insulin-like growth factor binding protein (IGFBP-2)
    JOURNAL EMBO J. 8, 2497-2502 (1989)
    STANDARD full automatic
    COMMENT NCBI gi: 33009
    FEATURES Location/Qualifiers
    source
    1. .1433
    /organism=“Homo sapiens”
    /dev_stage=“fetal”
    /tissue_type=“liver”
    misc_feature 1416. .1420
    /note=“pot. polyadenylation signal”
    polyA_site 1433
    /note=“polyadenylation site”
    CDS 118. .1104
    /note=“precursor polypeptide; (AA -39 to 289); NCBI gi:
    33010.”
    /codon_start=1
    /translation=“MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARAEVLFR
    CPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGEACG
    VYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAEYGASPEQVADNGDDHSEGG
    LVENHVDSTMNMLGGGGSAGRKPLKSGMKELAVFREKVTEQHRQMGKGGKHHLGLEEP
    KKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHLYSLHIPNCDKHGLYNLKQCK
    MSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEACGVHTQRMQ”
    CDS 118. .234
    /note=“signal peptide; (AA -39 to -1); NCBI gi: 33011.”
    /codon_start=1
    /translation=“MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARA”
    CDS 235. .1101
    /note=“mature IGFBP-2; (AA 1 to 289); NCBI gi: 33012.”
    /codon_start=1
    /translation=“EVLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVR
    EPGCGCCSVCARLEGEACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAE
    YGASPEQVADNGDDHSEGGLVENHVDSTMNMLGGGGSAGRKPLKSGMKELAVFREKVT
    EQHRQMGKGGKHHKGLEEPKKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHLY
    SLHIPNCDKEGLYNLKQCKMSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNE
    QQEACGVHTQRMQ”
    BASE COUNT   239 a   466 c   501 g   227 t
    ORIGIN
     HSIGFBP2 Length:  1433 May 11, 1994 10:06 Type: N Check: 6232 ..
  • FIG. 2 is a representation of the nucleotide sequence of IGFBP-3. [0037]
    LOCUS HUMGFIBPA   2474 bp ss-mRNA     PRI    15-JUN-1990
    DEFINITION Human growth hormone-dependent insulin-like growth factor-binding
    protein mRNA, complete cds.
    ACCESSION M31159
    KEYWORDS insulin-like growth factor binding protein.
    SOURCE Human plasma, eDNA to mRNA, clone BP-53.
    ORGANISM Homo sapiens
    Eukaryota; Animalia; Chordata; Vertebrata; Mammalia; Theria;
    Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
    REFERENCE 1 (bases 1 to 2474)
    AUTHORS Wood,W.I., Cachianes,G., Henzel,W.J., Winslow,G.A., Spencer,S.A.,
    Hellmiss,R., Martin,J.L. and Baxter,R.C.
    TITLE Cloning and expression of the growth hormone-dependent insulin-like
    growth factor-binding protein
    JOURNAL Mol. Endocrinol. 2, 1176-1185 (1988)
    STANDARD full automatic
    COMMENT NCBI gi: 183115
    FEATURES Location/Qualifiers
    mRNA <1. .2474
    /note=“GFIBP mRNA”
    CDS 110. .985
    /gene=“IGFBP1”
    /note=“insulin-like growth factor-binding protein; NCBI
    gi: 183116.”
    /codon_start=1
    /translation=“MQRARPTLWAAALTLLVLLRGPPVARAGASSGGLGPVVRCEPCD
    ARALAQCAPPPAVCAELVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPSPDEAR
    PLQALLDGRGLCVNASAVSRLAYLLJPAPPAPGNASESEEDRSAGSVESPSVSSTHRV
    SDPKFWPLHSKIIIIKKGHAKDSQRYKDYESQSTDTQNFSSESKRETEYGPCRREME
    DTLNHLKFLNVLSPRGHIPNCDKKGFYKKKKQCRPSKGRKRGFCWCVCDKYGQPLPGYT
    TKGKEDVHCYSMQSK”
    source 1. .2474
    /organism=“Homo sapiens”
    BASE COUNT   597 a   646 c   651 g   580 t
    ORIGIN
     HUMGFIBPA Length: 2474 May 11, 1994 10:00 Type: N Check: 9946 ..
  • FIG. 3 is a representation of the nucleotide sequence of IGF-l-receptor. [0038]
    LOCUS HSIGFIRR   4989 bp  RNA     PRI    28-MAR-1991
    DEFINITION Human mRNA for insulin-like growth factor I receptor
    ACCESSION X04434 M24599
    KEYWORDS glycoprotein; insulin receptor;
    insulin-like growth factor I receptor; membrane glycoprotein;
    receptor; tyrosine kinase.
    SOURCE human
    ORGANISM Homo sapiens
    Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia;
    Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.
    REFERENCE 1 (bases 1 to 4989)
    AUTHORS Ullrich,A., Gray,A., Tam,A.W., Yang-Feng,T., Tsubokawa,M.,
    Collins,C., Henzel,W., Bon,T.L., Kathuria,S., Chen,E., Jakobs,S.,
    Francke , U., Ramachandran, J. and Fujita-Yamaguchi, Y.
    TITLE Insulin-like growth factor I receptor primary structure: comparison
    with insulin receptor suggests structural dererminants that define
    functional specificity
    JOURNAL EMBO J. 5, 2503-2512 (1986)
    STANDARD full automatic
    COMMENT NCBI gi: 33058
    FEATURES Location/Qualifiers
    source 1. .4989
    /organism=“Homo sapiens”
    /tissue_type=“placenta”
    /clone—lib=“ (lamda)gt10”
    /clone=“ (lambda) IGF-1-R.85, (lambda) IGF-1-R.76”
    sig_peptide 32. .121
    mat_peptide 122. .4132
    /note=“IGF-I receptor”
    misc_feature 122. .2251
    /note=“alpha-subunit (AA 1 - 710)”
    misc_feature 182. .190
    /note=“pot.N-linked glycosylation site (AA 21 - 23)”
    misc_feature 335. .343
    /note=“pot.N-linked glycostlation site (AA 72 - 74)”
    misc_feature 434. .442
    /note=“pot.N-linked glycostlation site (AA 105 - 107)”
    misc_feature 761. .769
    /note=“pot.N-linked glycostlation site (AA 214 - 216)”
    misc_feature 971. .979
    /note=“pot.N-linked glycostlation site (AA 284 - 286)”
    misc feature 1280. .1288
    /note=“pot.N-linked glycostlation site (AA 387 - 389)”
    misc_feature 1343. .1351
    /note=“pot.N-linked glycosylation site (AA 408 - 410)”
    misc_feature 1631. .1639
    /note=“pot.N-linked glycostlation site (AA 504 - 506)”
    misc_feature 1850. .1858
    /note=“pot.N-linked glycosylation site (AA 577 - 579)”
    misc feature 1895. .1903
    /note.“pot.N-linked glycosylation site (AA 592 - 594)”
    misc_feature 1949. .1957
    /note=“pot.N- linked glycosylation site (AA 610 - 612)”
    misc_feature 2240. .2251
    /note=“putative proreceptor processing site (AA 707 -
    710)”
    misc_feature 2252. .4132
    /note=“beta-subunit (AA 711 - 1337)”
    misc_feature 2270. .2278
    /note=“pot.N-linked glycosylation site (AA 717 - 719]”
    misc_feature 2297. .2305
    /note=“pot.N-linked glycosylation site (AA 726 - 728)”
    misc feature 2321. .2329
    /note=“pot.N-linked glycosylation site (AA 734 - 736)”
    misc_feature 2729. .2737
    /note=“pot.N-linked glycosylation site (AA 870 - 872)”
    misc feature 2768. .2776
    /note=“pot.N-linked glycosylation site (AA 883 - 885)”
    misc_feature 2837. .2908
    /note=“transmembrane region (AA 906 - 929)”
    misc feature 2918. .2926
    /note=“pot.N-linked glycosylation site (AA 933 - 935)”
    misc_feature 3047. .3049
    /note=“pot.ATP binding site (AA 976)”
    misc feature 3053. .3055
    /note=“pot.ATP binding site (AA 978)”
    misc feature 3062. .3064
    /note=“pot.ATP binding site (AA 981)”
    misc_feature 3128. .3130
    /note=“pot.ATP binding site (AA 1003)”
    CDS 32. .4132
    /product=“IGF-I receptor”
    /note=“50 stops when translation attempted, frame 1, code
    0”
    BASE COUNT   1216 a   1371 c   1320 g   1082 t
    ORIGIN
     HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N Check: 133 ..
  • FIG. 4A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 and BP3S) at 0.5 μM and 5 μM; * no oligonucleotide added. [0039]
  • FIG. 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (FIG. 4A), showing relative band intensities of IGFBP-3 and the 24 kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides; * no oligonucleotide added. [0040]
  • FIG. 5A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5 μM compared with several control oligonucleotides at 0.5 μM. (a) oligonucleotide BP3AS2NS; (b) oligonucleotide BP3AS4; (c) oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added. [0041]
  • FIG. 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (FIG. 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in FIG. 5A, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide. [0042]
  • FIG. 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense; IGFR.S: sense. [0043]
  • FIG. 7 is a graphical representation showing inhibition of IGFBP-3 production in culture medium following initial treatment with antisense oligonucleotides once daily over a 2 day period. [0044]
  • FIG. 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.[0045]
    • EXAMPLE 1 In Vitro Assay
  • Cells [0046]
  • The differentiated human keratinocyte cell line, HaCaT (9) was used in the in vitro assay. Cells at passage numbers 33 to 36 were maintained as monolayer cultures in 5% v/v CO[0047] 2 at 37° C. in Keratinocyte-SFM (Gibco) containing EGF and bovine pituitary extract as supplied. Media containing foetal calf serum were avoided because of the high content of IGF-I binding proteins in serum.
  • Feeder layer plates of lethally irradiated 3T3 fibroblasts were prepared exactly as described by Rheinwald and Green (10). [0048]
    • EXAMPLE 2 In Vitro Assay
  • Thymidine Incorporation Assay [0049]
  • Cells were grown to 4 days post confluence in 2 cm[0050] 2 wells with daily medium changes of Keratinocyte-SFM, then the medium was changed to DMEM (Cytosystems, Australia), with the following additions: 25 mM Hepes, 0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co, USA), 50 IU/ml penicillin and 50 μg/ml streptomycin (Flow Laboratories). After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in 0.5 ml fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours. [3H]-Thymidine (0.1 μCi/well) was then added and the cells incubated for a further 3 hours. The medium was then aspirated and the cells washed once with ice-cold PBS and twice with ice-cold 10% v/v TCA. The TCA-precipitated monolayers were then solubilized with 0.25M NaOH (200 μl/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).
    • EXAMPLE 3 Western Ligand Blotting
  • HaCaT conditioned medium (250 μl) was concentrated by adding 750 μl cold ethanol, incubating at −20° C. for 2 hours and centrifuging at 16,000 g for 20 min at 4° C. The resulting pellet was air dried, resuspended thoroughly in non-reducing Laemmli sample buffer, heated to 90° C. for 5 minutes and separated on 12% w/v SDS-PAGE according to the method of Laemmli (1970). Separated proteins were electrophoretically transferred to nitrocellulose membrane (0.45 mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25 mM Tris, 192 mM glycine and 20% v/v methanol. IGFBPs were then visualised by the procedure of Hossenlopp et al (11), using [[0051] 125I]-IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.
    • EXAMPLE 4 Antisense Oligonucleotides
  • Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Adelaide, South Australia, Australia. The following antisense sequences were used: BP3AS2, 5′-GCG CCC GCT GCA TGA CGC CTG CAA C-3′ (SEQ ID NO. 4), a 25mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, 5′-CGG GCG GCT CAC CTG GAG CTG GCG-3′ (SEQ ID NO. 5), a 24 mer complementary to the [0052] exon 1/intron 1 splice site; BP3AS4, 5′-AGG CGG CTG ACG GCA CTA-3′ (SEQ ID NO. 6), an 18 mer complementary to a region of the coding sequence lacking RNA secondary structure and oligonucleotide-dimer formation (using the computer software “OLIGO for PC”). Since BP3AS4 was found to be ineffective at inhibiting IGFBP-3 synthesis, it was used as a control. The following additional control oligonucleotide sequences were used: BP3S, 5′-CAG GCG TCA TGC AGC GGG C-3′ (SEQ ID NO. 7), an 18 mer sense control sequence equivalent to the start codon region; BP3AS2NS, 5′-CGG AGA TGC CGC ATG CCA GCG CAG G-3′ (SEQ ID NO. 8), a 25 mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, 5′-GAC AGC GTC GGA GCG ATC-3′ (SEQ ID NO. 9), an 18 mer randomised sequence with the same GC content as BP3AS4NS. Design of the oligonucleotides was based on the human IGFBP-3 cDNA sequence of Spratt et al (12).
  • Cells were grown to one day post confluence in 2 cm[0053] 2 wells with daily medium changes of 0.5 ml Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte-SFM for a further 4 days. Daily additions of 0.5 ml fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 5 μl oligonucleotide in PBS was added to give the final concentrations indicated, then the wells were shaken to mix the oligonucleotide. After the final addition, cells were incubated for 24 hours and the medium collected for assay of IGFBPs. Cells were then counted after trypsinisation in a Coulter Industrial D Counter, Coulter Bedfordshire, UK. Cell numbers after oligonucleotide treatment differed by less than 10%.
    • EXAMPLE5 Antisense Oligonucleotides Inhibit IGFBP-3 Synthesis
  • HaCaT cells secrete mainly IGFBP-3 (>95%), with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 (<5%). The effect on IGFBP-3 and IGFBP-4 synthesis of antisense oligonucleotides at two concentrations, 5 μM and 0.5 μM, was tested. Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the [0054] intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in FIGS. 4A and 4B, all oligonucleotides at 5 μM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately 50% compared to the sense control (FIG. 4B). The antisense oligonucleotide directed to the start codon appeared to be more effective of the two, the difference being more apparent at the lower concentration of 0.5 μM. The cells of IGFBP4 secreted by the HaCaT cells make photographic reproduction of the bands on Western ligand blots difficult, however densitometry measurements provide adequate relative quantitation. This resulted in the significant observation that IGFBP4 levels were unaffected by oligonucleotide addition to the cells, suggesting that the observed inhibitory effects on IGFBP-3 are specific.
  • To further investigate the inhibitory effects of the more effective of the two antisense oligonucleotides, BP3AS2, inhibition by this oligonucleotide at 0.5 μM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5 μM. As shown in FIGS. 5A and 5B, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of BP3AS2. The other control oligonucleotides caused no reduction in IGFBP-3 levels at 0.5 μM, compared to untreated cells. Of possible significance is the fact that this control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has the highest potential T[0055] m of the three control oligonucleotides used in this experiment, enhancing the probability of non-specific base pairing with ron-target mRNAs. However, the lack of inhibition of IGFBP4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.
    • EXAMPLE 6 Antisense Oligonucleotides of IGFBP2
  • Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: [0056]
    ATTCGGGGCGAGGGA AAGAAGCGGAGGAGG CCCGCTCGCAGGGCC
    TTCGGGGCGAGGGAG AGAAGCGGAGGAGGC CCGCTCGCAGGGCCG
    TCGGGGCGAGGGAGG GAAGCGGAGGAGGCG CGCTCGCAGGGCCGT
    CGGGGCGAGGGAGGA AAGCGGAGGAGGCGG GCTCGCAGGGCCGTG
    GGGGCGAGGGAGGAG AGCGGAGGAGGCGGC CTCGCAGGGCCGTGC
    GGGCGAGGGAGGAGG GCGGAGGAGGCGGCT TCGCAGGGCCGTGCA
    GGCGAGGGAGGAGGA CGGAGGAGGCGGCTC CGCAGGGCCGTGCAC
    GCGAGGGAGGAGGAA GGAGGAGGCGGCTCC GCAGGGCCGTGCACC
    CGAGGGAGGAGGAAG GAGGAGGCGGCTCCC CAGGGCCGTGCACCT
    GAGGGAGGAGGAAGA AGGAGGCGGCTCCCG AGGGCCGTGCACCTG
    AGGGAGGAGGAAGAA GGAGGCGGCTCCCGC GGGCCGTGCACCTGC
    GGGAGGAGGAAGAAG GAGGCGGCTCCCGCT GGCCGTGCACCTGCC
    GGAGGAGGAAGAAGC AGGCGGCTCCCGCTC GCCGTGCACCTGCCC
    GAGGAGGAAGAAGCG GGCGGCTCCCGCTCG CCGTGCACCTGCCCG
    AGGAGGAAGAAGCGG GCGGCTCCCGCTCGC CGTGCACCTGCCCGC
    GGAGGAAGAAGCGGA CGGCTCCCGCTCGCA GTGCACCTGCCCGCC
    GAGGAAGAAGCGGAG GGCTCCCGCTCGCAG TGCACCTGCCCGCCC
    AGGAAGAAGCGGAGG GCTCCCGCTCGCAGG GCACCTGCCCGCCCG
    GGAAGAAGCGGAGGA CTCCCGCTCGCAGGG CACCTGCCCGCCCGC
    GAAGAAGCGGAGGAG TCCCGCTCGCAGGGC ACCTGCCCGCCCGCC
    CCTGCCCGCCCGCCC CATGCTGCCGAGAGT CGCTGCTGCCGCTGC
    CTGCCCGCCCGCCCG ATGCTGCCGAGAGTG GCTGCTGCCGCTGCT
    TGCCCGCCCGCCCGC TGCTGCCGAGAGTGG CTGCTGCCGCTGCTG
    GCCCGCCCGCCCGCT GCTGCCGAGAGTGGG TGCTGCCGCTGCTGC
    CCCGCCCGCCCGCTC CTGCCGAGAGTGGGC GCTGCCGCTGCTGCT
    CCGCCCGCCCGCTCG TGCCGAGAGTGGGCT CTGCCGCTGCTGCTG
    CGCCCGCCCGCTCGC GCCGAGAGTGGGCTG TGCCGCTGCTGCTGC
    GCCCGCCCGCTCGCT CCGAGAGTGGGCTGC GCCGCTGCTGCTGCT
    CCCGCCCGCTCGCTC CGAGAGTGGGCTGCC CCGCTGCTGCTGCTG
    CCGCCCGCTCGCTCG GAGAGTGGGCTGCCC CGCTGCTGCTGCTGC
    CGCCCGCTCGCTCGC AGAGTGGGCTGCCCC GCTGCTGCTGCTGCT
    GCCCGCTCGCTCGCT GAGTGGGCTGCCCCG CTGCTGCTGCTGCTA
    CCCGCTCGCTCGCTC AGTGGGCTGCCCCGC TGCTGCTGCTGCTAC
    CCGCTCGCTCGCTCG GTGGGCTGCCCCGCG GCTGCTGCTGCTACT
    CGCTCGCTCGCTCGC TGGGCTGCCCCGCGC CTGCTGCTGCTACTG
    GCTCGCTCGCTCGCC GGGCTGCCCCGCGCT TGCTGCTGCTACTGG
    CTCGCTCGCTCGCCC GGCTGCCCCGCGCTG GCTGCTGCTACTGGG
    TCGCTCGCTCGCCCG GCTGCCCCGCGCTGC CTGCTGCTACTGGGC
    CGCTCGCTCGCCCGC CTGCCCCGCGCTGCC TGCTGCTACTGGGCG
    GCTCGCTCGCCCGCC TGCCCCGCGCTGCCG GCTGCTACTGGGCGC
    CTCGCTCGCCCGCCG GCCCCGCGCTGCCGC CTGCTACTGGGCGCG
    TCGCTCGCCCGCCGC CCCCGCGCTGCCGCT TGCTACTGGGCGCGA
    CGCTCGCCCGCCGCG CCCGCGCTGCCGCTG GCTACTGGGCGCGAG
    GCTCGCCCGCCGCGC CCGCGCTGCCGCTGC CTACTGGGCGCGAGT
    CTCGCCCGCCGCGCC CGCGCTGCCGCTGCC TACTGGGCGCGAGTG
    TCGCCCGCCGCGCCG GCGCTGCCGCTGCCG ACTGGGCGCGAGTGG
    CGCCCGCCGCGCCGC CGCTGCCGCTGCCGC CTGGGCGCGAGTGGC
    GCCCGCCGCGCCGCG GCTGCCGCTGCCGCC TGGGCGCGAGTGGCG
    CCCGCCGCGCCGCGC CTGCCGCTGCCGCCG GGGCGCGAGTGGCGG
    CCGCCGCGCCGCGCT TGCCGCTGCCGCCGC GGCGCGAGTGGCGGC
    CGCCGCGCCGCGCTG GCCGCTGCCGCCGCC GCGCGAGTGGCGGCG
    GCCGCGCCGCGCTGC CCGCTGCCGCCGCCG CGCGAGTGGCGGCGG
    CCGCGCCGCGCTGCC CGCTGCCGCCGCCGC GCGAGTGGCGGCGGC
    CGCGCCGCGCTGCCG GCTGCCGCCGCCGCC CGAGTGGCGGCGGCG
    GCGCCGCGCTGCCGA CTGCCGCCGCCGCCG GAGTGGCGGCGGCGG
    CGCCGCGCTGCCGAC TGCCGCCGCCGCCGC AGTGGCGGCGGCGGC
    GCCGCGCTGCCGACC GCCGCCGCCGCCGCT GTGGCGGCGGCGGCG
    CCGCGCTGCCGACCG CCGCCGCCGCCGCTG TGGCGGCGGCGGCGG
    CGCGCTGCCGACCGC CGCCGCCGCCGCTGC GGCGGCGGCGGCGGG
    GCGCTGCCGACCGCC GCCGCCGCCGCTGCT GCGGCGGCGGCGGGG
    CGCTGCCGACCGCCA CCGCCGCCGCTGCTG CGGCGGCGGCGGGGC
    GCTGCCGACCGCCAG CGCCGCCGCTGCTGC GGCGGCGGCGGGGCG
    CTGCCGACCGCCAGC GCCGCCGCTGCTGCC GCGGCGGCGGGGCGC
    TGCCGACCGCCAGCA CCGCCGCTGCTGCCG CGGCGGCGGGGCGCG
    GCCGACCGCCAGCAT CGCCGCTGCTGCCGC GGCGGCGGGGCGCGC
    CCGACCGCCAGCATG GCCGCTGCTGCCGCT GCGGCGGGGCGCGCG
    CGACCGCCAGCATGC CCGCTGCTGCCGCTG CGGCGGGGCGCGCGC
    GACCGCCAGCATGCT CGCTGCTGCCGCTGC GGCGGGGCGCGCGCG
    ACCGCCAGCATGCTG GCTGCTGCCGCTGCT GCGGGGCGCGCGCGG
    CCGCCAGCATGCTGC CTGCTGCCGCTGCTG CGGGGCGCGCGCGGA
    CGCCAGCATGCTGCC TGCTGCCGCTGCTGC GGGGCGCGCGCGGAG
    GCCAGCATGCTGCCG GCTGCCGCTGCTGCC GGGCGCGCGCGGAGG
    CCAGCATGCTGCCGA CTGCCGCTGCTGCCG GGCGCGCGCGGAGGT
    CAGCATGCTGCCGAG TGCCGCTGCTGCCGC GCGCGCGCGGAGGTG
    AGCATGCTGCCGAGA GCCGCTGCTGCCGCT CGCGCGCGGAGGTGC
    GCATGCTGCCGAGAG CCGCTGCTGCCGCTG GCGCGCGGAGGTGCT
    CGCGCGGAGGTGCTG CGGGCCCCCGCCGGT GCATGCCATGCGCGG
    GCGCGGAGGTGCTGT GGGCCCCCGCCGGTT CATGCCATGCGCGGA
    CGCGGAGGTGCTGTT GGCCCCCGCCGGTTG ATGCCATGCGCGGAG
    GCGGAGGTGCTGTTC GCCCCCGCCGGTTGC TGCCATGCGCGGAGC
    CGGAGGTGCTGTTCC CCCCCGCCGGTTGCG GCCATGCGCGGAGCT
    GGAGGTGCTGTTCCG CCCCGCCGGTTGCGC CCATGCGCGGAGCTC
    GAGGTGCTGTTCCGC CCCGCCGGTTGCGCC CATGCGCGGAGCTCG
    AGGTGCTGTTCCGCT CCGCCGGTTGCGCCG ATGCGCGGAGCTCGT
    GGTGCTGTTCCGCTG CGCCGGTTGCGCCGC TGCGCGGAGCTCGTC
    GTGCTGTTCCGCTGC GCCGGTTGCGCCGCC GCGCGGAGCTCGTCC
    TGCTGTTCCGCTGCC CCGGTTGCGCCGCCC CGCGGAGCTCGTCCG
    GCTGTTCCGCTGCCC CGGTTGCGCCGCCCG GCGGAGCTCGTCCGG
    CTGTTCCGCTGCCCG GGTTGCGCCGCCCGC CGGAGCTCGTCCGGG
    TGTTCCGCTGCCCGC GTTGCGCCGCCCGCC GGAGCTCGTCCGGGA
    GTTCCGCTGCCCGCC TTGCGCCGCCCGCCG GAGCTCGTCCGGGAG
    TTCCGCTGCCCGCCC TGCGCCGCCCGCCGC AGCTCGTCCGGGAGC
    TCCGCTGCCCGCCCT GCGCCGCCCGCCGCG GCTCGTCCGGGAGCC
    CCGCTGCCCGCCCTG CGCCGCCCGCCGCGG CTCGTCCGGGAGCCG
    CGCTGCCCGCCCTGC GCCGCCCGCCGCGGT TCGTCCGGGAGCCGG
    GCTGCCCGCCCTGCA CCGCCCGCCGCGGTG CGTCCGGGAGCCGGG
    CTGCCCGCCCTGCAC CGCCCGCCGCGGTGG GTCCGGGAGCCGGGC
    TGCCCGCCCTGCACA GCCCGCCGCGGTGGC TCCGGGAGCCGGGCT
    GCCCGCCCTGCACAC CCCGCCGCGGTGGCC CCGGGAGCCGGGCTG
    CCCGCCCTGCACACC CCGCCGCGGTGGCCG CGGGAGCCGGGCTGC
    CCGCCCTGCACACCC CGCCGCGGTGGCCGC GGGAGCCGGGCTGCG
    CGCCCTGCACACCCG GCCGCGGTGGCCGCA GGAGCCGGGCTGCGG
    GCCCTGCACACCCGA CCGCGGTGGCCGCAG GAGCCGGGCTGCGGC
    CCCTGCACACCCGAG CGCGGTGGCCGCAGT AGCCGGGCTGCGGCT
    CCTGCACACCCGAGC GCGGTGGCCGCAGTG GCCGGGCTGCGGCTG
    CTGCACACCCGAGCG CGGTGGCCGCAGTGG CCGGGCTGCGGCTGC
    TGCACACCCGAGCGC GGTGGCCGCAGTGGC CGGGCTGCGGCTGCT
    GCACACCCGAGCGCC GTGGCCGCAGTGGCC GGGCTGCGGCTGCTG
    CACACCCGAGCGCCT TGGCCGCAGTGGCCG GGCTGCGGCTGCTGC
    ACACCCGAGCGCCTG GGCCGCAGTGGCCGG GCTGCGGCTGCTGCT
    CACCCGAGCGCCTGG GCCGCAGTGGCCGGA CTGCGGCTGCTGCTC
    ACCCGAGCGCCTGGC CCGCAGTGGCCGGAG TGCGGCTGCTGCTCG
    CCCGAGCGCCTGGCC CGCAGTGGCCGGAGG GCGGCTGCTGCTCGG
    CCGAGCGCCTGGCCG GCAGTGGCCGGAGGC CGGCTGCTGCTCGGT
    CGAGCGCCTGGCCGC CAGTGGCCGGAGGCG GGCTGCTGCTCGGTG
    GAGCGCCTGGCCGCC AGTGGCCGGAGGCGC GCTGCTGCTCGGTGT
    AGCGCCTGGCCGCCT GTGGCCGGAGGCGCC CTGCTGCTCGGTGTG
    GCGCCTGGCCGCCTG TGGCCGGAGGCGCCC TGCTGCTCGGTGTGC
    CGCCTGGCCGCCTGC GGCCGGAGGCGCCCG GCTGCTCGGTGTGCG
    GCCTGGCCGCCTGCG GCCGGAGGCGCCCGC CTGCTCGGTGTGCGC
    CCTGGCCGCCTGCGG CCGGAGGCGCCCGCA TGCTCGGTGTGCGCC
    CTGGCCGCCTGCGGG CGGAGGCGCCCGCAT GCTCGGTGTGCGCCC
    TGGCCGCCTGCGGGC GGAGGCGCCCGCATG CTCGGTGTGCGCCCG
    GGCCGCCTGCGGGCC GAGGCGCCCGCATGC TCGGTGTGCGCCCGG
    GCCGCCTGCGGGCCC AGGCGCCCGCATGCC CGGTGTGCGCCCGGC
    CCGCCTGCGGGCCCC GGCGCCCGCATGCCA GGTGTGCGCCCGGCT
    CGCCTGCGGGCCCCC GCGCCCGCATGCCAT GTGTGCGCCCGGCTG
    GCCTGCGGGCCCCCG CGCCCGCATGCCATG TGTGCGCCCGGCTGG
    CCTGCGGGCCCCCGC GCCCGCATGCCATGC GTGCGCCCGGCTGGA
    CTGCGGGCCCCCGCC CCCGCATGCCATGCG TGCGCCCGGCTGGAG
    TGCGGGCCCCCGCCG CCGCATGCCATGCGC GCGCCCGGCTGGAGG
    GCGGGCCCCCGCCGG CGCATGCCATGCGCG CGCCCGGCTGGAGGG
    GCCCGGCTGGAGGGC GCGCTGCTATCCCCA AGGGCACTTGTGAGA
    CCCGGCTGGAGGGCG CGCTGCTATCCCCAC GGGCACTTGTGAGAA
    CCGGCTGGAGGGCGA GCTGCTATCCCCACC GGCACTTGTGAGAAG
    CGGCTGGAGGGCGAG CTGCTATCCCCACCC GCACTTGTGAGAAGC
    GGCTGGAGGGCGAGG TGCTATCCCCACCCG CACTTGTGAGAAGCG
    GCTGGAGGGCGAGGC GCTATCCCCACCCGG ACTTGTGAGAAGCGC
    CTGGAGGGCGAGGCG CTATCCCCACCCGGG CTTGTGAGAAGCGCC
    TGGAGGGCGAGGCGT TATCCCCACCCGGGC TTGTGAGAAGCGCCG
    GGAGGGCGAGGCGTG ATCCCCACCCGGGCT TGTGAGAAGCGCCGG
    GAGGGCGAGGCGTGC TCCCCACCCGGGCTC GTGAGAAGCGCCGGG
    AGGGCGAGGCGTGCG CCCCACCCGGGCTCC TGAGAAGCGCCGGGA
    GGGCGAGGCGTGCGG CCCACCCGGGCTCCG GAGAAGCGCCGGGAC
    GGCGAGGCGTGCGGC CCACCCGGGCTCCGA AGAAGCGCCGGGACG
    GCGAGGCGTGCGGCG CACCCGGGCTCCGAG GAAGCGCCGGGACGC
    CGAGGCGTGCGGCGT ACCCGGGCTCCGAGC AAGCGCCGGGACGCC
    GAGGCGTGCGGCGTC CCCGGGCTCCGAGCT AGCGCCGGGACGCCG
    AGGCGTGCGGCGTCT CCGGGCTCCGAGCTG GCGCCGGGACGCCGA
    GGCGTGCGGCGTCTA CGGGCTCCGAGCTGC CGCCGGGACGCCGAG
    GCGTGCGGCGTCTAC GGGCTCCGAGCTGCC GCCGGGACGCCGAGT
    CGTGCGGCGTCTACA GGCTCCGAGCTGCCC CCGGGACGCCGAGTA
    GTGCGGCGTCTACAC GCTCCGAGCTGCCCC CGGGACGCCGAGTAT
    TGCGGCGTCTACACC CTCCGAGCTGCCCCT GGGACGCCGAGTATG
    GCGGCGTCTACACCC TCCGAGCTGCCCCTG GGACGCCGAGTATGG
    CGGCGTCTACACCCC CCGAGCTGCCCCTGC GACGCCGAGTATGGC
    GGCGTCTACACCCCG CGAGCTGCCCCTGCA ACGCCGAGTATGGCG
    GCGTCTACACCCCGC GAGCTGCCCCTGCAG CGCCGAGTATGGCGC
    CGTCTACACCCCGCG AGCTGCCCCTGCAGG GCCGAGTATGGCGCC
    GTCTACACCCCGCGC GCTGCCCCTGCAGGC CCGAGTATGGCGCCA
    TCTACACCCCGCGCT CTGCCCCTGCAGGCG CGAGTATGGCGCCAG
    CTACACCCCGCGCTG TGCCCCTGCAGGCGC GAGTATGGCGCCAGC
    TACACCCCGCGCTGC GCCCCTGCAGGCGCT AGTATGGCGCCAGCC
    ACACCCCGCGCTGCG CCCCTGCAGGCGCTG GTATGGCGCCAGCCC
    CACCCCGCGCTGCGG CCCTGCAGGCGCTGG TATGGCGCCAGCCCG
    ACCCCGCGCTGCGGC CCTGCAGGCGCTGGT ATGGCGCCAGCCCGG
    CCCCGCGCTGCGGCC CTGCAGGCGCTGGTC TGGCGCCAGCCCGGA
    CCCGCGCTGCGGCCA TGCAGGCGCTGGTCA GGCGCCAGCCCGGAG
    CCGCGCTGCGGCCAG GCAGGCGCTGGTCAT GCGCCAGCCCGGAGC
    CGCGCTGCGGCCAGG CAGGCGCTGGTCATG CGCCAGCCCGGAGCA
    GCGCTGCGGCCAGGG AGGCGCTGGTCATGG GCCAGCCCGGAGCAG
    CGCTGCGGCCAGGGG GGCGCTGGTCATGGG CCAGCCCGGAGCAGG
    GCTGCGGCCAGGGGC GCGCTGGTCATGGGC CAGCCCGGAGCAGGT
    CTGCGGCCAGGGGCT CGCTGGTCATGGGCG AGCCCGGAGCAGGTT
    TGCGGCCAGGGGCTG GCTGGTCATGGGCGA GCCCGGAGCAGGTTG
    GCGGCCAGGGGCTGC CTGGTCATGGGCGAG CCCGGAGCAGGTTGC
    CGGCCAGGGGCTGCG TGGTCATGGGCGAGG CCGGAGCAGGTTGCA
    GGCCAGGGGCTGCGC GGTCATGGGCGAGGG CGGAGCAGGTTGCAG
    GCCAGGGGCTGCGCT GTCATGGGCGAGGGC GGAGCAGGTTGCAGA
    CCAGGGGCTGCGCTG TCATGGGCGAGGGCA GAGCAGGTTGCAGAC
    CAGGGGCTGCGCTGC CATGGGCGAGGGCAC AGCAGGTTGCAGACA
    AGGGGCTGCGCTGCT ATGGGCGAGGGCACT GCAGGTTGCAGACAA
    GGGGCTGCGCTGCTA TGGGCGAGGGCACTT CAGGTTGCAGACAAT
    GGGCTGCGCTGCTAT GGGCGAGGGCACTTG AGGTTGCAGACAATG
    GGCTGCGCTGCTATC GGCGAGGGCACTTGT GGTTGCAGACAATGG
    GCTGCGCTGCTATCC GCGAGGGCACTTGTG GTTGCAGACAATGGC
    CTGCGCTGCTATCCC CGAGGGCACTTGTGA TTGCAGACAATGGCG
    TGCGCTGCTATCCCC GAGGGCACTTGTGAG TGCAGACAATGGCGA
    GCAGACAATGGCGAT CACCATGAACATGTT GTATGAAGGAGCTGG
    CAGACAATGGCGATG ACCATGAACATGTTG TATGAAGGAGCTGGC
    AGACAATGGCGATGA CCATGAACATGTTGG ATGAAGGAGCTGGCC
    GACAATGGCGATGAC CATGAACATGTTGGG TGAAGGAGCTGGCCG
    ACAATGGCGATGACC ATGAACATGTTGGGC GAAGGAGCTGGCCGT
    CAATGGCGATGACCA TGAACATGTTGGGCG AAGGAGCTGGCCGTG
    AATGGCGATGACCAC GAACATGTTGGGCGG AGGAGCTGGCCGTGT
    ATGGCGATGACCACT AACATGTTGGGCGGG GGAGCTGGCCGTGTT
    TGGCGATGACCACTC ACATGTTGGGCGGGG GAGCTGGCCGTGTTC
    GGCGATGACCACTCA CATGTTGGGCGGGGG AGCTGGCCGTGTTCC
    GCGATGACCACTCAG ATGTTGGGCGGGGGA GCTGGCCGTGTTCCG
    CGATGACCACTCAGA TGTTGGGCGGGGGAG CTGGCCGTGTTCCGG
    GATGACCACTCAGAA GTTGGGCGGGGGAGG TGGCCGTGTTCCGGG
    ATGACCACTCAGAAG TTGGGCGGGGGAGGC GGCCGTGTTCCGGGA
    TGACCACTCAGAAGG TGGGCGGGGGAGGCA GCCGTGTTCCGGGAG
    GACCACTCAGAAGGA GGGCGGGGGAGGCAG CCGTGTTCCGGGAGA
    ACCACTCAGAAGGAG GGCGGGGGAGGCAGT CGTGTTCCGGGAGAA
    CCACTCAGAAGGAGG GCGGGGGAGGCAGTG GTGTTCCGGGAGAAG
    CACTCAGAAGGAGGC CGGGGGAGGCAGTGC TGTTCCGGGAGAAGG
    ACTCAGAAGGAGGCC GGGGGAGGCAGTGCT GTTCCGGGAGAAGGT
    CTCAGAAGGAGGCCT GGGGAGGCAGTGCTG TTCCGGGAGAAGGTC
    TCAGAAGGAGGCCTG GGGAGGCAGTGCTGG TCCGGGAGAAGGTCA
    CAGAAGGAGGCCTGG GGAGGCAGTGCTGGC CCGGGAGAAGGTCAC
    AGAAGGAGGCCTGGT GAGGCAGTGCTGGCC CGGGAGAAGGTCACT
    GAAGGAGGCCTGGTG AGGCAGTGCTGGCCG GGGAGAAGGTCACTG
    AAGGAGGCCTGGTGG GGCAGTGCTGGCCGG GGAGAAGGTCACTGA
    AGGAGGCCTGGTGGA GCAGTGCTGGCCGGA GAGAAGGTCACTGAG
    GGAGGCCTGGTGGAG CAGTGCTGGCCGGAA AGAAGGTCACTGAGC
    GAGGCCTGGTGGAGA AGTGCTGGCCGGAAG GAAGGTCACTGAGCA
    AGGCCTGGTGGAGAA GTGCTGGCCGGAAGC AAGGTCACTGAGCAG
    GGCCTGGTGGAGAAC TGCTGGCCGGAAGCC AGGTCACTGAGCAGC
    GCCTGGTGGAGAACC GCTGGCCGGAAGCCC GGTCACTGAGCAGCA
    CCTGGTGGAGAACCA CTGGCCGGAAGCCCC GTCACTGAGCAGCAC
    CTGGTGGAGAACCAC TGGCCGGAAGCCCCT TCACTGAGCAGCACC
    TGGTGGAGAACCACG GGCCGGAAGCCCCTC CACTGAGCAGCACCG
    GGTGGAGAACCACGT GCCGGAAGCCCCTCA ACTGAGCAGCACCGG
    GTGGAGAACCACGTG CCGGAAGCCCCTCAA CTGAGCAGCACCGGC
    TGGAGAACCACGTGG CGGAAGCCCCTCAAG TGAGCAGCACCGGCA
    GGAGAACCACGTGGA GGAAGCCCCTCAAGT GAGCAGCACCGGCAG
    GAGAACCACGTGGAC GAAGCCCCTCAAGTC AGCAGCACCGGCAGA
    AGAACCACGTGGACA AAGCCCCTCAAGTCG GCAGCACCGGCAGAT
    GAACCACGTGGACAG AGCCCCTCAAGTCGG CAGCACCGGCAGATG
    AACCACGTGGACAGC GCCCCTCAAGTCGGG AGCACCGGCAGATGG
    ACCACGTGGACAGCA CCCCTCAAGTCGGGT GCACCGGCAGATGGG
    CCACGTGGACAGCAC CCCTCAAGTCGGGTA CACCGGCAGATGGGC
    CACGTGGACAGCACC CCTCAAGTCGGGTAT ACCGGCAGATGGGCA
    ACGTGGACAGCACCA CTCAAGTCGGGTATG CCGGCAGATGGGCAA
    CGTGGACAGCACCAT TCAAGTCGGGTATGA CGGCAGATGGGCAAG
    GTGGACAGCACCATG CAAGTCGGGTATGAA GGCAGATGGGCAAGG
    TGGACAGCACCATGA AAGTCGGGTATGAAG GCAGATGGGCAAGGG
    GGACAGCACCATGAA AGTCGGGTATGAAGG CAGATGGGCAAGGGT
    GACAGCACCATGAAC GTCGGGTATGAAGGA AGATGGGCAAGGGTG
    ACAGCACCATGAACA TCGGGTATGAAGGAG GATGGGCAAGGGTGG
    CAGCACCATGAACAT CGGGTATGAAGGAGC ATGGGCAAGGGTGGC
    AGCACCATGAACATG GGGTATGAAGGAGCT TGGGCAAGGGTGGCA
    GCACCATGAACATGT GGTATGAAGGAGCTG GGGCAAGGGTGGCAA
    GGCAAGGGTGGCAAG CCCTGCCAGGACTCC CCATGCGCCTTCCGG
    GCAAGGGTGGCAAGC CCTGCCAGGACTCCC CATGCGCCTTCCGGA
    CAAGGGTGGCAAGCA CTGCCAGGACTCCCT ATGCGCCTTCCGGAT
    AAGGGTGGCAAGCAT TGCCAGGACTCCCTG TGCGCCTTCCGGATG
    AGGGTGGCAAGCATC GCCAGGACTCCCTGC GCGCCTTCCGGATGA
    GGGTGGCAAGCATCA CCAGGACTCCCTGCC CGCCTTCCGGATGAG
    GGTGGCAAGCATCAC CAGGACTCCCTGCCA GCCTTCCGGATGAGC
    GTGGCAAGCATCACC AGGACTCCCTGCCAA CCTTCCGGATGAGCG
    TGGCAAGCATCACCT GGACTCCCTGCCAAC CTTCCGGATGAGCGG
    GGCAAGCATCACCTT GACTCCCTGCCAACA TTCCGGATGAGCGGG
    GCAAGCATCACCTTG ACTCCCTGCCAACAG TCCGGATGAGCGGGG
    CAAGCATCACCTTGG CTCCCTGCCAACAGG CCGGATGAGCGGGGC
    AAGCATCACCTTGGC TCCCTGCCAACAGGA CGGATGAGCGGGGCC
    AGCATCACCTTGGCC CCCTGCCAACAGGAA GGATGAGCGGGGCCC
    GCATCACCTTGGCCT CCTGCCAACAGGAAC GATGAGCGGGGCCCT
    CATCACCTTGGCCTG CTGCCAACAGGAACT ATGAGCGGGGCCCTC
    ATCACCTTGGCCTGG TGCCAACAGGAACTG TGAGCGGGGCCCTCT
    TCACCTTGGCCTGGA GCCAACAGGAACTGG GAGCGGGGCCCTCTG
    CACCTTGGCCTGGAG CCAACAGGAACTGGA AGCGGGGCCCTCTGG
    ACCTTGGCCTGGAGG CAACAGGAACTGGAC GCGGGGCCCTCTGGA
    CCTTGGCCTGGAGGA AACAGGAACTGGACC CGGGGCCCTCTGGAG
    CTTGGCCTGGAGGAG ACAGGAACTGGACCA GGGGCCCTCTGGAGC
    TTGGCCTGGAGGAGC CAGGAACTGGACCAG GGGCCCTCTGGAGCA
    TGGCCTGGAGGAGCC AGGAACTGGACCAGG GGCCCTCTGGAGCAC
    GGCCTGGAGGAGCCC GGAACTGGACCAGGT GCCCTCTGGAGCACC
    GCCTGGAGGAGCCCA GAACTGGACCAGGTC CCCTCTGGAGCACCT
    CCTGGAGGAGCCCAA AACTGGACCAGGTCC CCTCTGGAGCACCTC
    CTGGAGGAGCCCAAG ACTGGACCAGGTCCT CTCTGGAGCACCTCT
    TGGAGGAGCCCAAGA CTGGACCAGGTCCTG TCTGGAGCACCTCTA
    GGAGGAGCCCAAGAA TGGACCAGGTCCTGG CTGGAGCACCTCTAC
    GAGGAGCCCAAGAAG GGACCAGGTCCTGGA TGGAGCACCTCTACT
    AGGAGCCCAAGAAGC GACCAGGTCCTGGAG GGAGCACCTCTACTC
    GGAGCCCAAGAAGCT ACCAGGTCCTGGAGC GAGCACCTCTACTCC
    GAGCCCAAGAAGCTG CCAGGTCCTGGAGCG AGCACCTCTACTCCC
    AGCCCAAGAAGCTGC CAGGTCCTGGAGCGG GCACCTCTACTCCCT
    GCCCAAGAAGCTGCG AGGTCCTGGAGCGGA CACCTCTACTCCCTG
    CCCAAGAAGCTGCGA GGTCCTGGAGCGGAT ACCTCTACTCCCTGC
    CCAAGAAGCTGCGAC GTCCTGGAGCGGATC CCTCTACTCCCTGCA
    CAAGAAGCTGCGACC TCCTGGAGCGGATCT CTCTACTCCCTGCAC
    AAGAAGCTGCGACCA CCTGGAGCGGATCTC TCTACTCCCTGCACA
    AGAAGCTGCGACCAC CTGGAGCGGATCTCC CTACTCCCTGCACAT
    GAAGCTGCGACCACC TGGAGCGGATCTCCA TACTCCCTGCACATC
    AAGCTGCGACCACCC GGAGCGGATCTCCAC ACTCCCTGCACATCC
    AGCTGCGACCACCCC GAGCGGATCTCCACC CTCCCTGCACATCCC
    GCTGCGACCACCCCC AGCGGATCTCCACCA TCCCTGCACATCCCC
    CTGCGACCACCCCCT GCGGATCTCCACCAT CCCTGCACATCCCCA
    TGCGACCACCCCCTG CGGATCTCCACCATG CCTGCACATCCCCAA
    GCGACCACCCCCTGC GGATCTCCACCATGC CTGCACATCCCCAAC
    CGACCACCCCCTGCC GATCTCCACCATGCG TGCACATCCCCAACT
    GACCACCCCCTGCCA ATCTCCACCATGCGC GCACATCCCCAACTG
    ACCACCCCCTGCCAG TCTCCACCATGCGCC CACATCCCCAACTGT
    CCACCCCCTGCCAGG CTCCACCATGCGCCT ACATCCCCAACTGTG
    CACCCCCTGCCAGGA TCCACCATGCGCCTT CATCCCCAACTGTGA
    ACCCCCTGCCAGGAC CCACCATGCGCCTTC ATCCCCAACTGTGAC
    CCCCCTGCCAGGACT CACCATGCGCCTTCC TCCCCAACTGTGACA
    CCCCTGCCAGGACTC ACCATGCGCCTTCCG CCCCAACTGTGACAA
    CCCAACTGTGACAAG CGGGCAGCGTGGGGA GAGCCCCCACCATCC
    CCAACTGTGACAAGC GGGCAGCGTGGGGAG AGCCCCCACCATCCG
    CAACTGTGACAAGCA GGCAGCGTGGGGAGT GCCCCCACCATCCGG
    AACTGTGACAAGCAT GCAGCGTGGGGAGTG CCCCCACCATCCGGG
    ACTGTGACAAGCATG CAGCGTGGGGAGTGC CCCCACCATCCGGGG
    CTGTGACAAGCATGG AGCGTGGGGAGTGCT CCCACCATCCGGGGG
    TGTGACAAGCATGGC GCGTGGGGAGTGCTG CCACCATCCGGGGGG
    GTGACAAGCATGGCC CGTGGGGAGTGCTGG CACCATCCGGGGGGA
    TGACAAGCATGGCCT GTGGGGAGTGCTGGT ACCATCCGGGGGGAC
    GACAAGCATGGCCTG TGGGGAGTGCTGGTG CCATCCGGGGGGACC
    ACAAGCATGGCCTGT GGGGAGTGCTGGTGT CATCCGGGGGGACCC
    CAAGCATGGCCTGTA GGGAGTGCTGGTGTG ATCCGGGGGGACCCC
    AAGCATGGCCTGTAC GGAGTGCTGGTGTGT TCCGGGGGGACCCCG
    AGCATGGCCTGTACA GAGTGCTGGTGTGTG CCGGGGGGACCCCGA
    GCATGGCCTGTACAA AGTGCTGGTGTGTGA CGGGGGGACCCCGAG
    CATGGCCTGTACAAC GTGCTGGTGTGTGAA GGGGGGACCCCGAGT
    ATGGCCTGTACAACC TGCTGGTGTGTGAAC GGGGGACCCCGAGTG
    TGGCCTGTACAACCT GCTGGTGTGTGAACC GGGGACCCCGAGTGT
    GGCCTGTACAACCTC CTGGTGTGTGAACCC GGGACCCCGAGTGTC
    GCCTGTACAACCTCA TGGTGTGTGAACCCC GGACCCCGAGTGTCA
    CCTGTACAACCTCAA GGTGTGTGAACCCCA GACCCCGAGTGTCAT
    CTGTACAACCTCAAA GTGTGTGAACCCCAA ACCCCGAGTGTCATC
    TGTACAACCTCAAAC TGTGTGAACCCCAAC CCCCGAGTGTCATCT
    GTACAACCTCAAACA GTGTGAACCCCAACA CCCGAGTGTCATCTC
    TACAACCTCAAACAG TGTGAACCCCAACAC CCGAGTGTCATCTCT
    ACAACCTCAAACAGT GTGAACCCCAACACC CGAGTGTCATCTCTT
    CAACCTCAAACAGTG TGAACCCCAACACCG GAGTGTCATCTCTTC
    AACCTCAAACAGTGC GAACCCCAACACCGG AGTGTCATCTCTTCT
    ACCTCAAACAGTGCA AACCCCAACACCGGG GTGTCATCTCTTCTA
    CCTCAAACAGTGCAA ACCCCAACACCGGGA TGTCATCTCTTCTAC
    CTCAAACAGTGCAAG CCCCAACACCGGGAA GTCATCTCTTCTACA
    TCAAACAGTGCAAGA CCCAACACCGGGAAG TCATCTCTTCTACAA
    CAAACAGTGCAAGAT CCAACACCGGGAAGC CATCTCTTCTACAAT
    AAACAGTGCAAGATG CAACACCGGGAAGCT ATCTCTTCTACAATG
    AACAGTGCAAGATGT AACACCGGGAAGCTG TCTCTTCTACAATGA
    ACAGTGCAAGATGTC ACACCGGGAAGCTGA CTCTTCTACAATGAG
    CAGTGCAAGATGTCT CACCGGGAAGCTGAT TCTTCTACAATGAGC
    AGTGCAAGATGTCTC ACCGGGAAGCTGATC CTTCTACAATGAGCA
    GTGCAAGATGTCTCT CCGGGAAGCTGATCC TTCTACAATGAGCAG
    TGCAAGATGTCTCTG CGGGAAGCTGATCCA TCTACAATGAGCAGC
    GCAAGATGTCTCTGA GGGAAGCTGATCCAG CTACAATGAGCAGCA
    CAAGATGTCTCTGAA GGAAGCTGATCCAGG TACAATGAGCAGCAG
    AAGATGTCTCTGAAC GAAGCTGATCCAGGG ACAATGAGCAGCAGG
    AGATGTCTCTGAACG AAGCTGATCCAGGGA CAATGAGCAGCAGGA
    GATGTCTCTGAACGG AGCTGATCCAGGGAG AATGAGCAGCAGGAG
    ATGTCTCTGAACGGG GCTGATCCAGGGAGC ATGAGCAGCAGGAGG
    TGTCTCTGAACGGGC CTGATCCAGGGAGCC TGAGCAGCAGGAGGC
    GTCTCTGAACGGGCA TGATCCAGGGAGCCC GAGCAGCAGGAGGCT
    TCTCTGAACGGGCAG GATCCAGGGAGCCCC AGCAGCAGGAGGCTT
    CTCTGAACGGGCAGC ATCCAGGGAGCCCCC GCAGCAGGAGGCTTG
    TCTGAACGGGCAGCG TCCAGGGAGCCCCCA CAGCAGGAGGCTTGC
    CTGAACGGGCAGCGT CCAGGGAGCCCCCAC AGCAGGAGGCTTGCG
    TGAACGGGCAGCGTG CAGGGAGCCCCCACC GCAGGAGGCTTGCGG
    GAACGGGCAGCGTGG AGGGAGCCCCCACCA CAGGAGGCTTGCGGG
    AACGGGCAGCGTGGG GGGAGCCCCCACCAT AGGAGGCTTGCGGGG
    ACGGGCAGCGTGGGG GGAGCCCCCACCATC GGAGGCTTGCGGGGT
    GAGGCTTGCGGGGTG GGCGCCCCTGCCCCC GTGGTGGGTGCTGGA
    AGGCTTGCGGGGTGC GCGCCCCTGCCCCCC TGGTGGGTGCTGGAG
    GGCTTGCGGGGTGCA CGCCCCTGCCCCCCG GGTGGGTGCTGGAGG
    GCTTGCGGGGTGCAC GCCCCTGCCCCCCGC GTGGGTGCTGGAGGA
    CTTGCGGGGTGCACA CCCCTGCCCCCCGCC TGGGTGCTGGAGGAT
    TTGCGGGGTGCACAC CCCTGCCCCCCGCCC GGGTGCTGGAGGATT
    TGCGGGGTGCACACC CCTGCCCCCCGCCCC GGTGCTGGAGGATTT
    GCGGGGTGCACACCC CTGCCCCCCGCCCCT GTGCTGGAGGATTTT
    CGGGGTGCACACCCA TGCCCCCCGCCCCTC TGCTGGAGGATTTTC
    GGGGTGCACACCCAG GCCCCCCGCCCCTCT GCTGGAGGATTTTCC
    GGGTGCACACCCAGC CCCCCCGCCCCTCTC CTGGAGGATTTTCCA
    GGTGCACACCCAGCG CCCCCGCCCCTCTCC TGGAGGATTTTCCAG
    GTGCACACCCAGCGG CCCCGCCCCTCTCCA GGAGGATTTTCCAGT
    TGCACACCCAGCGGA CCCGCCCCTCTCCAA GAGGATTTTCCAGTT
    GCACACCCAGCGGAT CCGCCCCTCTCCAAA AGGATTTTCCAGTTC
    CACACCCAGCGGATG CGCCCCTCTCCAAAC GGATTTTCCAGTTCT
    ACACCCAGCGGATGC GCCCCTCTCCAAACA GATTTTCCAGTTCTG
    CACCCAGCGGATGCA CCCCTCTCCAAACAC ATTTTCCAGTTCTGA
    ACCCAGCGGATGCAG CCCTCTCCAAACACC TTTTCCAGTTCTGAC
    CCCAGCGGATGCAGT CCTCTCCAAACACCG TTTCCAGTTCTGACA
    CCAGCGGATGCAGTA CTCTCCAAACACCGG TTCCAGTTCTGACAC
    CAGCGGATGCAGTAG TCTCCAAACACCGGC TCCAGTTCTGACACA
    AGCGGATGCAGTAGA CTCCAAACACCGGCA CCAGTTCTGACACAC
    GCGGATGCAGTAGAC TCCAAACACCGGCAG CAGTTCTGACACACG
    CGGATGCAGTAGACC CCAAACACCGGCAGA AGTTCTGACACACGT
    GGATGCAGTAGACCG CAAACACCGGCAGAA GTTCTGACACACGTA
    GATGCAGTAGACCGC AAACACCGGCAGAAA TTCTGACACACGTAT
    ATGCAGTAGACCGCA AACACCGGCAGAAAA TCTGACACACGTATT
    TGCAGTAGACCGCAG ACACCGGCAGAAAAC CTGACACACGTATTT
    GCAGTAGACCGCAGC CACCGGCAGAAAACG TGACACACGTATTTA
    CAGTAGACCGCAGCC ACCGGCAGAAAACGG GACACACGTATTTAT
    AGTAGACCGCAGCCA CCGGCAGAAAACGGA ACACACGTATTTATA
    GTAGACCGCAGCCAG CGGCAGAAAACGGAG CACACGTATTTATAT
    TAGACCGCAGCCAGC GGCAGAAAACGGAGA ACACGTATTTATATT
    AGACCGCAGCCAGCC GCAGAAAACGGAGAG CACGTATTTATATTT
    GACCGCAGCCAGCCG CAGAAAACGGAGAGT ACGTATTTATATTTG
    ACCGCAGCCAGCCGG AGAAAACGGAGAGTG CGTATTTATATTTGG
    CCGCAGCCAGCCGGT GAAAACGGAGAGTGC GTATTTATATTTGGA
    CGCAGCCAGCCGGTG AAAACGGAGAGTGCT TATTTATATTTGGAA
    GCAGCCAGCCGGTGC AAACGGAGAGTGCTT ATTTATATTTGGAAA
    CAGCCAGCCGGTGCC AACGGAGAGTGCTTG TTTATATTTGGAAAG
    AGCCAGCCGGTGCCT ACGGAGAGTGCTTGG TTATATTTGGAAAGA
    GCCAGCCGGTGCCTG CGGAGAGTGCTTGGG TATATTTGGAAAGAG
    CCAGCCGGTGCCTGG GGAGAGTGCTTGGGT ATATTTGGAAAGAGA
    CAGCCGGTGCCTGGC GAGAGTGCTTGGGTG TATTTGGAAAGAGAC
    AGCCGGTGCCTGGCG AGAGTGCTTGGGTGG ATTTGGAAAGAGACC
    GCCGGTGCCTGGCGC GAGTGCTTGGGTGGT TTTGGAAAGAGACCA
    CCGGTGCCTGGCGCC AGTGCTTGGGTGGTG TTGGAAAGAGACCAG
    CGGTGCCTGGCGCCC GTGCTTGGGTGGTGG TGGAAAGAGACCAGC
    GGTGCCTGGCGCCCC TGCTTGGGTGGTGGG GGAAAGAGACCAGCA
    GTGCCTGGCGCCCCT GCTTGGGTGGTGGGT GAAAGAGACCAGCAC
    TGCCTGGCGCCCCTG CTTGGGTGGTGGGTG AAAGAGACCAGCACC
    GCCTGGCGCCCCTGC TTGGGTGGTGGGTGC AAGAGACCAGCACCG
    CCTGGCGCCCCTGCC TGGGTGGTGGGTGCT AGAGACCAGCACCGA
    CTGGCGCCCCTGCCC GGGTGGTGGGTGCTG GAGACCAGCACCGAG
    TGGCGCCCCTGCCCC GGTGGTGGGTGCTGG AGACCAGCACCGAGC
    GACCAGCACCGAGCT CACCTGCTCCTTCTT GGGTACAGGTTTGGG
    ACCAGCACCGAGCTC ACCTGCTCCTTCTTG GGTACAGGTTTGGGG
    CCAGCACCGAGCTCG CCTGCTCCTTCTTGC GTACAGGTTTGGGGA
    CAGCACCGAGCTCGG CTGCTCCTTCTTGCT TACAGGTTTGGGGAG
    AGCACCGAGCTCGGC TGCTCCTTCTTGCTT ACAGGTTTGGGGAGG
    GCACCGAGCTCGGCA GCTCCTTCTTGCTTT CAGGTTTGGGGAGGG
    CACCGAGCTCGGCAC CTCCTTCTTGCTTTC AGGTTTGGGGAGGGG
    ACCGAGCTCGGCACC TCCTTCTTGCTTTCC GGTTTGGGGAGGGGG
    CCGAGCTCGGCACCT CCTTCTTGCTTTCCC CTTTGGGGAGGGGGA
    CGAGCTCGGCACCTC CTTCTTGCTTTCCCC TTTGGGGAGGGGGAA
    GAGCTCGGCACCTCC TTCTTGCTTTCCCCG TTGGGGAGGGGGAAG
    AGCTCGGCACCTCCC TCTTGCTTTCCCCGC TGGGGAGGGGGAAGA
    GCTCGGCACCTCCCC CTTGCTTTCCCCGGG GGGGAGGGGGAAGAG
    CTCGGCACCTCCCCG TTGCTTTCCCCGGGG GGGAGGGGGAAGAGA
    TCGGCACCTCCCCGG TGCTTTCCCCGGGGG GGAGGGGGAAGAGAA
    CGGCACCTCCCCGGC GCTTTCCCCGGGGGA GAGGGGGAAGAGAAA
    GGCACCTCCCCGGCC CTTTCCCCGGGGGAG AGGGGGAAGAGAAAT
    GCACCTCCCCGGCCT TTTCCCCGGGGGAGG GGGGGAAGAGAAATT
    CACCTCCCCGGCCTC TTCCCCGGGGGAGGA GGGGAAGAGAAATTT
    ACCTCCCCGGCCTCT TCCCCGGGGGAGGAA GGGAAGAGAAATTTT
    CCTCCCCGGCCTCTC CCCCGGGGGAGGAAG GGAAGAGAAATTTTT
    CTCCCCGGCCTCTCT CCCGGGGGAGGAAGG GAAGAGAAATTTTTA
    TCCCCGGCCTCTCTC CCGGGGGAGGAAGGG AAGAGAAATTTTTAT
    CCCCGGCCTCTCTCT CGGGGGAGGAAGGGG AGAGAAATTTTTATT
    CCCGGCCTCTCTCTT GGGGGAGGAAGGGGG GAGAAATTTTTATTT
    CCGGCCTCTCTCTTC GGGGAGGAAGGGGGT AGAAATTTTTATTTT
    CGGCCTCTCTCTTCC GGGAGGAAGGGGGTT GAAATTTTTATTTTT
    GGCCTCTCTCTTCCC GGAGGAAGGGGGTTG AAATTTTTATTTTTG
    GCCTCTCTCTTCCCA GAGGAAGGGGGTTGT AATTTTTATTTTTGA
    CCTCTCTCTTCCCAG AGGAAGGGGGTTGTG ATTTTTATTTTTGAA
    CTCTCTCTTCCCAGC GGAAGGGGGTTGTGG TTTTTATTTTTGAAC
    TCTCTCTTCCCAGCT GAAGGGGGTTGTGGT TTTTATTTTTGAACC
    CTCTCTTCCCAGCTG AAGGGGGTTGTGGTC TTTATTTTTGAACCC
    TCTCTTCCCAGCTGC AGGGGGTTGTGGTCG TTATTTTTGAACCCC
    CTCTTCCCAGCTGCA GGGGGTTGTGGTCGG TATTTTTGAACCCCT
    TCTTCCCAGCTGCAG GGGGTTGTGGTCGGG ATTTTTGAACCCCTG
    CTTCCCAGCTGCAGA GGGTTGTGGTCGGGG TTTTTGAACCCCTGT
    TTCCCAGCTGCAGAT GGTTGTGGTCGGGGA TTTTGAACCCCTGTG
    TCCCAGCTGCAGATG GTTGTGGTCGGGGAG TTTGAACCCCTGTGT
    CCCAGCTGCAGATGC TTGTGGTCGGGGAGC TTGAACCCCTGTGTC
    CCAGCTGCAGATGCC TGTGGTCGGGGAGCT TGAACCCCTGTGTCC
    CAGCTGCAGATGCCA GTGGTCGGGGAGCTG GAACCCCTGTGTCCC
    AGCTGCAGATGCCAC TGGTCGGGGAGCTGG AACCCCTGTGTCCCT
    GCTGCAGATGCCACA GGTCGGGGAGCTGGG ACCCCTGTGTCCCTT
    CTGCAGATGCCACAC GTCGGGGAGCTGGGG CCCCTGTGTCCCTTT
    TGCAGATGCCACACC TCGGGGAGCTGGGGT CCCTGTGTCCCTTTT
    GCAGATGCCACACCT CGGGGAGCTGGGGTA CCTGTGTCCCTTTTG
    CAGATGCCACACCTG GGGGAGCTGGGGTAC CTGTGTCCCTTTTGC
    AGATGCCACACCTGC GGGAGCTGGGGTACA TGTGTCCCTTTTGCA
    GATGCCACACCTGCT GGAGCTGGGGTACAG GTGTCCCTTTTGCAT
    ATGCCACACCTGCTC GAGCTGGGGTACAGG TGTCCCTTTTGCATA
    TGCCACACCTGCTCC AGCTGGGGTACAGGT GTCCCTTTTGCATAA
    GCCACACCTGCTCCT GCTGGGGTACAGGTT TCCCTTTTGCATAAG
    CCACACCTGCTCCTT CTGGGGTACAGGTTT CCCTTTTGCATAAGA
    CACACCTGCTCCTTC TGGGGTACAGGTTTG CCTTTTGCATAAGAT
    ACACCTGCTCCTTCT GGGGTACAGGTTTGG CTTTTGCATAAGATT
    TTTTGCATAAGATTA
    TTTGCATAAGATTAA
    TTGCATAAGATTAAA
    TGCATAAGATTAAAG
    GCATAAGATTAAAGG
    CATAAGATTAAAGGA
    ATAAGATTAAAGGAA
    TAAGATTAAAGGAAG
    AAGATTAAAGGAAGG
    AGATTAAAGGAAGGA
    GATTAAAGGAAGGAA
    ATTAAAGGAAGGAAA
    TTAAAGGAAGGAAAA
    TAAAGGAAGGAAAAG
    AAAGGAAGGAAAAGT
    • EXAMPLE 7 Antisense Oligonucleotides of IGFBP3
  • Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: [0057]
    CTCAGCGCCCAGCCG CCACAGCTTCGCGCC ATCCCTGCGCGCCCA
    TCAGCGCCCAGCCGC CACAGCTTCGCGCCG TCCCTGCGCGCCCAG
    CAGCGCCCAGCCGCT ACAGCTTCGCGCCGT CCCTGCGCGCCCAGC
    AGCGCCCAGCCGCTT CAGCTTCGCGCCGTG CCTGCGCGCCCAGCC
    GCGCCCAGCCGCTTC AGCTTCGCGCCGTGT CTGCGCGCCCAGCCT
    CGCCCAGCCGCTTCC GCTTCGCGCCGTGTA TGCGCGCCCAGCCTG
    GCCCAGCCGCTTCCT CTTCGCGCCGTGTAC GCGCGCCCAGCCTGC
    CCCAGCCGCTTCCTG TTCGCGCCGTGTACT CGCGCCCAGCCTGCC
    CCAGCCGCTTCCTGC TCGCGCCGTGTACTG GCGCCCAGCCTGCCA
    CAGCCGCTTCCTGCC CGCGCCGTGTACTGT CGCCCAGCCTGCCAA
    AGCCGCTTCCTGCCT GCGCCGTGTACTGTC GCCCAGCCTGCCAAG
    GCCGCTTCCTGCCTG CGCCGTGTACTGTCG CCCAGCCTGCCAAGC
    CCGCTTCCTGCCTGG GCCGTGTACTGTCGC CCAGCCTGCCAAGCA
    CGCTTCCTGCCTGGA CCGTGTACTGTCGCC CAGCCTGCCAAGCAG
    GCTTCCTGCCTGGAT CGTGTACTGTCGCCC AGCCTGCCAAGCAGC
    CTTCCTGCCTGGATT GTGTACTGTCGCCCC GCCTGCCAAGCAGCG
    TTCCTGCCTGGATTC TGTACTGTCGCCCCA CCTGCCAAGCAGCGT
    TCCTGCCTGGATTCC GTACTGTCGCCCCAT CTGCCAAGCAGCGTG
    CCTGCCTGGATTCCA TACTGTCGCCCCATC TGCCAAGCAGCGTGC
    CTGCCTGGATTCCAC ACTGTCGCCCCATCC GCCAAGCAGCGTGCC
    TGCCTGGATTCCACA CTGTCGCCCCATCCC CCAAGCAGCGTGCCC
    GCCTGGATTCCACAG TGTCGCCCCATCCCT CAAGCAGCGTGCCCC
    CCTGGATTCCACAGC GTCGCCCCATCCCTG AAGCAGCGTGCCCCG
    CTGGATTCCACAGCT TCGCCCCATCCCTGC AGCAGCGTGCCCCGG
    TGGATTCCACAGCTT CGCCCCATCCCTGCG GCAGCGTGCCCCGGT
    GGATTCCACAGCTTC GCCCCATCCCTGCGC CAGCGTGCCCCGGTT
    GATTCCACAGCTTCG CCCCATCCCTGCGCG AGCGTGCCCCGGTTG
    ATTCCACAGCTTCGC CCCATCCCTGCGCGC GCGTGCCCCGGTTGC
    TTCCACAGCTTCGCG CCATCCCTGCGCGCC CGTGCCCCGGTTGCA
    TCCACAGCTTCGCGC CATCCCTGCGCGCCC GTGCCCCGGTTGCAG
    TGCCCCGGTTGCAGG TGACTCTGCTGGTGC GGGGGCTTGGGTCCC
    GCCCCGGTTGCAGGC GACTCTGCTGGTGCT GGGGCTTGGGTCCCG
    CCCCGGTTGCAGGCG ACTCTGCTGGTGCTG GGGCTTGGGTCCCGT
    CCCGGTTGCAGGCGT CTCTGCTGGTGCTGC GGCTTGGGTCCCGTG
    CCGGTTGCAGGCGTC TCTGCTGGTGCTGCT GCTTGGGTCCCGTGG
    CGGTTGCAGGCGTCA CTGCTGGTGCTGCTC CTTGGGTCCCGTGGT
    GGTTGCAGGCGTCAT TGCTGGTGCTGCTCC TTGGGTCCCGTGGTG
    GTTGCAGGCGTCATG GCTGGTGCTGCTCCG TGGGTCCCGTGGTGC
    TTGCAGGCGTCATGC CTGGTGCTGCTCCGC GGGTCCCGTGGTGCG
    TGCAGGCGTCATGCA TGGTGCTGCTCCGCG GGTCCCGTGGTGCGC
    GCAGGCGTCATGCAG GGTGCTGCTCCGCGG GTCCCGTGGTGCGCT
    CAGGCGTCATGCAGC GTGCTGCTCCGCGGG TCCCGTGGTGCGCTG
    AGGCGTCATGCAGCG TGCTGCTCCGCGGGC CCCGTGGTGCGCTGC
    GGCGTCATGCAGCGG GCTGCTCCGCGGGCC CCGTGGTGCGCTGCG
    GCGTCATGCAGCGGG CTGCTCCGCGGGCCG CGTGGTGCGCTGCGA
    CGTCATGCAGCGGGC TGCTCCGCGGGCCGC GTGGTGCGCTGCGAG
    GTCATGCAGCGGGCG GCTCCGCGGGCCGCC TGGTGCGCTGCGAGC
    TCATGCAGCGGGCGC CTCCGCGGGCCGCCG GGTGCGCTGCGAGCC
    CATGCAGCGGGCGCG TCCGCGGGCCGCCGG GTGCGCTGCGAGCCG
    ATGCAGCGGGCGCGA CCGCGGGCCGCCGGT TGCGCTGCGAGCCGT
    TGCAGCGGGCGCGAC CGCGGGCCGCCGGTG GCGCTGCGAGCCGTG
    GCAGCGGGCGCGACC GCGGGCCGCCGGTGG CGCTGCGAGCCGTGC
    CAGCGGGCGCGACCC CGGGCCGCCGGTGGC GCTGCGAGCCGTGCG
    AGCGGGCGCGACCCA GGGCCGCCGGTGGCG CTGCGAGCCGTGCGA
    GCGGGCGCGACCCAC GGCCGCCGGTGGCGC TGCGAGCCGTGCGAC
    CGGGCGCGACCCACG GCCGCCGGTGGCGCG GCGAGCCGTGCGACG
    GGGCGCGACCCACGC CCGCCGGTGGCGCGG CGAGCCGTGCGACGC
    GGCGCGACCCACGCT CGCCGGTGGCGCGGG GAGCCGTGCGACGCG
    GCGCGACCCACGCTC GCCGGTGGCGCGGGC AGCCGTGCGACGCGC
    CGCGACCCACGCTCT CCGGTGGCGCGGGCT GCCGTGCGACGCGCG
    GCGACCCACGCTCTG CGGTGGCGCGGGCTG CCGTGCGACGCGCGT
    CGACCCACGCTCTGG GGTGGCGCGGGCTGG CGTGCGACGCGCGTG
    GACCCACGCTCTGGG GTGGCGCGGGCTGGC GTGCGACGCGCGTGC
    ACCCACGCTCTGGGC TGGCGCGGGCTGGCG TGCGACGCGCGTGCA
    CCCACGCTCTGGGCC GGCGCGGGCTGGCGC GCGACGCGCGTGCAC
    CCACGCTCTGGGCCG GCGCGGGCTGGCGCG CGACGCGCGTGCACT
    CACGCTCTGGGCCGC CGCGGGCTGGCGCGA GACGCGCGTGCACTG
    ACGCTCTGGGCCGCT GCGGGCTGGCGCGAG ACGCGCGTGCACTGG
    CGCTCTGGGCCGCTG CGGGCTGGCGCGAGC CGCGCGTGCACTGGC
    GCTCTGGGCCGCTGC GGGCTGGCGCGAGCT GCGCGTGCACTGGCC
    CTCTGGGCCGCTGCG GGCTGGCGCGAGCTC CGCGTGCACTGGCCC
    TCTGGGCCGCTGCGC GCTGGCGCGAGCTCG GCGTGCACTGGCCCA
    CTGGGCCGCTGCGCT CTGGCGCGAGCTCGG CGTGCACTGGCCCAG
    TGGGCCGCTGCGCTG TGGCGCGAGCTCGGG GTGCACTGGCCCAGT
    GGGCCGCTGCGCTGA GGCGCGAGCTCGGGG TGCACTGGCCCAGTG
    GGCCGCTGCGCTGAC GCGCGAGCTCGGGGG GCACTGGCCCAGTGC
    GCCGCTGCGCTGACT CGCGAGCTCGGGGGG CACTGGCCCAGTGCG
    CCGCTGCGCTGACTC GCGAGCTCGGGGGGC ACTGGCCCAGTGCGC
    CGCTGCGCTGACTCT CGAGCTCGGGGGGCT CTGGCCCAGTGCGCG
    GCTGCGCTGACTCTG GAGCTCGGGGGGCTT TGGCCCAGTGCGCGC
    CTGCGCTGACTCTGC AGCTCGGGGGGCTTG GGCCCAGTGCGCGCC
    TGCGCTGACTCTGCT GCTCGGGGGGCTTGG GCCCAGTGCGCGCCT
    GCGCTGACTCTGCTG CTCGGGGGGCTTGGG CCCAGTGCGCGCCTC
    CGCTGACTCTGCTGG TCGGGGGGCTTGGGT CCAGTGCGCGCCTCC
    GCTGACTCTGCTGGT CGGGGGGCTTGGGTC CAGTGCGCGCCTCCG
    CTGACTCTGCTGGTG GGGGGGCTTGGGTCC AGTGCGCGCCTCCGC
    GTGCGCGCCTCCGCC GCTGCCTGACGTGCG TGTGGCTCCGGCCTT
    TGCGCGCCTCCGCCC CTGCCTGACGTGCGC GTGGCTCCGGCCTTC
    GCGCGCCTCCGCCCG TGCCTGACGTGCGCA TGGCTCCGGCCTTCG
    CGCGCCTCCGCCCGC GCCTGACGTGCGCAC GGCTCCGGCCTTCGC
    GCGCCTCCGCCCGCC CCTGACGTGCGCACT GCTCCGGCCTTCGCT
    CGCCTCCGCCCGCCG CTGACGTGCGCACTG CTCCGGCCTTCGCTG
    GCCTCCGCCCGCCGT TGACGTGCGCACTGA TCCGGCCTTCGCTGC
    CCTCCGCCCGCCGTG GACGTGCGCACTGAG CCGGCCTTCGCTGCC
    CTCCGCCCGCCGTGT ACGTGCGCACTGAGC CGGCCTTCGCTGCCA
    TCCGCCCGCCGTGTG CGTGCGCACTGAGCG GGCCTTCGCTGCCAG
    CCGCCCGCCGTGTGC GTGCGCACTGAGCGA GCCTTCGCTGCCAGC
    CGCCCGCCGTGTGCG TGCGCACTGAGCGAG CCTTCGCTGCCAGCC
    GCCCGCCGTGTGCGC GCGCACTGAGCGAGG CTTCGCTGCCAGCCG
    CCCGCCGTGTGCGCG CGCACTGAGCGAGGG TTCGCTGCCAGCCGT
    CCGCCGTGTGCGCGG GCACTGAGCGAGGGC TCGCTGCCAGCCGTC
    CGCCGTGTGCGCGGA CACTGAGCGAGGGCC CGCTGCCAGCCGTCG
    GCCGTGTGCGCGGAG ACTGAGCGAGGGCCA GCTGCCAGCCGTCGC
    CCGTGTGCGCGGAGC CTGAGCGAGGGCCAG CTGCCAGCCGTCGCC
    CGTGTGCGCGGAGCT TGAGCGAGGGCCAGC TGCCAGCCGTCGCCC
    GTGTGCGCGGAGCTG GAGCGAGGGCCAGCC GCCAGCCGTCGCCCG
    TGTGCGCGGAGCTGG AGCGAGGGCCAGCCG CCAGCCGTCGCCCGA
    GTGCGCGGAGCTGGT GCGAGGGCCAGCCGT CAGCCGTCGCCCGAC
    TGCGCGGAGCTGGTG CGAGGGCCAGCCGTG AGCCGTCGCCCGACG
    GCGCGGAGCTGGTGC GAGGGCCAGCCGTGC GCCGTCGCCCGACGA
    CGCGGAGCTGGTGCG AGGGCCAGCCGTGCG CCGTCGCCCGACGAG
    GCGGAGCTGGTGCGC GGGCCAGCCGTGCGG CGTCGCCCGACGAGG
    CGGAGCTGGTGCGCG GGCCAGCCGTGCGGC GTCGCCCGACGAGGC
    GGAGCTGGTGCGCGA GCCAGCCGTGCGGCA TCGCCCGACGAGGCG
    GAGCTGGTGCGCGAG CCAGCCGTGCGGCAT CGCCCGACGAGGCGC
    AGCTGGTGCGCGAGC CAGCCGTGCGGCATC GCCCGACGAGGCGCG
    GCTGGTGCGCGAGCC AGCCGTGCGGCATCT CCCGACGAGGCGCGA
    CTGGTGCGCGAGCCG GCCGTGCGGCATCTA CCGACGAGGCGCGAC
    TGGTGCGCGAGCCGG CCGTGCGGCATCTAC CGACGAGGCGCGACC
    GGTGCGCGAGCCGGG CGTGCGGCATCTACA GACGAGGCGCGACCG
    GTGCGCGAGCCGGGC GTGCGGCATCTACAC ACGAGGCGCGACCGC
    TGCGCGAGCCGGGCT TGCGGCATCTACACC CGAGGCGCGACCGCT
    GCGCGAGCCGGGCTG GCGGCATCTACACCG GAGGCGCGACCGCTG
    CGCGAGCCGGGCTGC CGGCATCTACACCGA AGGCGCGACCGCTGC
    GCGAGCCGGGCTGCG GGCATCTACACCGAG GGCGCGACCGCTGCA
    CGAGCCGGGCTGCGG GCATCTACACCGAGC GCGCGACCGCTGCAG
    GAGCCGGGCTGCGGC CATCTACACCGAGCG CGCGACCGCTGCAGG
    AGCCGGGCTGCGGCT ATCTACACCGAGCGC GCGACCGCTGCAGGC
    GCCGGGCTGCGGCTG TCTACACCGAGCGCT CGACCGCTGCAGGCG
    CCGGGCTGCGGCTGC CTACACCGAGCGCTG GACCGCTGCAGGCGC
    CGGGCTGCGGCTGCT TACACCGAGCGCTGT ACCGCTGCAGGCGCT
    GGGCTGCGGCTGCTG ACACCGAGCGCTGTG CCGCTGCAGGCGCTG
    GGCTGCGGCTGCTGC CACCGAGCGCTGTGG CGCTGCAGGCGCTGC
    GCTGCGGCTGCTGCC ACCGAGCGCTGTGGC GCTGCAGGCGCTGCT
    CTGCGGCTGCTGCCT CCGAGCGCTGTGGCT CTGCAGGCGCTGCTG
    TGCGGCTGCTGCCTG CGAGCGCTGTGGCTC TGCAGGCGCTGCTGG
    GCGGCTGCTGCCTGA GAGCGCTGTGGCTCC GCAGGCGCTGCTGGA
    CGGCTGCTGCCTGAC AGCGCTGTGGCTCCG CAGGCGCTGCTGGAC
    GGCTGCTGCCTGACG GCGCTGTGGCTCCGG AGGCGCTGCTGGACG
    GCTGCTGCCTGACGT CGCTGTGGCTCCGGC GGCGCTGCTGGACGG
    CTGCTGCCTGACGTG GCTGTGGCTCCGGCC GCGCTGCTGGACGGC
    TGCTGCCTGACGTGC CTGTGGCTCCGGCCT CGCTGCTGGACGGCC
    GCTGCTGGACGGCCG CCTACCTGCTGCCAG CGCAGCGCCGGCAGT
    CTGCTGGACGGCCGC CTACCTGCTGCCAGC GCAGCGCCGGCAGTG
    TGCTGGACGGCCGCG TACCTGCTGCCAGCG CAGCGCCGGCAGTGT
    GCTGGACGGCCGCGG ACCTGCTGCCAGCGC AGCGCCGGCAGTGTG
    CTGGACGGCCGCGGG CCTGCTGCCAGCGCC GCGCCGGCAGTGTGG
    TGGACGGCCGCGGGC CTGCTGCCAGCGCCG CGCCGGCAGTGTGGA
    GGACGGCCGCGGGCT TGCTGCCAGCGCCGC GCCGGCAGTGTGGAG
    GACGGCCGCGGGCTC GCTGCCAGCGCCGCC CCGGCAGTGTGGAGA
    ACGGCCGCGGGCTCT CTGCCAGCGCCGCCA CGGCAGTGTGGAGAG
    CGGCCGCGGGCTCTG TGCCAGCGCCGCCAG GGCAGTGTGGAGAGC
    GGCCGCGGGCTCTGC GCCAGCGCCGCCAGC GCAGTGTGGAGAGCC
    GCCGCGGGCTCTGCG CCAGCGCCGCCAGCT CAGTGTGGAGAGCCC
    CCGCGGGCTCTGCGT CAGCGCCGCCAGCTC AGTGTGGAGAGCCCG
    CGCGGGCTCTGCGTC AGCGCCGCCAGCTCC GTGTGGAGAGCCCGT
    GCGGGCTCTGCGTCA GCGCCGCCAGCTCCA TGTGGAGAGCCCGTC
    CGGGCTCTGCGTCAA CGCCGCCAGCTCCAG GTGGAGAGCCCGTCC
    GGGCTCTGCGTCAAC GCCGCCAGCTCCAGG TGGAGAGCCCGTCCG
    GGCTCTGCGTCAACG CCGCCAGCTCCAGGA GGAGAGCCCGTCCGT
    GCTCTGCGTCAACGC CGCCAGCTCCAGGAA GAGAGCCCGTCCGTC
    CTCTGCGTCAACGCT GCCAGCTCCAGGAAA AGAGCCCGTCCGTCT
    TCTGCGTCAACGCTA CCAGCTCCAGGAAAT GAGCCCGTCCGTCTC
    CTGCGTCAACGCTAG CAGCTCCAGGAAATG AGCCCGTCCGTCTCC
    TGCGTCAACGCTAGT AGCTCCAGGAAATGC GCCCGTCCGTCTCCA
    GCGTCAACGCTAGTG GCTCCAGGAAATGCT CCCGTCCGTCTCCAG
    CGTCAACGCTAGTGC CTCCAGGAAATGCTA CCGTCCGTCTCCAGC
    GTCAACGCTAGTGCC TCCAGGAAATGCTAG CGTCCGTCTCCAGCA
    TCAACGCTAGTGCCG CCAGGAAATGCTAGT GTCCGTCTCCAGCAC
    CAACGCTAGTGCCGT CAGGAAATGCTAGTG TCCGTCTCCAGCACG
    AACGCTAGTGCCGTC AGGAAATGCTAGTGA CCGTCTCCAGCACGC
    ACGCTAGTGCCGTCA GGAAATGCTAGTGAG CGTCTCCAGCACGCA
    CGCTAGTGCCGTCAG GAAATGCTAGTGAGT GTCTCCAGCACGCAC
    GCTAGTGCCGTCAGC AAATGCTAGTGAGTC TCTCCAGCACGCACC
    CTAGTGCCGTCAGCC AATGCTAGTGAGTCG CTCCAGCACGCACCG
    TAGTGCCGTCAGCCG ATGCTAGTGAGTCGG TCCAGCACGCACCGG
    AGTGCCGTCAGCCGC TGCTAGTGAGTCGGA CCAGCACGCACCGGG
    GTGCCGTCAGCCGCC GCTAGTGAGTCGGAG CAGCACGCACCGGGT
    TGCCGTCAGCCGCCT CTAGTGAGTCGGAGG AGCACGCACCGGGTG
    GCCGTCAGCCGCCTG TAGTGAGTCGGAGGA GCACGCACCGGGTGT
    CCGTCAGCCGCCTGC AGTGAGTCGGAGGAA CACGCACCGGGTGTC
    CGTCAGCCGCCTGCG GTGAGTCGGAGGAAG ACGCACCGGGTGTCT
    GTCAGCCGCCTGCGC TGAGTCGGAGGAAGA CGCACCGGGTGTCTG
    TCAGCCGCCTGCGCG GAGTCGGAGGAAGAC GCACCGGGTGTCTGA
    CAGCCGCCTGCGCGC AGTCGGAGGAAGACC CACCGGGTGTCTGAT
    AGCCGCCTGCGCGCC GTCGGAGGAAGACCG ACCGGGTGTCTGATC
    GCCGCCTGCGCGCCT TCGGAGGAAGACCGC CCGGGTGTCTGATCC
    CCGCCTGCGCGCCTA CGGAGGAAGACCGCA CGGGTGTCTGATCCC
    CGCCTGCGCGCCTAC GGAGGAAGACCGCAG GGGTGTCTGATCCCA
    GCCTGCGCGCCTACC GAGGAAGACCGCAGC GGTGTCTGATCCCAA
    CCTGCGCGCCTACCT AGGAAGACCGCAGCG GTGTCTGATCCCAAG
    CTGCGCGCCTACCTG GGAAGACCGCAGCGC TGTCTGATCCCAAGT
    TGCGCGCCTACCTGC GAAGACCGCAGCGCC GTCTGATCCCAAGTT
    GCGCGCCTACCTGCT AAGACCGCAGCGCCG TCTGATCCCAAGTTC
    CGCGCCTACCTGCTG AGACCGCAGCGCCGG CTGATCCCAAGTTCC
    GCGCCTACCTGCTGC GACCGCAGCGCCGGC TGATCCCAAGTTCCA
    CGCCTACCTGCTGCC ACCGCAGCGCCGGCA GATCCCAAGTTCCAC
    GCCTACCTGCTGCCA CCGCAGCGCCGGCAG ATCCCAAGTTCCACC
    TCCCAAGTTCCACCC AAGACAGCCAGCGCT TTCTCCTCCGAGTCC
    CCCAAGTTCCACCCC AGACAGCCAGCGCTA TCTCCTCCGAGTCCA
    CCAAGTTCCACCCCC GACAGCCAGCGCTAC CTCCTCCGAGTCCAA
    CAAGTTCCACCCCCT ACAGCCAGCGCTACA TCCTCCGAGTCCAAG
    AAGTTCCACCCCCTC CAGCCAGCGCTACAA CCTCCGAGTCCAAGC
    AGTTCCACCCCCTCC AGCCAGCGCTACAAA CTCCGAGTCCAAGCG
    GTTCCACCCCCTCCA GCCAGCGCTACAAAG TCCGAGTCCAAGCGG
    TTCCACCCCCTCCAT CCAGCGCTACAAAGT CCGAGTCCAAGCGGG
    TCCACCCCCTCCATT CAGCGCTACAAAGTT CGAGTCCAAGCGGGA
    CCACCCCCTCCATTC AGCGCTACAAAGTTG GAGTCCAAGCGGGAG
    CACCCCCTCCATTCA GCGCTACAAAGTTGA AGTCCAAGCGGGAGA
    ACCCCCTCCATTCAA CGCTACAAAGTTGAC GTCCAAGCGGGAGAC
    CCCCCTCCATTCAAA GCTACAAAGTTGACT TCCAAGCGGGAGACA
    CCCCTCCATTCAAAG CTACAAAGTTGACTA CCAAGCGGGAGACAG
    CCCTCCATTCAAAGA TACAAAGTTGACTAC CAAGCGGGAGACAGA
    CCTCCATTCAAAGAT ACAAAGTTGACTACG AAGCGGGAGACAGAA
    CTCCATTCAAAGATA CAAAGTTGACTACGA AGCGGGAGACAGAAT
    TCCATTCAAAGATAA AAAGTTGACTACGAG GCGGGAGACAGAATA
    CCATTCAAAGATAAT AAGTTGACTACGAGT CGGGAGACAGAATAT
    CATTCAAAGATAATC AGTTGACTACGAGTC GGGAGACAGAATATG
    ATTCAAAGATAATCA GTTGACTACGAGTCT GGAGACAGAATATGG
    TTCAAAGATAATCAT TTGACTACGAGTCTC GAGACAGAATATGGT
    TCAAAGATAATCATC TGACTACGAGTCTCA AGACAGAATATGGTC
    CAAAGATAATCATCA GACTACGAGTCTCAG GACAGAATATGGTCC
    AAAGATAATCATCAT ACTACGAGTCTCAGA ACAGAATATGGTCCC
    AAGATAATCATCATC CTACGAGTCTCAGAG CAGAATATGGTCCCT
    AGATAATCATCATCA TACGAGTCTCAGAGC AGAATATGGTCCCTG
    GATAATCATCATCAA ACGAGTCTCAGAGCA GAATATGGTCCCTGC
    ATAATCATCATCAAG CGAGTCTCAGAGCAC AATATGGTCCCTGCC
    TAATCATCATCAAGA GAGTCTCAGAGCACA ATATGGTCCCTGCCG
    AATCATCATCAAGAA AGTCTCAGAGCACAG TATGGTCCCTGCCGT
    ATCATCATCAAGAAA GTCTCAGAGCACAGA ATGGTCCCTGCCGTA
    TCATCATCAAGAAAG TCTCAGAGCACAGAT TGGTCCCTGCCGTAG
    CATCATCAAGAAAGG CTCAGAGCACAGATA GGTCCCTGCCGTAGA
    ATCATCAAGAAAGGG TCAGAGCACAGATAC GTCCCTGCCGTAGAG
    TCATCAAGAAAGGGC CAGAGCACAGATACC TCCCTGCCGTAGAGA
    CATCAAGAAAGGGCA AGAGCACAGATACCC CCCTGCCGTAGAGAA
    ATCAAGAAAGGGCAT GAGCACAGATACCCA CCTGCCGTAGAGAAA
    TCAAGAAAGGGCATG AGCACAGATACCCAG CTGCCGTAGAGAAAT
    CAAGAAAGGGCATGC GCACAGATACCCAGA TGCCGTAGAGAAATG
    AAGAAAGGGCATGCT CACAGATACCCAGAA GCCGTAGAGAAATGG
    AGAAAGGGCATGCTA ACAGATACCCAGAAC CCGTAGAGAAATGGA
    GAAAGGGCATGCTAA CAGATACCCAGAACT CGTAGAGAAATGGAA
    AAAGGGCATGCTAAA AGATACCCAGAACTT GTAGAGAAATGGAAG
    AAGGGCATGCTAAAG GATACCCAGAACTTC TAGAGAAATGGAAGA
    AGGGCATGCTAAAGA ATACCCAGAACTTCT AGAGAAATGGAAGAC
    GGGCATGCTAAAGAC TACCCAGAACTTCTC GAGAAATGGAAGACA
    GGCATGCTAAAGACA ACCCAGAACTTCTCC AGAAATGGAAGACAC
    GCATGCTAAAGACAG CCCAGAACTTCTCCT GAAATGGAAGACACA
    CATGCTAAAGACAGC CCAGAACTTCTCCTC AAATGGAAGACACAC
    ATGCTAAAGACAGCC CAGAACTTCTCCTCC AATGGAAGACACACT
    TGCTAAAGACAGCCA AGAACTTCTCCTCCG ATGGAAGACACACTG
    GCTAAAGACAGCCAG GAACTTCTCCTCCGA TGGAAGACACACTGA
    CTAAAGACAGCCAGC AACTTCTCCTCCGAG GGAAGACACACTGAA
    TAAAGACAGCCAGCG ACTTCTCCTCCGAGT GAAGACACACTGAAT
    AAAGACAGCCAGCGC CTTCTCCTCCGAGTC AAGACACACTGAATC
    AGACACACTGAATCA TTCCCAACTGTGACA GGCAGGAAGCGGGGC
    GACACACTGAATCAC TCCCAACTGTGACAA GCAGGAAGCGGGGCT
    ACACACTGAATCACC CCCAACTGTGACAAG CAGGAAGCGGGGCTT
    CACACTGAATCACCT CCAACTGTGACAAGA AGGAAGCGGGGCTTC
    ACACTGAATCACCTG CAACTGTGACAAGAA GGAAGCGGGGCTTCT
    CACTGAATCACCTGA AACTGTGACAAGAAG GAAGCGGGGCTTCTG
    ACTGAATCACCTGAA ACTGTGACAAGAAGG AAGCGGGGCTTCTGC
    CTGAATCACCTGAAG CTGTGACAAGAAGGG AGCGGGGCTTCTGCT
    TGAATCACCTGAAGT TGTGACAAGAAGGGA GCGGGGCTTCTGCTG
    GAATCACCTGAAGTT GTGACAAGAAGGGAT CGGGGCTTCTGCTGG
    AATCACCTGAAGTTC TGACAAGAAGGGATT GGGGCTTCTGCTGGT
    ATCACCTGAAGTTCC GACAAGAAGGGATTT GGGCTTCTGCTGGTG
    TCACCTGAAGTTCCT ACAAGAAGGGATTTT GGCTTCTGCTGGTGT
    CACCTGAAGTTCCTC CAAGAAGGGATTTTA GCTTCTGCTGGTGTG
    ACCTGAAGTTCCTCA AAGAAGGGATTTTAT CTTCTGCTGGTGTGT
    CCTGAAGTTCCTCAA AGAAGGGATTTTATA TTCTGCTGGTGTGTG
    CTGAAGTTCCTCAAT GAAGGGATTTTATAA TCTGCTGGTGTGTGG
    TGAAGTTCCTCAATG AAGGGATTTTATAAG CTGCTGGTGTGTGGA
    GAAGTTCCTCAATGT AGGGATTTTATAAGA TGCTGGTGTGTGGAT
    AAGTTCCTCAATGTG GGGATTTTATAAGAA GCTGGTGTGTGGATA
    AGTTCCTCAATGTGC GGATTTTATAAGAAA CTGGTGTGTGGATAA
    GTTCCTCAATGTGCT GATTTTATAAGAAAA TGGTGTGTGGATAAG
    TTCCTCAATGTGCTG ATTTTATAAGAAAAA GGTGTGTGGATAAGT
    TCCTCAATGTGCTGA TTTTATAAGAAAAAG GTGTGTGGATAAGTA
    CCTCAATGTGCTGAG TTTATAAGAAAAAGC TGTGTGGATAAGTAT
    CTCAATGTGCTGAGT TTATAAGAAAAAGCA GTGTGGATAAGTATG
    TCAATGTGCTGAGTC TATAAGAAAAAGCAG TGTGGATAAGTATGG
    CAATGTGCTGAGTCC ATAAGAAAAAGCAGT GTGGATAAGTATGGG
    AATGTGCTGAGTCCC TAAGAAAAAGCAGTG TGGATAAGTATGGGC
    ATGTGCTGAGTCCCA AAGAAAAAGCAGTGT GGATAAGTATGGGCA
    TGTGCTGAGTCCCAG AGAAAAAGCAGTGTC GATAAGTATGGGCAG
    GTGCTGAGTCCCAGG GAAAAAGCAGTGTCG ATAAGTATGGGCAGC
    TGCTGAGTCCCAGGG AAAAAGCAGTGTCGC TAAGTATGGGCAGCC
    GCTGAGTCCCAGGGG AAAAGCAGTGTCGCC AAGTATGGGCAGCCT
    CTGAGTCCCAGGGGT AAAGCAGTGTCGCCC AGTATGGGCAGCCTC
    TGAGTCCCAGGGGTG AAGCAGTGTCGCCCT GTATGGGCAGCCTCT
    GAGTCCCAGGGGTGT AGCAGTGTCGCCCTT TATGGGCAGCCTCTC
    AGTCCCAGGGGTGTA GCAGTGTCGCCCTTC ATGGGCAGCCTCTCC
    GTCCCAGGGGTGTAC CAGTGTCGCCCTTCC TGGGCAGCCTCTCCC
    TCCCAGGGGTGTACA AGTGTCGCCCTTCCA GGGCAGCCTCTCCCA
    CCCAGGGGTGTACAC GTGTCGCCCTTCCAA GGCAGCCTCTCCCAG
    CCAGGGGTGTACACA TGTCGCCCTTCCAAA GCAGCCTCTCCCAGG
    CAGGGGTGTACACAT GTCGCCCTTCCAAAG CAGCCTCTCCCAGGC
    AGGGGTGTACACATT TCGCCCTTCCAAAGG AGCCTCTCCCAGGCT
    GGGGTGTACACATTC CGCCCTTCCAAAGGC GCCTCTCCCAGGCTA
    GGGTGTACACATTCC GCCCTTCCAAAGGCA CCTCTCCCAGGCTAC
    GGTGTACACATTCCC CCCTTCCAAAGGCAG CTCTCCCAGGCTACA
    GTGTACACATTCCCA CCTTCCAAAGGCAGG TCTCCCAGGCTACAC
    TGTACACATTCCCAA CTTCCAAAGGCAGGA CTCCCAGGCTACACC
    GTACACATTCCCAAC TTCCAAAGGCAGGAA TCCCAGGCTACACCA
    TACACATTCCCAACT TCCAAAGGCAGGAAG CCCAGGCTACACCAC
    ACACATTCCCAACTG CCAAAGGCAGGAAGC CCAGGCTACACCACC
    CACATTCCCAACTGT CAAAGGCAGGAAGCG CAGGCTACACCACCA
    ACATTCCCAACTGTG AAAGGCAGGAAGCGG AGGCTACACCACCAA
    CATTCCCAACTGTGA AAGGCAGGAAGCGGG GGCTACACCACCAAG
    ATTCCCAACTGTGAC AGGCAGGAAGCGGGG GCTACACCACCAAGG
    CTACACCACCAAGGG CGCCTGCCGCAAGTT CCAAGGACATGACCA
    TACACCACCAAGGGG GCCTGCCGCAAGTTA CAAGGACATGACCAG
    ACACCACCAAGGGGA CCTGCCGCAAGTTAA AAGGACATGACCAGC
    CACCACCAAGGGGAA CTGCCGCAAGTTAAT AGGACATGACCAGCA
    ACCACCAAGGGGAAG TGCCGCAAGTTAATG GGACATGACCAGCAG
    CCACCAAGGGGAAGG GCCGCAAGTTAATGT GACATGACCAGCAGC
    CACCAAGGGGAAGGA CCGCAAGTTAATGTG ACATGACCAGCAGCT
    ACCAAGGGGAAGGAG CGCAAGTTAATGTGG CATGACCAGCAGCTG
    CCAAGGGGAAGGAGG GCAAGTTAATGTGGA ATGACCAGCAGCTGG
    CAAGGGGAAGGAGGA CAAGTTAATGTGGAG TGACCAGCAGCTGGC
    AAGGGGAAGGAGGAC AAGTTAATGTGGAGC GACCAGCAGCTGGCT
    AGGGGAAGGAGGACG AGTTAATGTGGAGCT ACCAGCAGCTGGCTA
    GGGGAAGGAGGACGT GTTAATGTGGAGCTC CCAGCAGCTGGCTAC
    GGGAAGGAGGACGTG TTAATGTGGAGCTCA CAGCAGCTGGCTACA
    GGAAGGAGGACGTGC TAATGTGGAGCTCAA AGCAGCTGGCTACAG
    GAAGGAGGACGTGCA AATGTGGAGCTCAAA GCAGCTGGCTACAGC
    AAGGAGGACGTGCAC ATGTGGAGCTCAAAT CAGCTGGCTACAGCC
    AGGAGGACGTGCACT TGTGGAGCTCAAATA AGCTGGCTACAGCCT
    GGAGGACGTGCACTG GTGGAGCTCAAATAT GCTGGCTACAGCCTC
    GAGGACGTGCACTGC TGGAGCTCAAATATG CTGGCTACAGCCTCG
    AGGACGTGCACTGCT GGAGCTCAAATATGC TGGCTACAGCCTCGA
    GGACGTGCACTGCTA GAGCTCAAATATGCC GGCTACAGCCTCGAT
    GACGTGCACTGCTAC AGCTCAAATATGCCT GCTACAGCCTCGATT
    ACGTGCACTGCTACA GCTCAAATATGCCTT CTACAGCCTCGATTT
    CGTGCACTGCTACAG CTCAAATATGCCTTA TACAGCCTCGATTTA
    GTGCACTGCTACAGC TCAAATATGCCTTAT ACAGCCTCGATTTAT
    TGCACTGCTACAGCA CAAATATGCCTTATT CAGCCTCGATTTATA
    GCACTGCTACAGCAT AAATATGCCTTATTT AGCCTCGATTTATAT
    CACTGCTACAGCATG AATATGCCTTATTTT GCCTCGATTTATATT
    ACTGCTACAGCATGC ATATGCCTTATTTTG CCTCGATTTATATTT
    CTGCTACAGCATGCA TATGCCTTATTTTGC CTCGATTTATATTTC
    TGCTACAGCATGCAG ATGCCTTATTTTGCA TCGATTTATATTTCT
    GCTACAGCATGCAGA TGCCTTATTTTGCAC CGATTTATATTTCTG
    CTACAGCATGCAGAG GCCTTATTTTGCACA GATTTATATTTCTGT
    TACAGCATGCAGAGC CCTTATTTTGCACAA ATTTATATTTCTGTT
    ACAGCATGCAGAGCA CTTATTTTGCACAAA TTTATATTTCTGTTT
    CAGCATGCAGAGCAA TTATTTTGCACAAAA TTATATTTCTGTTTG
    AGCATGCAGAGCAAG TATTTTGCACAAAAG TATATTTCTGTTTGT
    GCATGCAGAGCAAGT ATTTTGCACAAAAGA ATATTTCTGTTTGTG
    CATGCAGAGCAAGTA TTTTGCACAAAAGAC TATTTCTGTTTGTGG
    ATGCAGAGCAAGTAG TTTGCACAAAAGACT ATTTCTGTTTGTGGT
    TGCAGAGCAAGTAGA TTGCACAAAAGACTG TTTCTGTTTGTGGTG
    GCAGAGCAAGTAGAC TGCACAAAAGACTGC TTCTGTTTGTGGTGA
    CAGAGCAAGTAGACG GCACAAAAGACTGCC TCTGTTTGTGGTGAA
    AGAGCAAGTAGACGC CACAAAAGACTGCCA CTGTTTGTGGTGAAC
    GAGCAAGTAGACGCC ACAAAAGACTGCCAA TGTTTGTGGTGAACT
    AGCAAGTAGACGCCT CAAAAGACTGCCAAG GTTTGTGGTGAACTG
    GCAAGTAGACGCCTG AAAAGACTGCCAAGG TTTGTGGTGAACTGA
    CAAGTAGACGCCTGC AAAGACTGCCAAGGA TTGTGGTGAACTGAT
    AAGTAGACGCCTGCC AAGACTGCCAAGGAC TGTGGTGAACTGATT
    AGTAGACGCCTGCCG AGACTGCCAAGGACA GTGGTGAACTGATTT
    GTAGACGCCTGCCGC GACTGCCAAGGACAT TGGTGAACTGATTTT
    TAGACGCCTGCCGCA ACTGCCAAGGACATG GGTGAACTGATTTTT
    AGACGCCTGCCGCAA CTGCCAAGGACATGA GTGAACTGATTTTTT
    GACGCCTGCCGCAAG TGCCAAGGACATGAC TGAACTGATTTTTTT
    ACGCCTGCCGCAAGT GCCAAGGACATGACC GAACTGATTTTTTTT
    AACTGATTTTTTTTA CTTTGAATGGTAAAC TTGAATTTTCTTGTC
    ACTGATTTTTTTTAA TTTGAATGGTAAACT TGAATTTTCTTGTCG
    CTGATTTTTTTTAAA TTGAATGGTAAACTT GAATTTTCTTGTCGC
    TGATTTTTTTTAAAC TGAATGGTAAACTTG AATTTTCTTGTCGCT
    GATTTTTTTTAAACC GAATGGTAAACTTGA ATTTTCTTGTCGCTT
    ATTTTTTTTAAACCA AATGGTAAACTTGAG TTTTCTTGTCGCTTC
    TTTTTTTTAAACCAA ATGGTAAACTTGAGC TTTCTTGTCGCTTCC
    TTTTTTTAAACCAAA TGGTAAACTTGAGCA TTCTTGTCGCTTCCT
    TTTTTTAAACCAAAG GGTAAACTTGAGCAT TCTTGTCGCTTCCTA
    TTTTTAAACCAAAGT GTAAACTTGAGCATC CTTGTCGCTTCCTAT
    TTTTAAACCAAAGTT TAAACTTGAGCATCT TTGTCGCTTCCTATC
    TTTAAACCAAAGTTT AAACTTGAGCATCTT TGTCGCTTCCTATCA
    TTAAACCAAAGTTTA AACTTGAGCATCTTT GTCGCTTCCTATCAA
    TAAACCAAAGTTTAG ACTTGAGCATCTTTT TCGCTTCCTATCAAA
    AAACCAAAGTTTAGA CTTGAGCATCTTTTC CGCTTCCTATCAAAA
    AACCAAAGTTTAGAA TTGAGCATCTTTTCA GCTTCCTATCAAAAT
    ACCAAAGTTTAGAAA TGAGCATCTTTTCAC CTTCCTATCAAAATA
    CCAAAGTTTAGAAAG GAGCATCTTTTCACT TTCCTATCAAAATAT
    CAAAGTTTAGAAAGA AGCATCTTTTCACTT TCCTATCAAAATATT
    AAAGTTTAGAAAGAG GCATCTTTTCACTTT CCTATCAAAATATTC
    AAGTTTAGAAAGAGG CATCTTTTCACTTTC CTATCAAAATATTCA
    AGTTTAGAAAGAGGT ATCTTTTCACTTTCC TATCAAAATATTCAG
    GTTTAGAAAGAGGTT TCTTTTCACTTTCCA ATCAAAATATTCAGA
    TTTAGAAAGAGGTTT CTTTTCACTTTCCAG TCAAAATATTCAGAG
    TTAGAAAGAGGTTTT TTTTCACTTTCCAGT CAAAATATTCAGAGA
    TAGAAAGAGGTTTTT TTTCACTTTCCAGTA AAAATATTCAGAGAC
    AGAAAGAGGTTTTTG TTCACTTTCCAGTAG AAATATTCAGAGACT
    GAAAGAGGTTTTTGA TCACTTTCCAGTAGT AATATTCAGAGACTC
    AAAGAGGTTTTTGAA CACTTTCCAGTAGTC ATATTCAGAGACTCG
    AAGAGGTTTTTGAAA ACTTTCCAGTAGTCA TATTCAGAGACTCGA
    AGAGGTTTTTGAAAT CTTTCCAGTAGTCAG ATTCAGAGACTCGAG
    GAGGTTTTTGAAATG TTTCCAGTAGTCAGC TTCAGAGACTCGAGC
    AGGTTTTTGAAATGC TTCCAGTAGTCAGCA TCAGAGACTCGAGCA
    GGTTTTTGAAATGCC TCCAGTAGTCAGCAA CAGAGACTCGAGCAC
    GTTTTTGAAATGCCT CCAGTAGTCAGCAAA AGAGACTCGAGCACA
    TTTTTGAAATGCCTA CAGTAGTCAGCAAAG GAGACTCGAGCACAG
    TTTTGAAATGCCTAT AGTAGTCAGCAAAGA AGACTCGAGCACAGC
    TTTGAAATGCCTATG GTAGTCAGCAAAGAG GACTCGAGCACAGCA
    TTGAAATGCCTATGG TAGTCAGCAAAGAGC ACTCGAGCACAGCAC
    TGAAATGCCTATGGT AGTCAGCAAAGAGCA CTCGAGCACAGCACC
    GAAATGCCTATGGTT GTCAGCAAAGAGCAG TCGAGCACAGCACCC
    AAATGCCTATGGTTT TCAGCAAAGAGCAGT CGAGCACAGCACCCA
    AATGCCTATGGTTTC CAGCAAAGAGCAGTT GAGCACAGCACCCAG
    ATGCCTATGGTTTCT AGCAAAGAGCAGTTT AGCACAGCACCCAGA
    TGCCTATGGTTTCTT GCAAAGAGCAGTTTG GCACAGCACCCAGAC
    GCCTATGGTTTCTTT CAAAGAGCAGTTTGA CACAGCACCCAGACT
    CCTATGGTTTCTTTG AAAGAGCAGTTTGAA ACAGCACCCAGACTT
    CTATGGTTTCTTTGA AAGAGCAGTTTGAAT CAGCACCCAGACTTC
    TATGGTTTCTTTGAA AGAGCAGTTTGAATT AGCACCCAGACTTCA
    ATGGTTTCTTTGAAT GAGCAGTTTGAATTT GCACCCAGACTTCAT
    TGGTTTCTTTGAATG AGCAGTTTGAATTTT CACCCAGACTTCATG
    GGTTTCTTTGAATGG GCAGTTTGAATTTTC ACCCAGACTTCATGC
    GTTTCTTTGAATGGT CAGTTTGAATTTTCT CCCAGACTTCATGCG
    TTTCTTTGAATGGTA AGTTTGAATTTTCTT CCAGACTTCATGCGC
    TTCTTTGAATGGTAA GTTTGAATTTTCTTG CAGACTTCATGCGCC
    TCTTTGAATGGTAAA TTTGAATTTTCTTGT AGACTTCATGCGCCC
    GACTTCATGCGCCCG ACTTTGTGACTTAGG CCCCGTACAGTGCGC
    ACTTCATGCGCCCGT CTTTGTGACTTAGGC CCCGTACAGTGCGCA
    CTTCATGCGCCCGTG TTTGTGACTTAGGCG CCGTACAGTGCGCAC
    TTCATGCGCCCGTGG TTGTGACTTAGGCGG CGTACAGTGCGCACA
    TCATGCGCCCGTGGA TGTGACTTAGGCGGC GTACAGTGCGCACAG
    CATGCGCCCGTGGAA GTGACTTAGGCGGCT TACAGTGCGCACAGG
    ATGCGCCCGTGGAAT TGACTTAGGCGGCTG ACAGTGCGCACAGGC
    TGCGCCCGTGGAATG GACTTAGGCGGCTGT CAGTGCGCACAGGCT
    GCGCCCGTGGAATGC ACTTAGGCGGCTGTG AGTGCGCACAGGCTT
    CGCCCGTGGAATGCT CTTAGGCGGCTGTGT GTGCGCACAGGCTTT
    GCCCGTGGAATGCTC TTAGGCGGCTGTGTT TGCGCACAGGCTTTA
    CCCGTGGAATGCTCA TAGGCGGCTGTGTTG GCGCACAGGCTTTAT
    CCGTGGAATGCTCAC AGGCGGCTGTGTTGC CGCACAGGCTTTATC
    CGTGGAATGCTCACC GGCGGCTGTGTTGCC GCACAGGCTTTATCG
    GTGGAATGCTCACCA GCGGCTGTGTTGCCT CACAGGCTTTATCGA
    TGGAATGCTCACCAC CGGCTGTGTTGCCTA ACAGGCTTTATCGAG
    GGAATGCTCACCACA GGCTGTGTTGCCTAT CAGGCTTTATCGAGA
    GAATGCTCACCACAT GCTGTGTTGCCTATG AGGCTTTATCGAGAA
    AATGCTCACCACATG CTGTGTTGCCTATGT GGCTTTATCGAGAAT
    ATGCTCACCACATGT TGTGTTGCCTATGTA GCTTTATCGAGAATA
    TGCTCACCACATGTT GTGTTGCCTATGTAG CTTTATCGAGAATAG
    GCTCACCACATGTTG TGTTGCCTATGTAGA TTTATCGAGAATAGG
    CTCACCACATGTTGG GTTGCCTATGTAGAG TTATCGAGAATAGGA
    TCACCACATGTTGGT TTGCCTATGTAGAGA TATCGAGAATAGGAA
    CACCACATGTTGGTC TGCCTATGTAGAGAA ATCGAGAATAGGAAA
    ACCACATGTTGGTCG GCCTATGTAGAGAAC TCGAGAATAGGAAAA
    CCACATGTTGGTCGA CCTATGTAGAGAACA CGAGAATAGGAAAAC
    CACATGTTGGTCGAA CTATGTAGAGAACAC GAGAATAGGAAAACC
    ACATGTTGGTCGAAG TATGTAGAGAACACG AGAATAGGAAAACCT
    CATGTTGGTCGAAGC ATGTAGAGAACACGC GAATAGGAAAACCTT
    ATGTTGGTCGAAGCG TGTAGAGAACACGCT AATAGGAAAACCTTT
    TGTTGGTCGAAGCGG GTAGAGAACACGCTT ATAGGAAAACCTTTA
    GTTGGTCGAAGCGGC TAGAGAACACGCTTC TAGGAAAACCTTTAA
    TTGGTCGAAGCGGCC AGAGAACACGCTTCA AGGAAAACCTTTAAA
    TGGTCGAAGCGGCCG GAGAACACGCTTCAC GGAAAACCTTTAAAC
    GGTCGAAGCGGCCGA AGAACACGCTTCACC GAAAACCTTTAAACC
    GTCGAAGCGGCCGAC GAACACGCTTCACCC AAAACCTTTAAACCC
    TCGAAGCGGCCGACC AACACGCTTCACCCC AAACCTTTAAACCCC
    CGAAGCGGCCGACCA ACACGCTTCACCCCC AACCTTTAAACCCCG
    GAAGCGGCCGACCAC CACGCTTCACCCCCA ACCTTTAAACCCCGG
    AAGCGGCCGACCACT ACGCTTCACCCCCAC CCTTTAAACCCCGGT
    AGCGGCCGACCACTG CGCTTCACCCCCACT CTTTAAACCCCGGTC
    GCGGCCGACCACTGA GCTTCACCCCCACTC TTTAAACCCCGGTCA
    CGGCCGACCACTGAC CTTCACCCCCACTCC TTAAACCCCGGTCAT
    GGCCGACCACTGACT TTCACCCCCACTCCC TAAACCCCGGTCATC
    GCCGACCACTGACTT TCACCCCCACTCCCC AAACCCCGGTCATCC
    CCGACCACTGACTTT CACCCCCACTCCCCG AACCCCGGTCATCCG
    CGACCACTGACTTTG ACCCCCACTCCCCGT ACCCCGGTCATCCGG
    GACCACTGACTTTGT CCCCCACTCCCCGTA CCCCGGTCATCCGGA
    ACCACTGACTTTGTG CCCCACTCCCCGTAC CCCGGTCATCCGGAC
    CCACTGACTTTGTGA CCCACTCCCCGTACA CCGGTCATCCGGACA
    CACTGACTTTGTGAC CCACTCCCCGTACAG CGGTCATCCGGACAT
    ACTGACTTTGTGACT CACTCCCCGTACAGT GGTCATCCGGACATC
    CTGACTTTGTGACTT ACTCCCCGTACAGTG GTCATCCGGACATCC
    TGACTTTGTGACTTA CTCCCCGTACAGTGC TCATCCGGACATCCC
    GACTTTGTGACTTAG TCCCCGTACAGTGCG CATCCGGACATCCCA
    ATCCGGACATCCCAA TGAAACAAGGGCGTG TGTACTGCTTGGGGA
    TCCGGACATCCCAAC GAAACAAGGGCGTGG GTACTGCTTGGGGAC
    CCGGACATCCCAACG AAACAAGGGCGTGGA TACTGCTTGGGGACT
    CGGACATCCCAACGC AACAAGGGCGTGGAT ACTGCTTGGGGACTA
    GGACATCCCAACGCA ACAAGGGCGTGGATC CTGCTTGGGGACTAT
    GACATCCCAACGCAT CAAGGGCGTGGATCC TGCTTGGGGACTATT
    ACATCCCAACGCATG AAGGGCGTGGATCCC GCTTGGGGACTATTG
    CATCCCAACGCATGC AGGGCGTGGATCCCT CTTGGGGACTATTGG
    ATCCCAACGCATGCT GGGCGTGGATCCCTC TTGGGGACTATTGGA
    TCCCAACGCATGCTC GGCGTGGATCCCTCA TGGGGACTATTGGAG
    CCCAACGCATGCTCC GCGTGGATCCCTCAA GGGGACTATTGGAGA
    CCAACGCATGCTCCT CGTGGATCCCTCAAC GGGACTATTGGAGAA
    CAACGCATGCTCCTG GTGGATCCCTCAACC GGACTATTGGAGAAA
    AACGCATGCTCCTGG TGGATCCCTCAACCA GACTATTGGAGAAAA
    ACGCATGCTCCTGGA GGATCCCTCAACCAA ACTATTGGAGAAAAT
    CGCATGCTCCTGGAG GATCCCTCAACCAAG CTATTGGAGAAAATA
    GCATGCTCCTGGAGC ATCCCTCAACCAAGA TATTGGAGAAAATAA
    CATGCTCCTGGAGCT TCCCTCAACCAAGAA ATTGGAGAAAATAAG
    ATGCTCCTGGAGCTC CCCTCAACCAAGAAG TTGGAGAAAATAAGG
    TGCTCCTGGAGCTCA CCTCAACCAAGAAGA TGGAGAAAATAAGGT
    GCTCCTGGAGCTCAC CTCAACCAAGAAGAA GGAGAAAATAAGGTG
    CTCCTGGAGCTCACA TCAACCAAGAAGAAT GAGAAAATAAGGTGG
    TCCTGGAGCTCACAG CAACCAAGAAGAATG AGAAAATAAGGTGGA
    CCTGGAGCTCACAGC AACCAAGAAGAATGT GAAAATAAGGTGGAG
    CTGGAGCTCACAGCC ACCAAGAAGAATGTT AAAATAAGGTGGAGT
    TGGAGCTCACAGCCT CCAAGAAGAATGTTT AAATAAGGTGGAGTC
    GGAGCTCACAGCCTT CAAGAAGAATGTTTA AATAAGGTGGAGTCC
    GAGCTCACAGCCTTC AAGAAGAATGTTTAT ATAAGGTGGAGTCCT
    AGCTCACAGCCTTCT AGAAGAATGTTTATG TAAGGTGGAGTCCTA
    GCTCACAGCCTTCTG GAAGAATGTTTATGT AAGGTGGAGTCCTAC
    CTCACAGCCTTCTGT AAGAATGTTTATGTC AGGTGGAGTCCTACT
    TCACAGCCTTCTGTG AGAATGTTTATGTCT GGTGGAGTCCTACTT
    CACAGCCTTCTGTGG GAATGTTTATGTCTT GTGGAGTCCTACTTG
    ACAGCCTTCTGTGGT AATGTTTATGTCTTC TGGAGTCCTACTTGT
    CAGCCTTCTGTGGTG ATGTTTATGTCTTCA GGAGTCCTACTTGTT
    AGCCTTCTGTGGTGT TGTTTATGTCTTCAA GAGTCCTACTTGTTT
    GCCTTCTGTGGTGTC GTTTATGTCTTCAAG AGTCCTACTTGTTTA
    CCTTCTGTGGTGTCA TTTATGTCTTCAAGT GTCCTACTTGTTTAA
    CTTCTGTGGTGTCAT TTATGTCTTCAAGTG TCCTACTTGTTTAAA
    TTCTGTGGTGTCATT TATGTCTTCAAGTGA CCTACTTGTTTAAAA
    TCTGTGGTGTCATTT ATGTCTTCAAGTGAC CTACTTGTTTAAAAA
    CTGTGGTGTCATTTC TGTCTTCAAGTGACC TACTTGTTTAAAAAA
    TGTGGTGTCATTTCT GTCTTCAAGTGACCT ACTTGTTTAAAAAAT
    GTGGTGTCATTTCTG TCTTCAAGTGACCTG CTTGTTTAAAAAATA
    TGGTGTCATTTCTGA CTTCAAGTGACCTGT TTGTTTAAAAAATAT
    GGTGTCATTTCTGAA TTCAAGTGACCTGTA TGTTTAAAAAATATG
    GTGTCATTTCTGAAA TCAAGTGACCTGTAC GTTTAAAAAATATGT
    TGTCATTTCTGAAAC CAAGTGACCTGTACT TTTAAAAAATATGTA
    GTCATTTCTGAAACA AAGTGACCTGTACTG TTAAAAAATATGTAT
    TCATTTCTGAAACAA AGTGACCTGTACTGC TAAAAAATATGTATC
    CATTTCTGAAACAAG GTGACCTGTACTGCT AAAAAATATGTATCT
    ATTTCTGAAACAAGG TGACCTGTACTGCTT AAAAATATGTATCTA
    TTTCTGAAACAAGGG GACCTGTACTGCTTG AAAATATGTATCTAA
    TTCTGAAACAAGGGC ACCTGTACTGCTTGG AAATATGTATCTAAG
    TCTGAAACAAGGGCG CCTGTACTGCTTGGG AATATGTATCTAAGA
    CTGAAACAAGGGCGT CTGTACTGCTTGGGG ATATGTATCTAAGAA
    TATGTATCTAAGAAT GGCCCTCCTCTTCAG GCTTTTGCTGCGGCC
    ATGTATCTAAGAATG GCCCTCCTCTTCAGG CTTTTGCTGCGGCCC
    TGTATCTAAGAATGT CCCTCCTCTTCAGGA TTTTGCTGCGGCCCC
    GTATCTAAGAATGTT CCTCCTCTTCAGGAA TTTGCTGCGGCCCCG
    TATCTAAGAATGTTC CTCCTCTTCAGGAAT TTGCTGCGGCCCCGT
    ATCTAAGAATGTTCT TCCTCTTCAGGAATC TGCTGCGGCCCCGTG
    TCTAAGAATGTTCTA CCTCTTCAGGAATCT GCTGCGGCCCCGTGG
    CTAAGAATGTTCTAG CTCTTCAGGAATCTT CTGCGGCCCCGTGGG
    TAAGAATGTTCTAGG TCTTCAGGAATCTTC TGCGGCCCCGTGGGG
    AAGAATGTTCTAGGG CTTCAGGAATCTTCC GCGGCCCCGTGGGGT
    AGAATGTTCTAGGGC TTCAGGAATCTTCCT CGGCCCCGTGGGGTA
    GAATGTTCTAGGGCA TCAGGAATCTTCCTG GGCCCCGTGGGGTAG
    AATGTTCTAGGGCAC CAGGAATCTTCCTGA GCCCCGTGGGGTAGG
    ATGTTCTAGGGCACT AGGAATCTTCCTGAA CCCCGTGGGGTAGGA
    TGTTCTAGGGCACTC GGAATCTTCCTGAAG CCCGTGGGGTAGGAG
    GTTCTAGGGCACTCT GAATCTTCCTGAAGA CCGTGGGGTAGGAGG
    TTCTAGGGCACTCTG AATCTTCCTGAAGAC CGTGGGGTAGGAGGG
    TCTAGGGCACTCTGG ATCTTCCTGAAGACA GTGGGGTAGGAGGGA
    CTAGGGCACTCTGGG TCTTCCTGAAGACAT TGGGGTAGGAGGGAC
    TAGGGCACTCTGGGA CTTCCTGAAGACATG GGGGTAGGAGGGACA
    AGGGCACTCTGGGAA TTCCTGAAGACATGG GGGTAGGAGGGACAG
    GGGCACTCTGGGAAC TCCTGAAGACATGGC GGTAGGAGGGACAGA
    GGCACTCTGGGAACC CCTGAAGACATGGCC GTAGGAGGGACAGAG
    GCACTCTGGGAACCT CTGAAGACATGGCCC TAGGAGGGACAGAGA
    CACTCTGGGAACCTA TGAAGACATGGCCCA AGGAGGGACAGAGAG
    ACTCTGGGAACCTAT GAAGACATGGCCCAG GGAGGGACAGAGAGA
    CTCTGGGAACCTATA AAGACATGGCCCAGT GAGGGACAGAGAGAC
    TCTGGGAACCTATAA AGACATGGCCCAGTC AGGGACAGAGAGACG
    CTGGGAACCTATAAA GACATGGCCCAGTCG GGGACAGAGAGACGG
    TGGGAACCTATAAAG ACATGGCCCAGTCGA GGACAGAGAGACGGG
    GGGAACCTATAAAGG CATGGCCCAGTCGAA GACAGAGAGACGGGA
    GGAACCTATAAAGGC ATGGCCCAGTCGAAG ACAGAGAGACGGGAG
    GAACCTATAAAGGCA TGGCCCAGTCGAAGG CAGAGAGACGGGAGA
    AACCTATAAAGGCAG GGCCCAGTCGAAGGC AGAGAGACGGGAGAG
    ACCTATAAAGGCAGG GCCCAGTCGAAGGCC GAGAGACGGGAGAGT
    CCTATAAAGGCAGGT CCCAGTCGAAGGCCC AGAGACGGGAGAGTC
    CTATAAAGGCAGGTA CCAGTCGAAGGCCCA GAGACGGGAGAGTCA
    TATAAAGGCAGGTAT CAGTCGAAGGCCCAG AGACGGGAGAGTCAG
    ATAAAGGCAGGTATT AGTCGAAGGCCCAGG GACGGGAGAGTCAGC
    TAAAGGCAGGTATTT GTCGAAGGCCCAGGA ACGGGAGAGTCAGCC
    AAAGGCAGGTATTTC TCGAAGGCCCAGGAT CGGGAGAGTCAGCCT
    AAGGCAGGTATTTCG CGAAGGCCCAGGATG GGGAGAGTCAGCCTC
    AGGCAGGTATTTCGG GAAGGCCCAGGATGG GGAGAGTCAGCCTCC
    GGCAGGTATTTCGGG AAGGCCCAGGATGGC GAGAGTCAGCCTCCA
    GCAGGTATTTCGGGC AGGCCCAGGATGGCT AGAGTCAGCCTCCAC
    CAGGTATTTCGGGCC GGCCCAGGATGGCTT GAGTCAGCCTCCACA
    AGGTATTTCGGGCCC GCCCAGGATGGCTTT AGTCAGCCTCCACAT
    GGTATTTCGGGCCCT CCCAGGATGGCTTTT GTCAGCCTCCACATT
    GTATTTCGGGCCCTC CCAGGATGGCTTTTG TCAGCCTCCACATTC
    TATTTCGGGCCCTCC CAGGATGGCTTTTGC CAGCCTCCACATTCA
    ATTTCGGGCCCTCCT AGGATGGCTTTTGCT AGCCTCCACATTCAG
    TTTCGGGCCCTCCTC GGATGGCTTTTGCTG GCCTCCACATTCAGA
    TTCGGGCCCTCCTCT GATGGCTTTTGCTGC CCTCCACATTCAGAG
    TCGGGCCCTCCTCTT ATGGCTTTTGCTGCG CTCCACATTCAGAGG
    CGGGCCCTCCTCTTC TGGCTTTTGCTGCGG TCCACATTCAGAGGC
    GGGCCCTCCTCTTCA GGCTTTTGCTGCGGC CCACATTCAGAGGCA
    CACATTCAGAGGCAT GTGTTTTGTAGTTCA AAGGCAAAGCTTTAT
    ACATTCAGAGGCATC TGTTTTGTAGTTCAA AGGCAAAGCTTTATT
    CATTCAGAGGCATCA GTTTTGTAGTTCAAC GGCAAAGCTTTATTT
    ATTCAGAGGCATCAC TTTTGTAGTTCAACA GCAAAGCTTTATTTT
    TTCAGAGGCATCACA TTTGTAGTTCAACAA CAAAGCTTTATTTTC
    TCAGAGGCATCACAA TTGTAGTTCAACAAC AAAGCTTTATTTTCA
    CAGAGGCATCACAAG TGTAGTTCAACAACT AAGCTTTATTTTCAT
    AGAGGCATCACAAGT GTAGTTCAACAACTC AGCTTTATTTTCATC
    GAGGCATCACAAGTA TAGTTCAACAACTCA GCTTTATTTTCATCT
    AGGCATCACAAGTAA AGTTCAACAACTCAA CTTTATTTTCATCTC
    GGCATCACAAGTAAT GTTCAACAACTCAAG TTTATTTTCATCTCT
    GCATCACAAGTAATG TTCAACAACTCAAGA TTATTTTCATCTCTC
    CATCACAAGTAATGG TCAACAACTCAAGAC TATTTTCATCTCTCA
    ATCACAAGTAATGGC CAACAACTCAAGACG ATTTTCATCTCTCAT
    TCACAAGTAATGGCA AACAACTCAAGACGA TTTTCATCTCTCATC
    CACAAGTAATGGCAC ACAACTCAAGACGAA TTTCATCTCTCATCT
    ACAAGTAATGGCACA CAACTCAAGACGAAG TTCATCTCTCATCTT
    CAAGTAATGGCACAA AACTCAAGACGAAGC TCATCTCTCATCTTT
    AAGTAATGGCACAAT ACTCAAGACGAAGCT CATCTCTCATCTTTT
    AGTAATGGCACAATT CTCAAGACGAAGCTT ATCTCTCATCTTTTG
    GTAATGGCACAATTC TCAAGACGAAGCTTA TCTCTCATCTTTTGT
    TAATGGCACAATTCT CAAGACGAAGCTTAT CTCTCATCTTTTGTC
    AATGGCACAATTCTT AAGACGAAGCTTATT TCTCATCTTTTGTCC
    ATGGCACAATTCTTC AGACGAAGCTTATTT CTCATCTTTTGTCCT
    TGGCACAATTCTTCG GACGAAGCTTATTTC TCATCTTTTGTCCTC
    GGCACAATTCTTCGG ACGAAGCTTATTTCT CATCTTTTGTCCTCC
    GCACAATTCTTCGGA CGAAGCTTATTTCTG ATCTTTTGTCCTCCT
    CACAATTCTTCGGAT GAAGCTTATTTCTGA TCTTTTGTCCTCCTT
    ACAATTCTTCGGATG AAGCTTATTTCTGAG CTTTTGTCCTCCTTA
    CAATTCTTCGGATGA AGCTTATTTCTGAGG TTTTGTCCTCCTTAG
    AATTCTTCGGATGAC GCTTATTTCTGAGGA TTTGTCCTCCTTAGC
    ATTCTTCGGATGACT CTTATTTCTGAGGAT TTGTCCTCCTTAGCA
    TTCTTCGGATGACTG TTATTTCTGAGGATA TGTCCTCCTTAGCAC
    TCTTCGGATGACTGC TATTTCTGAGGATAA GTCCTCCTTAGCACA
    CTTCGGATGACTGCA ATTTCTGAGGATAAG TCCTCCTTAGCACAA
    TTCGGATGACTGCAG TTTCTGAGGATAAGC CCTCCTTAGCACAAT
    TCGGATGACTGCAGA TTCTGAGGATAAGCT CTCCTTAGCACAATG
    CGGATGACTGCAGAA TCTGAGGATAAGCTC TCCTTAGCACAATGT
    GGATGACTGCAGAAA CTGAGGATAAGCTCT CCTTAGCACAATGTA
    GATGACTGCAGAAAA TGAGGATAAGCTCTT CTTAGCACAATGTAA
    ATGACTGCAGAAAAT GAGGATAAGCTCTTT TTAGCACAATGTAAA
    TGACTGCAGAAAATA AGGATAAGCTCTTTA TAGCACAATGTAAAA
    GACTGCAGAAAATAG GGATAAGCTCTTTAA AGCACAATGTAAAAA
    ACTGCAGAAAATAGT GATAAGCTCTTTAAA GCACAATGTAAAAAA
    CTGCAGAAAATAGTG ATAAGCTCTTTAAAG CACAATGTAAAAAAG
    TGCAGAAAATAGTGT TAAGCTCTTTAAAGG ACAATGTAAAAAAGA
    GCAGAAAATAGTGTT AAGCTCTTTAAAGGC CAATGTAAAAAAGAA
    CAGAAAATAGTGTTT AGCTCTTTAAAGGCA AATGTAAAAAAGAAT
    AGAAAATAGTGTTTT GCTCTTTAAAGGCAA ATGTAAAAAAGAATA
    GAAAATAGTGTTTTG CTCTTTAAAGGCAAA TGTAAAAAAGAATAG
    AAAATAGTGTTTTGT TCTTTAAAGGCAAAG GTAAAAAAGAATAGT
    AAATAGTGTTTTGTA CTTTAAAGGCAAAGC TAAAAAAGAATAGTA
    AATAGTGTTTTGTAG TTTAAAGGCAAAGCT AAAAAAGAATAGTAA
    ATAGTGTTTTGTAGT TTAAAGGCAAAGCTT AAAAAGAATAGTAAT
    TAGTGTTTTGTAGTT TAAAGGCAAAGCTTT AAAAGAATAGTAATA
    AGTGTTTTGTAGTTC AAAGGCAAAGCTTTA AAAGAATAGTAATAT
    AAGAATAGTAATATC GACACTGGGAGCACA TGCTTTTCTTTATAA
    AGAATAGTAATATCA ACACTGGGAGCACAT GCTTTTCTTTATAAT
    GAATAGTAATATCAG CACTGGGAGCACATA CTTTTCTTTATAATT
    AATAGTAATATCAGA ACTGGGAGCACATAG TTTTCTTTATAATTC
    ATAGTAATATCAGAA CTGGGAGCACATAGA TTTCTTTATAATTCA
    TAGTAATATCAGAAC TGGGAGCACATAGAG TTCTTTATAATTCAC
    AGTAATATCAGAACA GGGAGCACATAGAGA TCTTTATAATTCACA
    GTAATATCAGAACAG GGAGCACATAGAGAT CTTTATAATTCACAC
    TAATATCAGAACAGG GAGCACATAGAGATT TTTATAATTCACACA
    AATATCAGAACAGGA AGCACATAGAGATTC TTATAATTCACACAT
    ATATCAGAACAGGAA GCACATAGAGATTCA TATAATTCACACATA
    TATCAGAACAGGAAG CACATAGAGATTCAC ATAATTCACACATAT
    ATCAGAACAGGAAGG ACATAGAGATTCACC TAATTCACACATATA
    TCAGAACAGGAAGGA CATAGAGATTCACCC AATTCACACATATAT
    CAGAACAGGAAGGAG ATAGAGATTCACCCA ATTCACACATATATG
    AGAACAGGAAGGAGG TAGAGATTCACCCAT TTCACACATATATGC
    GAACAGGAAGGAGGA AGAGATTCACCCATG TCACACATATATGCA
    AACAGGAAGGAGGAA GAGATTCACCCATGT CACACATATATGCAG
    ACAGGAAGGAGGAAT AGATTCACCCATGTT ACACATATATGCAGA
    CAGGAAGGAGGAATG GATTCACCCATGTTT CACATATATGCAGAG
    AGGAAGGAGGAATGG ATTCACCCATGTTTG ACATATATGCAGAGA
    GGAAGGAGGAATGGC TTCACCCATGTTTGT CATATATGCAGAGAA
    GAAGGAGGAATGGCT TCACCCATGTTTGTT ATATATGCAGAGAAG
    AAGGAGGAATGGCTT CACCCATGTTTGTTG TATATGCAGAGAAGA
    AGGAGGAATGGCTTG ACCCATGTTTGTTGA ATATGCAGAGAAGAT
    GGAGGAATGGCTTGC CCCATGTTTGTTGAA TATGCAGAGAAGATA
    GAGGAATGGCTTGCT CCATGTTTGTTGAAC ATGCAGAGAAGATAT
    AGGAATGGCTTGCTG CATGTTTGTTGAACT TGAGAGAAGATATG
    GGAATGGCTTGCTGG ATGTTTGTTGAACTT GCAGAGAAGATATGT
    GAATGGCTTGCTGGG TGTTTGTTGAACTTA CAGAGAAGATATGTT
    AATGGCTTGCTGGGG GTTTGTTGAACTTAG AGAGAAGATATGTTC
    ATGGCTTGCTGGGGA TTTGTTGAACTTAGA GAGAAGATATGTTCT
    TGGCTTGCTGGGGAG TTGTTGAACTTAGAG AGAAGATATGTTCTT
    GGCTTGCTGGGGAGC TGTTGAACTTAGAGT GAAGATATGTTCTTG
    GCTTGCTGGGGAGCC GTTGAACTTAGAGTC AAGATATGTTCTTGT
    CTTGCTGGGGAGCCC TTGAACTTAGAGTCA AGATATGTTCTTGTT
    TTGCTGGGGAGCCCA TGAACTTAGAGTCAT GATATGTTCTTGTTA
    TGCTGGGGAGCCCAT GAACTTAGAGTCATT ATATGTTCTTGTTAA
    GCTGGGGAGCCCATC AACTTAGAGTCATTC TATGTTCTTGTTAAC
    CTGGGGAGCCCATCC ACTTAGAGTCATTCT ATGTTCTTGTTAACA
    TGGGGAGCCCATCCA CTTAGAGTCATTCTC TGTTCTTGTTAACAT
    GGGGAGCCCATCCAG TTAGAGTCATTCTCA GTTCTTGTTAACATT
    GGGAGCCCATCCAGG TAGAGTCATTCTCAT TTCTTGTTAACATTG
    GGAGCCCATCCAGGA AGAGTCATTCTCATG TCTTGTTAACATTGT
    GAGCCCATCCAGGAC GAGTCATTCTCATGC CTTGTTAACATTGTA
    AGCCCATCCAGGACA AGTCATTCTCATGCT TTGTTAACATTGTAT
    GCCCATCCAGGACAC GTCATTCTCATGCTT TGTTAACATTGTATA
    CCCATCCAGGACACT TCATTCTCATGCTTT GTTAACATTGTATAC
    CCATCCAGGACACTG CATTCTCATGCTTTT TTAACATTGTATACA
    CATCCAGGACACTGG ATTCTCATGCTTTTC TAACATTGTATACAA
    ATCCAGGACACTGGG TTCTCATGCTTTTCT AACATTGTATACAAC
    TCCAGGACACTGGGA TCTCATGCTTTTCTT ACATTGTATACAACA
    CCAGGACACTGGGAG CTCATGCTTTTCTTT CATTGTATACAACAT
    CAGGACACTGGGAGC TCATGCTTTTCTTTA ATTGTATACAACATA
    AGGACACTGGGAGCA CATGCTTTTCTTTAT TTGTATACAACATAG
    GGACACTGGGAGCAC ATGCTTTTCTTTATA TGTATACAACATAGC
    GTATACAACATAGCC TGTTAGAGATGCTAT CCAGAGACTGGGCTG
    TATACAACATAGCCC GTTAGAGATGCTATA CAGAGACTGGGCTGC
    ATACAACATAGCCCC TTAGAGATGCTATAT AGAGACTGGGCTGCT
    TACAACATAGCCCCA TAGAGATGCTATATG GAGACTGGGCTGCTC
    ACAACATAGCCCCAA AGAGATGCTATATGA AGACTGGGCTGCTCT
    CAACATAGCCCCAAA GAGATGCTATATGAT GACTGGGCTGCTCTC
    AACATAGCCCCAAAT AGATGCTATATGATA ACTGGGCTGCTCTCC
    ACATAGCCCCAAATA GATGCTATATGATAC CTGGGCTGCTCTCCC
    CATAGCCCCAAATAT ATGCTATATGATACA TGGGCTGCTCTCCCG
    ATAGCCCCAAATATA TGCTATATGATACAA GGGCTGCTCTCCCGG
    TAGCCCCAAATATAG GCTATATGATACAAC GGCTGCTCTCCCGGA
    AGCCCCAAATATAGT CTATATGATACAACT GCTGCTCTCCCGGAG
    GCCCCAAATATAGTA TATATGATACAACTG CTGCTCTCCCGGAGG
    CCCCAAATATAGTAA ATATGATACAACTGT TGCTCTCCCGGAGGC
    CCCAAATATAGTAAG TATGATACAACTGTG GCTCTCCCGGAGGCC
    CCAAATATAGTAAGA ATGATACAACTGTGG CTCTCCCGGAGGCCA
    CAAATATAGTAAGAT TGATACAACTGTGGC TCTCCCGGAGGCCAA
    AAATATAGTAAGATC GATACAACTGTGGCC CTCCCGGAGGCCAAA
    AATATAGTAAGATCT ATACAACTGTGGCCA TCCCGGAGGCCAAAC
    ATATAGTAAGATCTA TACAACTGTGGCCAT CCCGGAGGCCAAACC
    TATAGTAAGATCTAT ACAACTGTGGCCATG CCGGAGGCCAAACCC
    ATAGTAAGATCTATA CAACTGTGGCCATGA CGGAGGCCAAACCCA
    TAGTAAGATCTATAC AACTGTGGCCATGAC GGAGGCCAAACCCAA
    AGTAAGATCTATACT ACTGTGGCCATGACT GAGGCCAAACCCAAG
    GTAAGATCTATACTA CTGTGGCCATGACTG AGGCCAAACCCAAGA
    TAAGATCTATACTAG TGTGGCCATGACTGA GGCCAAACCCAAGAA
    AAGATCTATACTAGA GTGGCCATGACTGAG GCCAAACCCAAGAAG
    AGATCTATACTAGAT TGGCCATGACTGAGG CCAAACCCAAGAAGG
    GATCTATACTAGATA GGCCATGACTGAGGA CAAACCCAAGAAGGT
    ATCTATACTAGATAA GCCATGACTGAGGAA AAACCCAAGAAGGTC
    TCTATACTAGATAAT CCATGACTGAGGAAA AACCCAAGAAGGTCT
    CTATACTAGATAATC CATGACTGAGGAAAG ACCCAAGAAGGTCTG
    TATACTAGATAATCC ATGACTGAGGAAAGG CCCAAGAAGGTCTGG
    ATACTAGATAATCCT TGACTGAGGAAAGGA CCAAGAAGGTCTGGC
    TACTAGATAATCCTA GACTGAGGAAAGGAG CAAGAAGGTCTGGCA
    ACTAGATAATCCTAG ACTGAGGAAAGGAGC AAGAAGGTCTGGCAA
    CTAGATAATCCTAGA CTGAGGAAAGGAGCT AGAAGGTCTGGCAAA
    TAGATAATCCTAGAT TGAGGAAAGGAGCTC GAAGGTCTGGCAAAG
    AGATAATCCTAGATG GAGGAAAGGAGCTCA AAGGTCTGGCAAAGT
    GATAATCCTAGATGA AGGAAAGGAGCTCAC AGGTCTGGCAAAGTC
    ATAATCCTAGATGAA GGAAAGGAGCTCACG GGTCTGGCAAAGTCA
    TAATCCTAGATGAAA GAAAGGAGCTCACGC GTCTGGCAAAGTCAG
    AATCCTAGATGAAAT AAAGGAGCTCACGCC TCTGGCAAAGTCAGG
    ATCCTAGATGAAATG AAGGAGCTCACGCCC CTGGCAAAGTCAGGC
    TCCTAGATGAAATGT AGGAGCTCACGCCCA TGGCAAAGTCAGGCT
    CCTAGATGAAATGTT GGAGCTCACGCCCAG GGCAAAGTCAGGCTC
    CTAGATGAAATGTTA GAGCTCACGCCCAGA GCAAAGTCAGGCTCA
    TAGATGAAATGTTAG AGCTCACGCCCAGAG CAAAGTCAGGCTCAG
    AGATGAAATGTTAGA GCTCACGCCCAGAGA AAAGTCAGGCTCAGG
    GATGAAATGTTAGAG CTCACGCCCAGAGAC AAGTCAGGCTCAGGG
    ATGAAATGTTAGAGA TCACGCCCAGAGACT AGTCAGGCTCAGGGA
    TGAAATGTTAGAGAT CACGCCCAGAGACTG GTCAGGCTCAGGGAG
    GAAATGTTAGAGATG ACGCCCAGAGACTGG TCAGGCTCAGGGAGA
    AAATGTTAGAGATGC CGCCCAGAGACTGGG CAGGCTCAGGGAGAC
    AATGTTAGAGATGCT GCCCAGAGACTGGGC AGGCTCAGGGAGACT
    ATGTTAGAGATGCTA CCCAGAGACTGGGCT GGCTCAGGGAGACTC
    GCTCAGGGAGACTCT CTCTCCTTGAAAACA TATTTTTTTAACTTT
    CTCAGGGAGACTCTG TCTCCTTGAAAACAG ATTTTTTTAACTTTT
    TCAGGGAGACTCTGC CTCCTTGAAAACAGA TTTTTTTAACTTTTT
    CAGGGAGACTCTGCC TCCTTGAAAACAGAG TTTTTTAACTTTTTG
    AGGGAGACTCTGCCC CCTTGAAAACAGAGG TTTTTAACTTTTTGG
    GGGAGACTCTGCCCT CTTGAAAACAGAGGG TTTTAACTTTTTGGG
    GGAGACTCTGCCCTG TTGAAAACAGAGGGG TTTAACTTTTTGGGG
    GAGACTCTGCCCTGC TGAAAACAGAGGGGT TTAACTTTTTGGGGG
    AGACTCTGCCCTGCT GAAAACAGAGGGGTC TAACTTTTTGGGGGG
    GACTCTGCCCTGCTG AAAACAGAGGGGTCT AACTTTTTGGGGGGA
    ACTCTGCCCTGCTGC AAACAGAGGGGTCTC ACTTTTTGGGGGGAA
    CTCTGCCCTGCTGCA AACAGAGGGGTCTCA CTTTTTGGGGGGAAA
    TCTGCCCTGCTGCAG ACAGAGGGGTCTCAA TTTTTGGGGGGAAAA
    CTGCCCTGCTGCAGA CAGAGGGGTCTCAAG TTTTGGGGGGAAAAG
    TGCCCTGCTGCAGAC AGAGGGGTCTCAAGA TTTGGGGGGAAAAGT
    GCCCTGCTGCAGACC GAGGGGTCTCAAGAC TTGGGGGGAAAAGTA
    CCCTGCTGCAGACCT AGGGGTCTCAAGACA TGGGGGGAAAAGTAT
    CCTGCTGCAGACCTC GGGGTCTCAAGACAT GGGGGGAAAAGTATT
    CTGCTGCAGACCTCG GGGTCTCAAGACATT GGGGGAAAAGTATTT
    TGCTGCAGACCTCGG GGTCTCAAGACATTC GGGGAAAAGTATTTT
    GCTGCAGACCTCGGT GTCTCAAGACATTCT GGGAAAAGTATTTTT
    CTGCAGACCTCGGTG TCTCAAGACATTCTG GGAAAAGTATTTTTG
    TGCAGACCTCGGTGT CTCAAGACATTCTGC GAAAAGTATTTTTGA
    GCAGACCTCGGTGTG TCAAGACATTCTGCC AAAAGTATTTTTGAG
    CAGACCTCGGTGTGG CAAGACATTCTGCCT AAAGTATTTTTGAGA
    AGACCTCGGTGTGGA AAGACATTCTGCCTA AAGTATTTTTGAGAA
    GACCTCGGTGTGGAC AGACATTCTGCCTAC AGTATTTTTGAGAAG
    ACCTCGGTGTGGACA GACATTCTGCCTACC GTATTTTTGAGAAGT
    CCTCGGTGTGGACAC ACATTCTGCCTACCT TATTTTTGAGAAGTT
    CTCGGTGTGGACACA CATTCTGCCTACCTA ATTTTTGAGAAGTTT
    TCGGTGTGGACACAC ATTCTGCCTACCTAT TTTTTGAGAAGTTTG
    CGGTGTGGACACACG TTCTGCCTACCTATT TTTTGAGAAGTTTGT
    GGTGTGGACACACGC TCTGCCTACCTATTA TTTGAGAAGTTTGTC
    GTGTGGACACACGCT CTGCCTACCTATTAG TTGAGAAGTTTGTCT
    TGTGGACACACGCTG TGCCTACCTATTAGC TGAGAAGTTTGTCTT
    GTGGACACACGCTGC GCCTACCTATTAGCT GAGAAGTTTGTCTTG
    TGGACACACGCTGCA CCTACCTATTAGCTT AGAAGTTTGTCTTGC
    GGACACACGCTGCAT CTACCTATTAGCTTT GAAGTTTGTCTTGCA
    GACACACGCTGCATA TACCTATTAGCTTTT AAGTTTGTCTTGCAA
    ACACACGCTGCATAG ACCTATTAGCTTTTC AGTTTGTCTTGCAAT
    CACACGCTGCATAGA CCTATTAGCTTTTCT GTTTGTCTTGCAATG
    ACACGCTGCATAGAG CTATTAGCTTTTCTT TTTGTCTTGCAATGT
    CACGCTGCATAGAGC TATTAGCTTTTCTTT TTGTCTTGCAATGTA
    ACGCTGCATAGAGCT ATTAGCTTTTCTTTA TGTCTTGCAATGTAT
    CGCTGCATAGAGCTC TTAGCTTTTCTTTAT GTCTTGCAATGTATT
    GCTGCATAGAGCTCT TAGCTTTTCTTTATT TCTTGCAATGTATTT
    CTGCATAGAGCTCTC AGCTTTTCTTTATTT CTTGCAATGTATTTA
    TGCATAGAGCTCTCC GCTTTTCTTTATTTT TTGCAATGTATTTAT
    GCATAGAGCTCTCCT CTTTTCTTTATTTTT TGCAATGTATTTATA
    CATAGAGCTCTCCTT TTTTCTTTATTTTTT GCAATGTATTTATAA
    ATAGAGCTCTCCTTG TTTCTTTATTTTTTT CAATGTATTTATAAA
    TAGAGCTCTCCTTGA TTCTTTATTTTTTTA AATGTATTTATAAAT
    AGAGCTCTCCTTGAA TCTTTATTTTTTTAA ATGTATTTATAAATA
    GAGCTCTCCTTGAAA CTTTATTTTTTTAAC TGTATTTATAAATAG
    AGCTCTCCTTGAAAA TTTATTTTTTTAACT GTATTTATAAATAGT
    GCTCTCCTTGAAAAC TTATTTTTTTAACTT TATTTATAAATAGTA
    ATTTATAAATAGTAA
    TTTATAAATAGTAAA
    TTATAAATAGTAAAT
    TATAAATAGTAAATA
    ATAAATAGTAAATAA
    TAAATAGTAAATAAA
    AAATAGTAAATAAAG
    AATAGTAAATAAAGT
    ATAGTAAATAAAGTT
    TAGTAAATAAAGTTT
    AGTAAATAAAGTTTT
    GTAAATAAAGTTTTT
    TAAATAAAGTTTTTA
    AAATAAAGTTTTTAC
    AATAAAGTTTTTACC
    ATAAAGTTTTTACCA
    TAAAGTTTTTACCAT
    AAAGTTTTTACCATT
    • EXAMPLE 8 Antisense Oligonucleotides of IGF-I Receptor
  • Antisense oligonucleotides to IGF-I may selected from molecules capable of interacting with one or the following sense oligonucleotides: [0058]
    TTTTTTTTTTTTTTG TCATCCCAAATAAAA GGCTCCGGAGGAGGG
    TTTTTTTTTTTTTGA CATCCCAAATAAAAG GCTCCGGAGGAGGGT
    TTTTTTTTTTTTGAG ATCCCAAATAAAAGG CTCCGGAGGAGGGTC
    TTTTTTTTTTTGAGA TCCCAAATAAAAGGA TCCGGAGGAGGGTCC
    TTTTTTTTTTGAGAA CCCAAATAAAAGGAA CCGGAGGAGGGTCCC
    TTTTTTTTTGAGAAA CCAAATAAAAGGAAT CGGAGGAGGGTCCCC
    TTTTTTTTGAGAAAG CAAATAAAAGGAATG GGAGGAGGGTCCCCG
    TTTTTTTGAGAAAGG AAATAAAAGGAATGA GAGGAGGGTCCCCGA
    TTTTTTGAGAAAGGG AATAAAAGGAATGAA AGGAGGGTCCCCGAC
    TTTTTGAGAAAGGGA ATAAAAGGAATGAAG GGAGGGTCCCCGACC
    TTTTGAGAAAGGGAA TAAAAGGAATGAAGT GAGGGTCCCCGACCT
    TTTGAGAAAGGGAAT AAAAGGAATGAAGTC AGGGTCCCCGACCTC
    TTGAGAAAGGGAATT AAAGGAATGAAGTCT GGGTCCCCGACCTCG
    TGAGAAAGGGAATTT AAGGAATGAAGTCTG GGTCCCCGACCTCGC
    GAGAAAGGGAATTTC AGGAATGAAGTCTGG GTCCCCGACCTCGCT
    AGAAAGGGAATTTCA GGAATGAAGTCTGGC TCCCCGACCTCGCTG
    GAAAGGGAATTTCAT GAATGAAGTCTGGCT CCCCGACCTCGCTGT
    AAAGGGAATTTCATC AATGAAGTCTGGCTC CCCGACCTCGCTGTG
    AAGGGAATTTCATCC ATGAAGTCTGGCTCC CCGACCTCGCTGTGG
    AGGGAATTTCATCCC TGAAGTCTGGCTCCG CGACCTCGCTGTGGG
    GGGAATTTCATCCCA GAAGTCTGGCTCCGG GACCTCGCTGTGGGG
    GGAATTTCATCCCAA AAGTCTGGCTCCGGA ACCTCGCTGTGGGGG
    GAATTTCATCCCAAA AGTCTGGCTCCGGAG CCTCGCTGTGGGGGC
    AATTTCATCCCAAAT GTCTGGCTCCGGAGG CTCGCTGTGGGGGCT
    ATTTCATCCCAAATA TCTGGCTCCGGAGGA TCGCTGTGGGGGCTC
    TTTCATCCCAAATAA CTGGCTCCGGAGGAG CGCTGTGGGGGCTCC
    TTCATCCCAAATAAA TGGCTCCGGAGGAGG GCTGTGGGGGCTCCT
    CTGTGGGGGCTCCTG AATCTGCGGGCCAGG AGAACTGCACGGTGA
    TGTGGGGGCTCCTGT ATCTGCGGGCCAGGC GAACTGCACGGTGAT
    GTGGGGGCTCCTGTT TCTGCGGGCCAGGCA AACTGCACGGTGATC
    TGGGGGCTCCTGTTT CTGCGGGCCAGGCAT ACTGCACGGTGATCG
    GGGGGCTCCTGTTTC TGCGGGCCAGGCATC CTGCACGGTGATCGA
    GGGGCTCCTGTTTCT GCGGGCCAGGCATCG TGCACGGTGATCGAG
    GGGCTCCTGTTTCTC CGGGCCAGGCATCGA GCACGGTGATCGAGG
    GGCTCCTGTTTCTCT GGGCCAGGCATCGAC CACGGTGATCGAGGG
    GCTCCTGTTTCTCTC GGCCAGGCATCGACA ACGGTGATCGAGGGC
    CTCCTGTTTCTCTCC GCCAGGCATCGACAT CGGTGATCGAGGGCT
    TCCTGTTTCTCTCCG CCAGGCATCGACATC GGTGATCGAGGGCTA
    CCTGTTTCTCTCCGC CAGGCATCGACATCC GTGATCGAGGGCTAC
    CTGTTTCTCTCCGCC AGGCATCGACATCCG TGATCGAGGGCTACC
    TGTTTCTCTCCGCCG GGCATCGACATCCGC GATCGAGGGCTACCT
    GTTTCTCTCCGCCGC GCATCGACATCCGCA ATCGAGGGCTACCTC
    TTTCTCTCCGCCGCG CATCGACATCCGCAA TCGAGGGCTACCTCC
    TTCTCTCCGCCGCGC ATCGACATCCGCAAC CGAGGGCTACCTCCA
    TCTCTCCGCCGCGCT TCGACATCCGCAACG GAGGGCTACCTCCAC
    CTCTCCGCCGCGCTC CGACATCCGCAACGA AGGGCTACCTCCACA
    TCTCCGCCGCGCTCT GACATCCGCAACGAC GGGCTACCTCCACAT
    CTCCGCCGCGCTCTC ACATCCGCAACGACT GGCTACCTCCACATC
    TCCGCCGCGCTCTCG CATCCGCAACGACTA GCTACCTCCACATCC
    CCGCCGCGCTCTCGC ATCCGCAACGACTAT CTACCTCCACATCCT
    CGCCGCGCTCTCGCT TCCGCAACGACTATC TACCTCCACATCCTG
    GCCGCGCTCTCGCTC CCGCAACGACTATCA ACCTCCACATCCTGC
    CCGCGCTCTCGCTCT CGCAACGACTATCAG CCTCCACATCCTGCT
    CGCGCTCTCGCTCTG GCAACGACTATCAGC CTCCACATCCTGCTC
    GCGCTCTCGCTCTGG CAACGACTATCAGCA TCCACATCCTGCTCA
    CGCTCTCGCTCTGGC AACGACTATCAGCAG CCACATCCTGCTCAT
    GCTCTCGCTCTGGCC ACGACTATCAGCAGC CACATCCTGCTCATC
    CTCTCGCTCTGGCCG CGACTATCAGCAGCT ACATCCTGCTCATCT
    TCTCGCTCTGGCCGA GACTATCAGCAGCTG CATCCTGCTCATCTC
    CTCGCTCTGGCCGAC ACTATCAGCAGCTGA ATCCTGCTCATCTCC
    TCGCTCTGGCCGACG CTATCAGCAGCTGAA TCCTGCTCATCTCCA
    CGCTCTGGCCGACGA TATCAGCAGCTGAAG CCTGCTCATCTCCAA
    GCTCTGGCCGACGAG ATCAGCAGCTGAAGC CTGCTCATCTCCAAG
    CTCTGGCCGACGAGT TCAGCAGCTGAAGCG TGCTCATCTCCAAGG
    TCTGGCCGACGAGTG CAGCAGCTGAAGCGC GCTCATCTCCAAGGC
    CTGGCCGACGAGTGG AGCAGCTGAAGCGCC CTCATCTCCAAGGCC
    TGGCCGACGAGTGGA GCAGCTGAAGCGCCT TCATCTCCAAGGCCG
    GGCCGACGAGTGGAG CAGCTGAAGCGCCTG CATCTCCAAGGCCGA
    GCCGACGAGTGGAGA AGCTGAAGCGCCTGG ATCTCCAAGGCCGAG
    CCGACGAGTGGAGAA GCTGAAGCGCCTGGA TCTCCAAGGCCGAGG
    CGACGAGTGGAGAAA CTGAAGCGCCTGGAG CTCCAAGGCCGAGGA
    GACGAGTGGAGAAAT TGAAGCGCCTGGAGA TCCAAGGCCGAGGAC
    ACGAGTGGAGAAATC GAAGCGCCTGGAGAA CCAAGGCCGAGGACT
    CGAGTGGAGAAATCT AAGCGCCTGGAGAAC CAAGGCCGAGGACTA
    GAGTGGAGAAATCTG AGCGCCTGGAGAACT AAGGCCGAGGACTAC
    AGTGGAGAAATCTGC GCGCCTGGAGAACTG AGGCCGAGGACTACC
    GTGGAGAAATCTGCG CGCCTGGAGAACTGC GGCCGAGGACTACCG
    TGGAGAAATCTGCGG GCCTGGAGAACTGCA GCCGAGGACTACCGC
    GGAGAAATCTGCGGG CCTGGAGAACTGCAC CCGAGGACTACCGCA
    GAGAAATCTGCGGGC CTGGAGAACTGCACG CGAGGACTACCGCAG
    AGAAATCTGCGGGCC TGGAGAACTGCACGG GAGGACTACCGCAGC
    GAAATCTGCGGGCCA GGAGAACTGCACGGT AGGACTACCGCAGCT
    AAATCTGCGGGCCAG GAGAACTGCACGGTG GGACTACCGCAGCTA
    GACTACCGCAGCTAC GTTCCGAGTGGCTGG TCCGCGGCTGGAAAC
    ACTACCGCAGCTACC TTCCGAGTGGCTGGC CCGCGGCTGGAAACT
    CTACCGCAGCTACCG TCCGAGTGGCTGGCC CGCGGCTGGAAACTC
    TACCGCAGCTACCGC CCGAGTGGCTGGCCT GCGGCTGGAAACTCT
    ACCGCAGCTACCGCT CGAGTGGCTGGCCTC CGGCTGGAAACTCTT
    CCGCAGCTACCGCTT GAGTGGCTGGCCTCG GGCTGGAAACTCTTC
    CGCAGCTACCGCTTC AGTGGCTGGCCTCGA GCTGGAAACTCTTCT
    GCAGCTACCGCTTCC GTGGCTGGCCTCGAG CTGGAAACTCTTCTA
    CAGCTACCGCTTCCC TGGCTGGCCTCGAGA TGGAAACTCTTCTAC
    AGCTACCGCTTCCCC GGCTGGCCTCGAGAG GGAAACTCTTCTACA
    GCTACCGCTTCCCCA GCTGGCCTCGAGAGC GAAACTCTTCTACAA
    CTACCGCTTCCCCAA CTGGCCTCGAGAGCC AAACTCTTCTACAAC
    TACCGCTTCCCCAAG TGGCCTCGAGAGCCT AACTCTTCTACAACT
    ACCGCTTCCCCAAGC GGCCTCGAGAGCCTC ACTCTTCTACAACTA
    CCGCTTCCCCAAGCT GCCTCGAGAGCCTCG CTCTTCTACAACTAC
    CGCTTCCCCAAGCTC CCTCGAGAGCCTCGG TCTTCTACAACTACG
    GCTTCCCCAAGCTCA CTCGAGAGCCTCGGA CTTCTACAACTACGC
    CTTCCCCAAGCTCAC TCGAGAGCCTCGGAG TTCTACAACTACGCC
    TTCCCCAAGCTCACG CGAGAGCCTCGGAGA TCTACAACTACGCCC
    TCCCCAAGCTCACGG GAGAGCCTCGGAGAC CTACAACTACGCCCT
    CCCCAAGCTCACGGT AGAGCCTCGGAGACC TACAACTACGCCCTG
    CCCAAGCTCACGGTC GAGCCTCGGAGACCT ACAACTACGCCCTGG
    CCAAGCTCACGGTCA AGCCTCGGAGACCTC CAACTACGCCCTGGT
    CAAGCTCACGGTCAT GCCTCGGAGACCTCT AACTACGCCCTGGTC
    AAGCTCACGGTCATT CCTCGGAGACCTCTT ACTACGCCCTGGTCA
    AGCTCACGGTCATTA CTCGGAGACCTCTTC CTACGCCCTGGTCAT
    GCTCACGGTCATTAC TCGGAGACCTCTTCC TACGCCCTGGTCATC
    CTCACGGTCATTACC CGGAGACCTCTTCCC ACGCCCTGGTCATCT
    TCACGGTCATTACCG GGAGACCTCTTCCCC CGCCCTGGTCATCTT
    CACGGTCATTACCGA GAGACCTCTTCCCCA GCCCTGGTCATCTTC
    ACGGTCATTACCGAG AGACCTCTTCCCCAA CCCTGGTCATCTTCG
    CGGTCATTACCGAGT GACCTCTTCCCCAAC CCTGGTCATCTTCGA
    GGTCATTACCGAGTA ACCTCTTCCCCAACC CTGGTCATCTTCGAG
    GTCATTACCGAGTAC CCTCTTCCCCAACCT TGGTCATCTTCGAGA
    TCATTACCGAGTACT CTCTTCCCCAACCTC GGTCATCTTCGAGAT
    CATTACCGAGTACTT TCTTCCCCAACCTCA GTCATCTTCGAGATG
    ATTACCGAGTACTTG CTTCCCCAACCTCAC TCATCTTCGAGATGA
    TTACCGAGTACTTGC TTCCCCAACCTCACG CATCTTCGAGATGAC
    TACCGAGTACTTGCT TCCCCAACCTCACGG ATCTTCGAGATGACC
    ACCGAGTACTTGCTG CCCCAACCTCACGGT TCTTCGAGATGACCA
    CCGAGTACTTGCTGC CCCAACCTCACGGTC CTTCGAGATGACCAA
    CGAGTACTTGCTGCT CCAACCTCACGGTCA TTCGAGATGACCAAT
    GAGTACTTGCTGCTG CAACCTCACGGTCAT TCGAGATGACCAATC
    AGTACTTGCTGCTGT AACCTCACGGTCATC CGAGATGACCAATCT
    GTACTTGCTGCTGTT ACCTCACGGTCATCC GAGATGACCAATCTC
    TACTTGCTGCTGTTC CCTCACGGTCATCCG AGATGACCAATCTCA
    ACTTGCTGCTGTTCC CTCACGGTCATCCGC GATGACCAATCTCAA
    CTTGCTGCTGTTCCG TCACGGTCATCCGCG ATGACCAATCTCAAG
    TTGCTGCTGTTCCGA CACGGTCATCCGCGG TGACCAATCTCAAGG
    TGCTGCTGTTCCGAG ACGGTCATCCGCGGC GACCAATCTCAAGGA
    GCTGCTGTTCCGAGT CGGTCATCCGCGGCT ACCAATCTCAAGGAT
    CTGCTGTTCCGAGTG GGTCATCCGCGGCTG CCAATCTCAAGGATA
    TGCTGTTCCGAGTGG GTCATCCGCGGCTGG CAATCTCAAGGATAT
    GCTGTTCCGAGTGGC TCATCCGCGGCTGGA AATCTCAAGGATATT
    CTGTTCCGAGTGGCT CATCCGCGGCTGGAA ATCTCAAGGATATTG
    TGTTCCGAGTGGCTG ATCCGCGGCTGGAAA TCTCAAGGATATTGG
    CTCAAGGATATTGGG TGAGAAAAATGCTGA ATGCGGTGTCCAATA
    TCAAGGATATTGGGC GAGAAAAATGCTGAC TGCGGTGTCCAATAA
    CAAGGATATTGGGCT AGAAAAATGCTGACC GCGGTGTCCAATAAC
    AAGGATATTGGGCTT GAAAAATGCTGACCT CGGTGTCCAATAACT
    AGGATATTGGGCTTT AAAAATGCTGACCTC GGTGTCCAATAACTA
    GGATATTGGGCTTTA AAAATGCTGACCTCT GTGTCCAATAACTAC
    GATATTGGGCTTTAC AAATGCTGACCTCTG TGTCCAATAACTACA
    ATATTGGGCTTTACA AATGCTGACCTCTGT GTCCAATAACTACAT
    TATTGGGCTTTACAA ATGCTGACCTCTGTT TCCAATAACTACATT
    ATTGGGCTTTACAAC TGCTGACCTCTGTTA CCAATAACTACATTG
    TTGGGCTTTACAACC GCTGACCTCTGTTAC CAATAACTACATTGT
    TGGGCTTTACAACCT CTGACCTCTGTTACC AATAACTACATTGTG
    GGGCTTTACAACCTG TGACCTCTGTTACCT ATAACTACATTGTGG
    GGCTTTACAACCTGA GACCTCTGTTACCTC TAACTACATTGTGGG
    GCTTTACAACCTGAG ACCTCTGTTACCTCT AACTACATTGTGGGG
    CTTTACAACCTGAGG CCTCTGTTACCTCTC ACTACATTGTGGGGA
    TTTACAACCTGAGGA CTCTGTTACCTCTCC CTACATTGTGGGGAA
    TTACAACCTGAGGAA TCTGTTACCTCTCCA TACATTGTGGGGAAT
    TACAACCTGAGGAAC CTGTTACCTCTCCAC ACATTGTGGGGAATA
    ACAACCTGAGGAACA TGTTACCTCTCCACT CATTGTGGGGAATAA
    CAACCTGAGGAACAT GTTACCTCTCCACTG ATTGTGGGGAATAAG
    AACCTGAGGAACATT TTACCTCTCCACTGT TTGTGGGGAATAAGC
    ACCTGAGGAACATTA TACCTCTCCACTGTG TGTGGGGAATAAGCC
    CCTGAGGAACATTAC ACCTCTCCACTGTGG GTGGGGAATAAGCCC
    CTGAGGAACATTACT CCTCTCCACTGTGGA TGGGGAATAAGCCCC
    TGAGGAACATTACTC CTCTCCACTGTGGAC GGGGAATAAGCCCCC
    GAGGAACATTACTCG TCTCCACTGTGGACT GGGAATAAGCCCCCA
    AGGAACATTACTCGG CTCCACTGTGGACTG GGAATAAGCCCCCAA
    GGAACATTACTCGGG TCCACTGTGGACTGG GAATAAGCCCCCAAA
    GAACATTACTCGGGG CCACTGTGGACTGGT AATAAGCCCCCAAAG
    AACATTACTCGGGGG CACTGTGGACTGGTC ATAAGCCCCCAAAGG
    ACATTACTCGGGGGG ACTGTGGACTGGTCC TAAGCCCCCAAAGGA
    CATTACTCGGGGGGC CTGTGGACTGGTCCC AAGCCCCCAAAGGAA
    ATTACTCGGGGGGCC TGTGGACTGGTCCCT AGCCCCCAAAGGAAT
    TTACTCGGGGGGCCA GTGGACTGGTCCCTG GCCCCCAAAGGAATG
    TACTCGGGGGGCCAT TGGACTGGTCCCTGA CCCCCAAAGGAATGT
    ACTCGGGGGGCCATC GGACTGGTCCCTGAT CCCCAAAGGAATGTG
    CTCGGGGGGCCATCA GACTGGTCCCTGATC CCCAAAGGAATGTGG
    TCGGGGGGCCATCAG ACTGGTCCCTGATCC CCAAAGGAATGTGGG
    CGGGCGGCCATCAGG CTGGTCCCTGATCCT CAAAGGAATGTGGGG
    GGGGGGCCATCAGGA TGGTCCCTGATCCTG AAAGGAATGTGGGGA
    GGGGGCCATCAGGAT GGTCCCTGATCCTGG AAGGAATGTGGGGAC
    GGGGCCATCAGGATT GTCCCTGATCCTGGA AGGAATGTGGGGACC
    GGGCCATCAGGATTG TCCCTGATCCTGGAT GGAATGTGGGGACCT
    GGCCATCAGGATTGA CCCTGATCCTGGATG GAATGTGGGGACCTG
    GCCATCAGGATTGAG CCTGATCCTGGATGC AATGTGGGGACCTGT
    CCATCAGGATTGAGA CTGATCCTGGATGCG ATGTGGGGACCTGTG
    CATCAGGATTGAGAA TGATCCTGGATGCGG TGTGGGGACCTGTGT
    ATCAGGATTGAGAAA GATCCTGGATGCGGT GTGGGGACCTGTGTC
    TCAGGATTGAGAAAA ATCCTGGATGCGGTG TGGGGACCTGTGTCC
    CAGGATTGAGAAAAA TCCTGGATGCGGTGT GGGGACCTGTGTCCA
    AGGATTGAGAAAAAT CCTGGATGCGGTGTC GGGACCTGTGTCCAG
    GGATTGAGAAAAATG CTGGATGCGGTGTCC GGACCTGTGTCCAGG
    GATTGAGAAAAATGC TGGATGCGGTGTCCA GACCTGTGTCCAGGG
    ATTGAGAAAAATGCT GGATGCGGTGTCCAA ACCTGTGTCCAGGGA
    TTGAGAAAAATGCTG GATGCGGTGTCCAAT CCTGTGTCCAGGGAC
    CTGTGTCCAGGGACC TGAGTACAACTACCG CGTGTGGGAAGCGGG
    TGTGTCCAGGGACCA GAGTACAACTACCGC GTGTGGGAAGCGGGC
    GTGTCCAGGGACCAT AGTACAACTACCGCT TGTGGGAAGCGGGCG
    TGTCCAGGGACCATG GTACAACTACCGCTG GTGGGAAGCGGGCGT
    GTCCAGGGACCATGG TACAACTACCGCTGC TGGGAAGCGGGCGTG
    TCCAGGGACCATGGA ACAACTACCGCTGCT GGGAAGCGGGCGTGC
    CCAGGGACCATGGAG CAACTACCGCTGCTG GGAAGCGGGCGTGCA
    CAGGGACCATGGAGG AACTACCGCTGCTGG GAAGCGGGCGTGCAC
    AGGGACCATGGAGGA ACTACCGCTGCTGGA AAGCGGGCGTGCACC
    GGGACCATGGAGGAG CTACCGCTGCTGGAC AGCGGGCGTGCACCG
    GGACCATGGAGGAGA TACCGCTGCTGGACC GCGGGCGTGCACCGA
    GACCATGGAGGAGAA ACCGCTGCTGGACCA CGGGCGTGCACCGAG
    ACCATGGAGGAGAAG CCGCTGCTGGACCAC GGGCGTGCACCGAGA
    CCATGGAGGAGAAGC CGCTGCTGGACCACA GGCGTGCACCGAGAA
    CATGGAGGAGAAGCC GCTGCTGGACCACAA GCGTGCACCGAGAAC
    ATGGAGGAGAAGCCG CTGCTGGACCACAAA CGTGCACCGAGAACA
    TGGAGGAGAAGCCGA TGCTGGACCACAAAC GTGCACCGAGAACAA
    GGAGGAGAAGCCGAT GCTGGACCACAAACC TGCACCGAGAACAAT
    GAGGAGAAGCCGATG CTGGACCACAAACCG GCACCGAGAACAATG
    AGGAGAAGCCGATGT TGGACCACAAACCGC CACCGAGAACAATGA
    GGAGAAGCCGATGTG GGACCACAAACCGCT ACCGAGAACAATGAG
    GAGAAGCCGATGTGT GACCACAAACCGCTG CCGAGAACAATGAGT
    AGAAGCCGATGTGTG ACCACAAACCGCTGC CGAGAACAATGAGTG
    GAAGCCGATGTGTGA CCACAAACCGCTGCC GAGAACAATGAGTGC
    AAGCCGATGTGTGAG CACAAACCGCTGCCA AGAACAATGAGTGCT
    AGCCGATGTGTGAGA ACAAACCGCTGCCAG GAACAATGAGTGCTG
    GCCGATGTGTGAGAA CAAACCGCTGCCAGA AACAATGAGTGCTGC
    CCGATGTGTGAGAAG AAACCGCTGCCAGAA ACAATGAGTGCTGCC
    CGATGTGTGAGAAGA AACCGCTGCCAGAAA CAATGAGTGCTGCCA
    GATGTGTGAGAAGAC ACCGCTGCCAGAAAA AATGAGTGCTGCCAC
    ATGTGTGAGAAGACC CCGCTGCCAGAAAAT ATGAGTGCTGCCACC
    TGTGTGAGAAGACCA CGCTGCCAGAAAATG TGAGTGCTGCCACCC
    GTGTGAGAAGACCAC GCTGCCAGAAAATGT GAGTGCTGCCACCCC
    TGTGAGAAGACCACC CTGCCAGAAAATGTG AGTGCTGCCACCCCG
    GTGAGAAGACCACCA TGCCAGAAAATGTGC GTGCTGCCACCCCGA
    TGAGAAGACCACCAT GCCAGAAAATGTGCC TGCTGCCACCCCGAG
    GAGAAGACCACCATC CCAGAAAATGTGCCC GCTGCCACCCCGAGT
    AGAAGACCACCATCA CAGAAAATGTGCCCA CTGCCACCCCGAGTG
    GAAGACCACCATCAA AGAAAATGTGCCCAA TGCCACCCCGAGTGC
    AAGACCACCATCAAC GAAAATGTGCCCAAG GCCACCCCGAGTGCC
    AGACCACCATCAACA AAAATGTGCCCAAGC CCACCCCGAGTGCCT
    GACCACCATCAACAA AAATGTGCCCAAGCA CACCCCGAGTGCCTG
    ACCACCATCAACAAT AATGTGCCCAAGCAC ACCCCGAGTGCCTGG
    CCACCATCAACAATG ATGTGCCCAAGCACG CCCCGAGTGCCTGGG
    CACCATCAACAATGA TGTGCCCAAGCACGT CCCGAGTGCCTGGGC
    ACCATCAACAATGAG GTGCCCAAGCACGTG CCGAGTGCCTGGGCA
    CCATCAACAATGAGT TGCCCAAGCACGTGT CGAGTGCCTGGGCAG
    CATCAACAATGAGTA GCCCAAGCACGTGTG GAGTGCCTGGGCAGC
    ATCAACAATGAGTAC CCCAAGCACGTGTGG AGTGCCTGGGCAGCT
    TCAACAATGAGTACA CCAAGCACGTGTGGG GTGCCTGGGCAGCTG
    CAACAATGAGTACAA CAAGCACGTGTGGGA TGCCTGGGCAGCTGC
    AACAATGAGTACAAC AAGCACGTGTGGGAA GCCTGGGCAGCTGCA
    ACAATGAGTACAACT AGCACGTGTGGGAAG CCTGGGCAGCTGCAG
    CAATGAGTACAACTA GCACGTGTGGGAAGC CTGGGCAGCTGCAGC
    AATGAGTACAACTAC CACGTGTGGGAAGCG TGGGCAGCTGCAGCG
    ATGAGTACAACTACC ACGTGTGGGAAGCGG GGGCAGCTGCAGCGC
    GGCAGCTGCAGCGCG CTATGCCGGTGTCTG GGCGCTGTGTGGACC
    GCAGCTGCAGCGCGC TATGCCGGTGTCTGT GCGCTGTGTGGACCG
    CAGCTGCAGCGCGCC ATGCCGGTGTCTGTG CGCTGTGTGGACCGT
    AGCTGCAGCGCGCCT TGCCGGTGTCTGTGT GCTGTGTGGACCGTG
    GCTGCAGCGCGCCTG GCCGGTGTCTGTGTG CTGTGTGGACCGTGA
    CTGCAGCGCGCCTGA CCGGTGTCTGTGTGC TGTGTGGACCGTGAC
    TGCAGCGCGCCTGAC CGGTGTCTGTGTGCC GTGTGGACCGTGACT
    GCAGCGCGCCTGACA GGTGTCTGTGTGCCT TGTGGACCGTGACTT
    CAGCGCGCCTGACAA GTGTCTGTGTGCCTG GTGGACCGTGACTTC
    AGCGCGCCTGACAAC TGTCTGTGTGCCTGC TGGACCGTGACTTCT
    GCGCGCCTGACAACG GTCTGTGTGCCTGCC GGACCGTGACTTCTG
    CGCGCCTGACAACGA TCTGTGTGCCTGCCT GACCGTGACTTCTGC
    GCGCCTGACAACGAC CTGTGTGCCTGCCTG ACCGTGACTTCTGCG
    CGCCTGACAACGACA TGTGTGCCTGCCTGC CCGTGACTTCTGCGC
    GCCTGACAACGACAC GTGTGCCTGCCTGCC CGTGACTTCTGCGCC
    CCTGACAACGACACG TGTGCCTGCCTGCCC GTGACTTCTGCGCCA
    CTGACAACGACACGG GTGCCTGCCTGCCCG TGACTTCTGCGCCAA
    TGACAACGACACGGC TGCCTGCCTGCCCGC GACTTCTGCGCCAAC
    GACAACGACACGGCC GCCTGCCTGCCCGCC ACTTCTGCGCCAACA
    ACAACGACACGGCCT CCTGCCTGCCCGCCC CTTCTGCGCCAACAT
    CAACGACACGGCCTG CTGCCTGCCCGCCCA TTCTGCGCCAACATC
    AACGACACGGCCTGT TGCCTGCCCGCCCAA TCTGCGCCAACATCC
    ACGACACGGCCTGTG GCCTGCCCGCCCAAC CTGCGCCAACATCCT
    CGACACGGCCTGTGT CCTGCCCGCCCAACA TGCGCCAACATCCTC
    GACACGGCCTGTGTA CTGCCCGCCCAACAC GCGCCAACATCCTCA
    ACACGGCCTGTGTAG TGCCCGCCCAACACC CGCCAACATCCTCAG
    CACGGCCTGTGTAGC GCCCGCCCAACACCT GCCAACATCCTCAGC
    ACGGCCTGTGTAGCT CCCGCCCAACACCTA CCAACATCCTCAGCG
    CGGCCTGTGTAGCTT CCGCCCAACACCTAC CAACATCCTCAGCGC
    GGCCTGTGTAGCTTG CGCCCAACACCTACA AACATCCTCAGCGCC
    GCCTGTGTAGCTTGC GCCCAACACCTACAG ACATCCTCAGCGCCG
    CCTGTGTAGCTTGCC CCCAACACCTACAGG CATCCTCAGCGCCGA
    CTGTGTAGCTTGCCG CCAACACCTACAGGT ATCCTCAGCGCCGAG
    TGTGTAGCTTGCCGC CAACACCTACAGGTT TCCTCAGCGCCGAGA
    GTGTAGCTTGCCGCC AACACCTACAGGTTT CCTCAGCGCCGAGAG
    TGTAGCTTGCCGCCA ACACCTACAGGTTTG CTCAGCGCCGAGAGC
    GTAGCTTGCCGCCAC CACCTACAGGTTTGA TCAGCGCCGAGAGCA
    TAGCTTGCCGCCACT ACCTACAGGTTTGAG CAGCGCCGAGAGCAG
    AGCTTGCCGCCACTA CCTACAGGTTTGAGG AGCGCCGAGAGCAGC
    GCTTGCCGCCACTAC CTACAGGTTTGAGGG GCGCCGAGAGCAGCG
    CTTGCCGCCACTACT TACAGGTTTGAGGGC CGCCGAGAGCAGCGA
    TTGCCGCCACTACTA ACAGGTTTGAGGGCT GCCGAGAGCAGCGAC
    TGCCGCCACTACTAC CAGGTTTGAGGGCTG CCGAGAGCAGCGACT
    GCCGCCACTACTACT AGGTTTGAGGGCTGG CGAGAGCAGCGACTC
    CCGCCACTACTACTA GGTTTGAGGGCTGGC GAGAGCAGCGACTCC
    CGCCACTACTACTAT GTTTGAGGGCTGGCG AGAGCAGCGACTCCG
    GCCACTACTACTATG TTTGAGGGCTGGCGC GAGCAGCGACTCCGA
    CCACTACTACTATGC TTGAGGGCTGGCGCT AGCAGCGACTCCGAG
    CACTACTACTATGCC TGAGGGCTGGCGCTG GCAGCGACTCCGAGG
    ACTACTACTATGCCG GAGGGCTGGCGCTGT CAGCGACTCCGAGGG
    CTACTACTATGCCGG AGGGCTGGCGCTGTG AGCGACTCCGAGGGG
    TACTACTATGCCGGT GGGCTGGCGCTGTGT GCGACTCCGAGGGGT
    ACTACTATGCCGGTG GGCTGGCGCTGTGTG CGACTCCGAGGGGTT
    CTACTATGCCGGTGT GCTGGCGCTGTGTGG GACTCCGAGGGGTTT
    TACTATGCCGGTGTC CTGGCGCTGTGTGGA ACTCCGAGGGGTTTG
    ACTATGCCGGTGTCT TGGCGCTGTGTGGAC CTCCGAGGGGTTTGT
    TCCGAGGGGTTTGTG CATCCGCAACGGCAG AGGTCTGTGAGGAAG
    CCGAGGGGTTTGTGA ATCCGCAACGGCAGC GGTCTGTGAGGAAGA
    CGAGGGGTTTGTGAT TCCGCAACGGCAGCC GTCTGTGAGGAAGAA
    GAGGGGTTTGTGATC CCGCAACGGCAGCCA TCTGTGAGGAAGAAA
    AGGGGTTTGTGATCC CGCAACGGCAGCCAG CTGTGAGGAAGAAAA
    GGGGTTTGTGATCCA GCAACGGCAGCCAGA TGTGAGGAAGAAAAG
    GGGTTTGTGATCCAC CAACGGCAGCCAGAG GTGAGGAAGAAAAGA
    GGTTTGTGATCCACG AACGGCAGCCAGAGC TGAGGAAGAAAAGAA
    GTTTGTGATCCACGA ACGGCAGCCAGAGCA GAGGAAGAAAAGAAA
    TTTGTGATCCACGAC CGGCAGCCAGAGCAT AGGAAGAAAAGAAAA
    TTGTGATCCACGACG GGCAGCCAGAGCATG GGAAGAAAAGAAAAC
    TGTGATCCACGACGG GCAGCCAGAGCATGT GAAGAAAAGAAAACA
    GTGATCCACGACGGC CAGCCAGAGCATGTA AAGAAAAGAAAACAA
    TGATCCACGACGGCG AGCCAGAGCATGTAC AGAAAAGAAAACAAA
    GATCCACGACGGCGA GCCAGAGCATGTACT GAAAAGAAAACAAAG
    ATCCACGACGGCGAG CCAGAGCATGTACTG AAAAGAAAACAAAGA
    TCCACGACGGCGAGT CAGAGCATGTACTGC AAAGAAAACAAAGAC
    CCACGACGGCGAGTG AGAGCATGTACTGCA AAGAAAACAAAGACC
    CACGACGGCGAGTGC GAGCATGTACTGCAT AGAAAACAAAGACCA
    ACGACGGCGAGTGCA AGCATGTACTGCATC GAAAACAAAGACCAT
    CGACGGCGAGTGCAT GCATGTACTGCATCC AAAACAAAGACCATT
    GACGGCGAGTGCATG CATGTACTGCATCCC AAACAAAGACCATTG
    ACGGCGAGTGCATGC ATGTACTGCATCCCT AACAAAGACCATTGA
    CGGCGAGTGCATGCA TGTACTGCATCCCTT ACAAAGACCATTGAT
    GGCGAGTGCATGCAG GTACTGCATCCCTTG CAAAGACCATTGATT
    GCGAGTGCATGCAGG TACTGCATCCCTTGT AAAGACCATTGATTC
    CGAGTGCATGCAGGA ACTGCATCCCTTGTG AAGACCATTGATTCT
    GAGTGCATGCAGGAG CTGCATCCCTTGTGA AGACCATTGATTCTG
    AGTGCATGCAGGAGT TGCATCCCTTGTGAA GACCATTGATTCTGT
    GTGCATGCAGGAGTG GCATCCCTTGTGAAG ACCATTGATTCTGTT
    TGCATGCAGGAGTGC CATCCCTTGTGAAGG CCATTGATTCTGTTA
    GCATGCAGGAGTGCC ATCCCTTGTGAAGGT CATTGATTCTGTTAC
    CATGCAGGAGTGCCC TCCCTTGTGAAGGTC ATTGATTCTGTTACT
    ATGCAGGAGTGCCCC CCCTTGTGAAGGTCC TTGATTCTGTTACTT
    TGCAGGAGTGCCCCT CCTTGTGAAGGTCCT TGATTCTGTTACTTC
    GCAGGAGTGCCCCTC CTTGTGAAGGTCCTT GATTCTGTTACTTCT
    CAGGAGTGCCCCTCG TTGTGAAGGTCCTTG ATTCTGTTACTTCTG
    AGGAGTGCCCCTCGG TGTGAAGGTCCTTGC TTCTGTTACTTCTGC
    GGAGTGCCCCTCGGG GTGAAGGTCCTTGCC TCTGTTACTTCTGCT
    GAGTGCCCCTCGGGC TGAAGGTCCTTGCCC CTGTTACTTCTGCTC
    AGTGCCCCTCGGGCT GAAGGTCCTTGCCCG TGTTACTTCTGCTCA
    GTGCCCCTCGGGCTT AAGGTCCTTGCCCGA GTTACTTCTGCTCAG
    TGCCCCTCGGGCTTC AGGTCCTTGCCCGAA TTACTTCTGCTCAGA
    GCCCCTCGGGCTTCA GGTCCTTGCCCGAAG TACTTCTGCTCAGAT
    CCCCTCGGGCTTCAT GTCCTTGCCCGAAGG ACTTCTGCTCAGATG
    CCCTCGGGCTTCATC TCCTTGCCCGAAGGT CTTCTGCTCAGATGC
    CCTCGGGCTTCATCC CCTTGCCCGAAGGTC TTCTGCTCAGATGCT
    CTCGGGCTTCATCCG CTTGCCCGAAGGTCT TCTGCTCAGATGCTC
    TCGGGCTTCATCCGC TTGCCCGAAGGTCTG CTGCTCAGATGCTCC
    CGGGCTTCATCCGCA TGCCCGAAGGTCTGT TGCTCAGATGCTCCA
    GGGCTTCATCCGCAA GCCCGAAGGTCTGTG GCTCAGATGCTCCAA
    GGCTTCATCCGCAAC CCCGAAGGTCTGTGA CTCAGATGCTCCAAG
    GCTTCATCCGCAACG CCGAAGGTCTGTGAG TCAGATGCTCCAAGG
    CTTCATCCGCAACGG CGAAGGTCTGTGAGG CAGATGCTCCAAGGA
    TTCATCCGCAACGGC GAAGGTCTGTGAGGA AGATGCTCCAAGGAT
    TCATCCGCAACGGCA AAGGTCTGTGAGGAA GATGCTCCAAGGATG
    ATGCTCCAAGGATGC GAATAACATTGCTTC CCTACGTGAAGATCC
    TGCTCCAAGGATGCA AATAACATTGCTTCA CTACGTGAAGATCCG
    GCTCCAAGGATGCAC ATAACATTGCTTCAG TACGTGAAGATCCGC
    CTCCAAGGATGCACC TAACATTGCTTCAGA ACGTGAAGATCCGCC
    TCCAAGGATGCACCA AACATTGCTTCAGAG CGTGAAGATCCGCCA
    CCAAGGATGCACCAT ACATTGCTTCAGAGC GTGAAGATCCGCCAT
    CAAGGATGCACCATC CATTGCTTCAGAGCT TGAAGATCCGCCATT
    AAGGATGCACCATCT ATTGCTTCAGAGCTG GAAGATCCGCCATTC
    AGGATGCACCATCTT TTGCTTCAGAGCTGG AAGATCCGCCATTCT
    GGATGCACCATCTTC TGCTTCAGAGCTGGA AGATCCGCCATTCTC
    GATGCACCATCTTCA GCTTCAGAGCTGGAG GATCCGCCATTCTCA
    ATGCACCATCTTCAA CTTCAGAGCTGGAGA ATCCGCCATTCTCAT
    TGCACCATCTTCAAG TTCAGAGCTGGAGAA TCCGCCATTCTCATG
    GCACCATCTTCAAGG TCAGAGCTGGAGAAC CCGCCATTCTCATGC
    CACCATCTTCAAGGG CAGAGCTGGAGAACT CGCCATTCTCATGCC
    ACCATCTTCAAGGGC AGAGCTGGAGAACTT GCCATTCTCATGCCT
    CCATCTTCAAGGGCA GAGCTGGAGAACTTC CCATTCTCATGCCTT
    CATCTTCAAGGGCAA AGCTGGAGAACTTCA CATTCTCATGCCTTG
    ATCTTCAAGGGCAAT GCTGGAGAACTTCAT ATTCTCATGCCTTGG
    TCTTCAAGGGCAATT CTGGAGAACTTCATG TTCTCATGCCTTGGT
    CTTCAAGGGCAATTT TGGAGAACTTCATGG TCTCATGCCTTGGTC
    TTCAAGGGCAATTTG GGAGAACTTCATGGG CTCATGCCTTGGTCT
    TCAAGGGCAATTTGC GAGAACTTCATGGGG TCATGCCTTGGTCTC
    CAAGGGCAATTTGCT AGAACTTCATGGGGC CATGCCTTGGTCTCC
    AAGGGCAATTTGCTC GAACTTCATGGGGCT ATGCCTTGGTCTCCT
    AGGGCAATTTGCTCA AACTTCATGGGGCTC TGCCTTGGTCTCCTT
    GGGCAATTTGCTCAT ACTTCATGGGGCTCA GCCTTGGTCTCCTTG
    GGCAATTTGCTCATT CTTCATGGGGCTCAT CCTTGGTCTCCTTGT
    GCAATTTGCTCATTA TTCATGGGGCTCATC CTTGGTCTCCTTGTC
    CAATTTGCTCATTAA TCATGGGGCTCATCG TTGGTCTCCTTGTCC
    AATTTGCTCATTAAC CATGGGGCTCATCGA TGGTCTCCTTGTCCT
    ATTTGCTCATTAACA ATGGGGCTCATCGAG GGTCTCCTTGTCCTT
    TTTGCTCATTAACAT TGGGGCTCATCGAGG GTCTCCTTGTCCTTC
    TTGCTCATTAACATC GGGGCTCATCGAGGT TCTCCTTGTCCTTCC
    TGCTCATTAACATCC GGGCTCATCGAGGTG CTCCTTGTCCTTCCT
    GCTCATTAACATCCG GGCTCATCGAGGTGG TCCTTGTCCTTCCTA
    CTCATTAACATCCGA GCTCATCGAGGTGGT CCTTGTCCTTCCTAA
    TCATTAACATCCGAC CTCATCGAGGTGGTG CTTGTCCTTCCTAAA
    CATTAACATCCGACG TCATCGAGGTGGTGA TTGTCCTTCCTAAAA
    ATTAACATCCGACGG CATCGAGGTGGTGAC TGTCCTTCCTAAAAA
    TTAACATCCGACGGG ATCGAGGTGGTGACG GTCCTTCCTAAAAAA
    TAACATCCGACGGGG TCGAGGTGGTGACGG TCCTTCCTAAAAAAC
    AACATCCGACGGGGG CGAGGTGGTGACGGG CCTTCCTAAAAAACC
    ACATCCGACGGGGGA GAGGTGGTGACGGGC CTTCCTAAAAAACCT
    CATCCGACGGGGGAA AGGTGGTGACGGGCT TTCCTAAAAAACCTT
    ATCCGACGGGGGAAT GGTGGTGACGGGCTA TCCTAAAAAACCTTC
    TCCGACGGGGGAATA GTGGTGACGGGCTAC CCTAAAAAACCTTCG
    CCGACGGGGGAATAA TGGTGACGGGCTACG CTAAAAAACCTTCGC
    CGACGGGGGAATAAC GGTGACGGGCTACGT TAAAAAACCTTCGCC
    GACGGGGGAATAACA GTGACGGGCTACGTG AAAAAACCTTCGCCT
    ACGGGGGAATAACAT TGACGGGCTACGTGA AAAAACCTTCGCCTC
    CGGGGGAATAACATT GACGGGCTACGTGAA AAAACCTTCGCCTCA
    GGGGGAATAACATTG ACGGGCTACGTGAAG AAACCTTCGCCTCAT
    GGGGAATAACATTGC CGGGCTACGTGAAGA AACCTTCGCCTCATC
    GGGAATAACATTGCT GGGCTACGTGAAGAT ACCTTCGCCTCATCC
    GGAATAACATTGCTT GGCTACGTGAAGATC CCTTCGCCTCATCCT
    CTTCGCCTCATCCTA CGACAACCAGAACTT AAGCAGGGAAAATGT
    TTCGCCTCATCCTAG GACAACCAGAACTTG AGCAGGGAAAATGTA
    TCGCCTCATCCTAGG ACAACCAGAACTTGC GCAGGGAAAATGTAC
    CGCCTCATCCTAGGA CAACCAGAACTTGCA CAGGGAAAATGTACT
    GCCTCATCCTAGGAG AACCAGAACTTGCAG AGGGAAAATGTACTT
    CCTCATCCTAGGAGA ACCAGAACTTGCAGC GGGAAAATGTACTTT
    CTCATCCTAGGAGAG CCAGAACTTGCAGCA GGAAAATGTACTTTG
    TCATCCTAGGAGAGG CAGAACTTGCAGCAA GAAAATGTACTTTGC
    CATCCTAGGAGAGGA AGAACTTGCAGCAAC AAAATGTACTTTGCT
    ATCCTAGGAGAGGAG GAACTTGCAGCAACT AAATGTACTTTGCTT
    TCCTAGGAGAGGAGC AACTTGCAGCAACTG AATGTACTTTGCTTT
    CCTAGGAGAGGAGCA ACTTGCAGCAACTGT ATGTACTTTGCTTTC
    CTAGGAGAGGAGCAG CTTGCAGCAACTGTG TGTACTTTGCTTTCA
    TAGGAGAGGAGCAGC TTGCAGCAACTGTGG GTACTTTGCTTTCAA
    AGGAGAGGAGCAGCT TGCAGCAACTGTGGG TACTTTGCTTTCAAT
    GGAGAGGAGCAGCTA GCAGCAACTGTGGGA ACTTTGCTTTCAATC
    GAGAGGAGCAGCTAG CAGCAACTGTGGGAC CTTTGCTTTCAATCC
    AGAGGAGCAGCTAGA AGCAACTGTGGGACT TTTGCTTTCAATCCC
    GAGGAGCAGCTAGAA GCAACTGTGGGACTG TTGCTTTCAATCCCA
    AGGAGCAGCTAGAAG CAACTGTGGGACTGG TGCTTTCAATCCCAA
    GGAGCAGCTAGAAGG AACTGTGGGACTGGG GCTTTCAATCCCAAA
    GAGCAGCTAGAAGGG ACTGTGGGACTGGGA CTTTCAATCCCAAAT
    AGCAGCTAGAAGGGA CTGTGGGACTGGGAC TTTCAATCCCAAATT
    GCAGCTAGAAGGGAA TGTGGGACTGGGACC TTCAATCCCAAATTA
    CAGCTAGAAGGGAAT GTGGGACTGGGACCA TCAATCCCAAATTAT
    AGCTAGAAGGGAATT TGGGACTGGGACCAC CAATCCCAAATTATG
    GCTAGAAGGGAATTA GGGACTGGGACCACC AATCCCAAATTATGT
    CTAGAAGGGAATTAC GGACTGGGACCACCG ATCCCAAATTATGTG
    TAGAAGGGAATTACT GACTGGGACCACCGC TCCCAAATTATGTGT
    AGAAGGGAATTACTC ACTGGGACCACCGCA CCCAAATTATGTGTT
    GAAGGGAATTACTCC CTGGGACCACCGCAA CCAAATTATGTGTTT
    AAGGGAATTACTCCT TGGGACCACCGCAAC CAAATTATGTGTTTC
    AGGGAATTACTCCTT GGGACCACCGCAACC AAATTATGTGTTTCC
    GGGAATTACTCCTTC GGACCACCGCAACCT AATTATGTGTTTCCG
    GGAATTACTCCTTCT GACCACCGCAACCTG ATTATGTGTTTCCGA
    GAATTACTCCTTCTA ACCACCGCAACCTGA TTATGTGTTTCCGAA
    AATTACTCCTTCTAC CCACCGCAACCTGAC TATGTGTTTCCGAAA
    ATTACTCCTTCTACG CACCGCAACCTGACC ATGTGTTTCCGAAAT
    TTACTCCTTCTACGT ACCGCAACCTGACCA TGTGTTTCCGAAATT
    TACTCCTTCTACGTC CCGCAACCTGACCAT GTGTTTCCGAAATTT
    ACTCCTTCTACGTCC CGCAACCTGACCATC TGTTTCCGAAATTTA
    CTCCTTCTACGTCCT GCAACCTGACCATCA GTTTCCGAAATTTAC
    TCCTTCTACGTCCTC CAACCTGACCATCAA TTTCCGAAATTTACC
    CCTTCTACGTCCTCG AACCTGACCATCAAA TTCCGAAATTTACCG
    CTTCTACGTCCTCGA ACCTGACCATCAAAG TCCGAAATTTACCGC
    TTCTACGTCCTCGAC CCTGACCATCAAAGC CCGAAATTTACCGCA
    TCTACGTCCTCGACA CTGACCATCAAAGCA CGAAATTTACCGCAT
    CTACGTCCTCGACAA TGACCATCAAAGCAG GAAATTTACCGCATG
    TACGTCCTCGACAAC GACCATCAAAGCAGG AAATTTACCGCATGG
    ACGTCCTCGACAACC ACCATCAAAGCAGGG AATTTACCGCATGGA
    CGTCCTCGACAACCA CCATCAAAGCAGGGA ATTTACCGCATGGAG
    GTCCTCGACAACCAG CATCAAAGCAGGGAA TTTACCGCATGGAGG
    TCCTCGACAACCAGA ATCAAAGCAGGGAAA TTACCGCATGGAGGA
    CCTCGACAACCAGAA TCAAAGCAGGGAAAA TACCGCATGGAGGAA
    CTCGACAACCAGAAC CAAAGCAGGGAAAAT ACCGCATGGAGGAAG
    TCGACAACCAGAACT AAAGCAGGGAAAATG CCGCATGGAGGAAGT
    CGCATGGAGGAAGTG CAGGAACAACGGGGA CCACCACGTCGAAGA
    GCATGGAGGAAGTGA AGGAACAACGGGGAG CACCACGTCGAAGAA
    CATGGAGGAAGTGAC GGAACAACGGGGAGA ACCACGTCGAAGAAT
    ATGGAGGAAGTGACG GAACAACGGGGAGAG CCACGTCGAAGAATC
    TGGAGGAAGTGACGG AACAACGGGGAGAGA CACGTCGAAGAATCG
    GGAGGAAGTGACGGG ACAACGGGGAGAGAG ACGTCGAAGAATCGC
    GAGGAAGTGACGGGG CAACGGGGAGAGAGC CGTCGAAGAATCGCA
    AGGAAGTGACGGGGA AACGGGGAGAGAGCC GTCGAAGAATCGCAT
    GGAAGTGACGGGGAC ACGGGGAGAGAGCCT TCGAAGAATCGCATC
    GAAGTGACGGGGACT CGGGGAGAGAGCCTC CGAAGAATCGCATCA
    AAGTGACGGGGACTA GGGGAGAGAGCCTCC GAAGAATCGCATCAT
    AGTGACGGGGACTAA GGGAGAGAGCCTCCT AAGAATCGCATCATC
    GTGACGGGGACTAAA GGAGAGAGCCTCCTG AGAATCGCATCATCA
    TGACGGGGACTAAAG GAGAGAGCCTCCTGT GAATCGCATCATCAT
    GACGGGGACTAAAGG AGAGAGCCTCCTGTG AATCGCATCATCATA
    ACGGGGACTAAAGGG GAGAGCCTCCTGTGA ATCGCATCATCATAA
    CGGGGACTAAAGGGC AGAGCCTCCTGTGAA TCGCATCATCATAAC
    GGGGACTAAAGGGCG GAGCCTCCTGTGAAA CGCATCATCATAACC
    GGGACTAAAGGGCGC AGCCTCCTGTGAAAG GCATCATCATAACCT
    GGACTAAAGGGCGCC GCCTCCTGTGAAAGT CATCATCATAACCTG
    GACTAAAGGGCGCCA CCTCCTGTGAAAGTG ATCATCATAACCTGG
    ACTAAAGGGCGCCAA CTCCTGTGAAAGTGA TCATCATAACCTGGC
    CTAAAGGGCGCCAAA TCCTGTGAAAGTGAC CATCATAACCTGGCA
    TAAAGGGCGCCAAAG CCTGTGAAAGTGACG ATCATAACCTGGCAC
    AAAGGGCGCCAAAGC CTGTGAAAGTGACGT TCATAACCTGGCACC
    AAGGGCGCCAAAGCA TGTGAAAGTGACGTC CATAACCTGGCACCG
    AGGGCGCCAAAGCAA GTGAAAGTGACGTCC ATAACCTGGCACCGG
    GGGCGCCAAAGCAAA TGAAAGTGACGTCCT TAACCTGGCACCGGT
    GGCGCCAAAGCAAAG GAAAGTGACGTCCTG AACCTGGCACCGGTA
    GCGCCAAAGCAAAGG AAAGTGACGTCCTGC ACCTGGCACCGGTAC
    CGCCAAAGCAAAGGG AAGTGACGTCCTGCA CCTGGCACCGGTACC
    GCCAAAGCAAAGGGG AGTGACGTCCTGCAT CTGGCACCGGTACCG
    CCAAAGCAAAGGGGA GTGACGTCCTGCATT TGGCACCGGTACCGG
    CAAAGCAAAGGGGAC TGACGTCCTGCATTT GGCACCGGTACCGGC
    AAAGCAAAGGGGACA GACGTCCTGCATTTC GCACCGGTACCGGCC
    AAGCAAAGGGGACAT ACGTCCTGCATTTCA CACCGGTACCGGCCC
    AGCAAAGGGGACATA CGTCCTGCATTTCAC ACCGGTACCGGCCCC
    GCAAAGGGGACATAA GTCCTGCATTTCACC CCGGTACCGGCCCCC
    CAAAGGGGACATAAA TCCTGCATTTCACCT CGGTACCGGCCCCCT
    AAAGGGGACATAAAC CCTGCATTTCACCTC GGTACCGGCCCCCTG
    AAGGGGACATAAACA CTGCATTTCACCTCC GTACCGGCCCCCTGA
    AGGGGACATAAACAC TGCATTTCACCTCCA TACCGGCCCCCTGAC
    GGGGACATAAACACC GCATTTCACCTCCAC ACCGGCCCCCTGACT
    GGGACATAAACACCA CATTTCACCTCCACC CCGGCCCCCTGACTA
    GGACATAAACACCAG ATTTCACCTCCACCA CGGCCCCCTGACTAC
    GACATAAACACCAGG TTTCACCTCCACCAC GGCCCCCTGACTACA
    ACATAAACACCAGGA TTCACCTCCACCACC GCCCCCTGACTACAG
    CATAAACACCAGGAA TCACCTCCACCACCA CCCCCTGACTACAGG
    ATAAACACCAGGAAC CACCTCCACCACCAC CCCCTGACTACAGGG
    TAAACACCAGGAACA ACCTCCACCACCACG CCCTGACTACAGGGA
    AAACACCAGGAACAA CCTCCACCACCACGT CCTGACTACAGGGAT
    AACACCAGGAACAAC CTCCACCACCACGTC CTGACTACAGGGATC
    ACACCAGGAACAACG TCCACCACCACGTCG TGACTACAGGGATCT
    CACCAGGAACAACGG CCACCACCACGTCGA GACTACAGGGATCTC
    ACCAGGAACAACGGG CACCACCACGTCGAA ACTACAGGGATCTCA
    CCAGGAACAACGGGG ACCACCACGTCGAAG CTACAGGGATCTCAT
    TACAGGGATCTCATC CACAGAGTATGATGG TGGACCTCCCGCCCA
    ACAGGGATCTCATCA ACAGAGTATGATGGG GGACCTCCCGCCCAA
    CAGGGATCTCATCAG CAGAGTATGATGGGC GACCTCCCGCCCAAC
    AGGGATCTCATCAGC AGAGTATGATGGGCA ACCTCCCGCCCAACA
    GGGATCTCATCAGCT GAGTATGATGGGCAG CCTCCCGCCCAACAA
    GGATCTCATCAGCTT AGTATGATGGGCAGG CTCCCGCCCAACAAG
    GATCTCATCAGCTTC GTATGATGGGCAGGA TCCCGCCCAACAAGG
    ATCTCATCAGCTTCA TATGATGGGCAGGAT CCCGCCCAACAAGGA
    TCTCATCAGCTTCAC ATGATGGGCAGGATG CCGCCCAACAAGGAC
    CTCATCAGCTTCACC TGATGGGCAGGATGC CGCCCAACAAGGACG
    TCATCAGCTTCACCG GATGGGCAGGATGCC GCCCAACAAGGACGT
    CATCAGCTTCACCGT ATGGGCAGGATGCCT CCCAACAAGGACGTG
    ATCAGCTTCACCGTT TGGGCAGGATGCCTG CCAACAAGGACGTGG
    TCAGCTTCACCGTTT GGGCAGGATGCCTGC CAACAAGGACGTGGA
    CAGCTTCACCGTTTA GGCAGGATGCCTGCG AACAAGGACGTGGAG
    AGCTTCACCGTTTAC GCAGGATGCCTGCGG ACAAGGACGTGGAGC
    GCTTCACCGTTTACT CAGGATGCCTGCGGC CAAGGACGTGGAGCC
    CTTCACCGTTTACTA AGGATGCCTGCGGCT AAGGACGTGGAGCCC
    TTCACCGTTTACTAC GGATGCCTGCGGCTC AGGACGTGGAGCCCG
    TCACCGTTTACTACA GATGCCTGCGGCTCC GGACGTGGAGCCCGG
    CACCGTTTACTACAA ATGCCTGCGGCTCCA GACGTGGAGCCCGGC
    ACCGTTTACTACAAG TGCCTGCGGCTCCAA ACGTGGAGCCCGGCA
    CCGTTTACTACAAGG GCCTGCGGCTCCAAC CGTGGAGCCCGGCAT
    CGTTTACTACAAGGA CCTGCGGCTCCAACA GTGGAGCCCGGCATC
    GTTTACTACAAGGAA CTGCGGCTCCAACAG TGGAGCCCGGCATCT
    TTTACTACAAGGAAG TGCGGCTCCAACAGC GGAGCCCGGCATCTT
    TTACTACAAGGAAGC GCGGCTCCAACAGCT GAGCCCGGCATCTTA
    TACTACAAGGAAGCA CGGCTCCAACAGCTG AGCCCGGCATCTTAC
    ACTACAAGGAAGCAC GGCTCCAACAGCTGG GCCCGGCATCTTACT
    CTACAAGGAAGCACC GCTCCAACAGCTGGA CCCGGCATCTTACTA
    TACAAGGAAGCACCC CTCCAACAGCTGGAA CCGGCATCTTACTAC
    ACTAGGAAGCACCCT TCCAACAGCTGGAAC CGGCATCTTACTACA
    CAAGGAAGCACCCTT CCAACAGCTGGAACA GGCATCTTACTACAT
    AAGGAAGCACCCTTT CAACAGCTGGAACAT GCATCTTACTACATG
    AGGAAGCACCCTTTA AACAGCTGGAACATG CATCTTACTACATGG
    GGAAGCACCCTTTAA ACAGCTGGAACATGG ATCTTACTACATGGG
    GAAGCACCCTTTAAG CAGCTGGAACATGGT TCTTACTACATGGGC
    AAGCACCCTTTAAGA AGCTGGAACATGGTG CTTACTACATGGGCT
    AGCACCCTTTAAGAA GCTGGAACATGGTGG TTACTACATGGGCTG
    GCACCCTTTAAGAAT CTGGAACATGGTGGA TACTACATGGGCTGA
    CACCCTTTAAGAATG TGGAACATGGTGGAC ACTACATGGGCTGAA
    ACCCTTTAAGAATGT GGAACATGGTGGACG CTACATGGGCTGAAG
    CCCTTTAAGAATGTC GAACATGGTGGACGT TACATGGGCTGAAGC
    CCTTTAAGAATGTCA AACATGGTGGACGTG ACATGGGCTGAAGCC
    CTTTAAGAATGTCAC ACATGGTGGACGTGG CATGGGCTGAAGCCC
    TTTAAGAATGTCACA CATGGTGGACGTGGA ATGGGCTGAAGCCCT
    TTAAGAATGTCACAG ATGGTGGACGTGGAC TGGGCTGAAGCCCTG
    TAAGAATGTCACAGA TGGTGGACGTGGACC GGGCTGAAGCCCTGG
    AAGAATGTCACAGAG GGTGGACGTGGACCT GGCTGAAGCCCTGGA
    AGAATGTCACAGAGT GTGGACGTGGACCTC GCTGAAGCCCTGGAC
    GAATGTCACAGAGTA TGGACGTGGACCTCC CTGAAGCCCTGGACT
    AATGTCACAGAGTAT GGACGTGGACCTCCC TGAAGCCCTGGACTC
    ATGTCACAGAGTATG GACGTGGACCTCCCG GAAGCCCTGGACTCA
    TGTCACAGAGTATGA ACGTGGACCTCCCGC AAGCCCTGGACTCAG
    GTCACAGAGTATGAT CGTGGACCTCCCGCC AGCCCTGGACTCAGT
    TCACAGAGTATGATG GTGGACCTCCCGCCC GCCCTGGACTCAGTA
    CCCTGGACTCAGTAC CGACCATATCCGTGG TTCCTTCCATTCCCT
    CCTGGACTCAGTACG GACCATATCCGTGGG TCCTTCCATTCCCTT
    CTGGACTCAGTACGC ACCATATCCGTGGGG CCTTCCATTCCCTTG
    TGGACTCAGTACGCC CCATATCCGTGGGGC CTTCCATTCCCTTGG
    GGACTCAGTACGCCG CATATCCGTGGGGCC TTCCATTCCCTTGGA
    GACTCAGTACGCCGT ATATCCGTGGGGCCA TCCATTCCCTTGGAC
    ACTCAGTACGCCGTT TATCCGTGGGGCCAA CCATTCCCTTGGACG
    CTCAGTACGCCGTTT ATCCGTGGGGCCAAG CATTCCCTTGGACGT
    TCAGTACGCCGTTTA TCCGTGGGGCCAAGA ATTCCCTTGGACGTT
    CAGTACGCCGTTTAC CCGTGGGGCCAAGAG TTCCCTTGGACGTTC
    AGTACGCCGTTTACG CGTGGGGCCAAGAGT TCCCTTGGACGTTCT
    GTACGCCGTTTACGT GTGGGGCCAAGAGTG CCCTTGGACGTTCTT
    TACGCCGTTTACGTC TGGGGCCAAGAGTGA CCTTGGACGTTCTTT
    ACGCCGTTTACGTCA GGGGCCAAGAGTGAG CTTGGACGTTCTTTC
    CGCCGTTTACGTCAA GGGCCAAGAGTGAGA TTGGACGTTCTTTCA
    GCCGTTTACGTCAAG GGCCAAGAGTGAGAT TGGACGTTCTTTCAG
    CCGTTTACGTCAAGG GCCAAGAGTGAGATC GGACGTTCTTTCAGC
    CGTTTACGTCAAGGC CCAAGAGTGAGATCT GACGTTCTTTCAGCA
    GTTTACGTCAAGGCT CAAGAGTGAGATCTT ACGTTCTTTCAGCAT
    TTTACGTCAAGGCTG AAGAGTGAGATCTTG CGTTCTTTCAGCATC
    TTACGTCAAGGCTGT AGAGTGAGATCTTGT GTTCTTTCAGCATCG
    TACGTCAAGGCTGTG GAGTGAGATCTTGTA TTCTTTCAGCATCGA
    ACGTCAAGGCTGTGA AGTGAGATCTTGTAC TCTTTCAGCATCGAA
    CGTCAAGGCTGTGAC GTGAGATCTTGTACA CTTTCAGCATCGAAC
    GTCAAGGCTGTGACC TGAGATCTTGTACAT TTTCAGCATCGAACT
    TCAAGGCTGTGACCC GAGATCTTGTACATT TTCAGCATCGAACTC
    CAAGGCTGTGACCCT AGATCTTGTACATTC TCAGCATCGAACTCC
    AAGGCTGTGACCCTC GATCTTGTACATTCG CAGCATCGAACTCCT
    AGGCTGTGACCCTCA ATCTTGTACATTCGC AGCATCGAACTCCTC
    GGCTGTGACCCTCAC TCTTGTACATTCGCA GCATCGAACTCCTCT
    GCTGTGACCCTCACC CTTGTACATTCGCAC CATCGAACTCCTCTT
    CTGTGACCCTCACCA TTGTACATTCGCACC ATCGAACTCCTCTTC
    TGTGACCCTCACCAT TGTACATTCGCACCA TCGAACTCCTCTTCT
    GTGACCCTCACCATG GTACATTCGCACCAA CGAACTCCTCTTCTC
    TGACCCTCACCATGG TACATTCGCACCAAT GAACTCCTCTTCTCA
    GACCCTCACCATGGT ACATTCGCACCAATG AACTCCTCTTCTCAG
    ACCCTCACCATGGTG CATTCGCACCAATGC ACTCCTCTTCTCAGT
    CCCTCACCATGGTGG ATTCGCACCAATGCT CTCCTCTTCTCAGTT
    CCTCACCATGGTGGA TTCGCACCAATGCTT TCCTCTTCTCAGTTA
    CTCACCATGGTGGAG TCGCACCAATGCTTC CCTCTTCTCAGTTAA
    TCACCATGGTGGAGA CGCACCAATGCTTCA CTCTTCTCAGTTAAT
    CACCATGGTGGAGAA GCACCAATGCTTCAG TCTTCTCAGTTAATC
    ACCATGGTGGAGAAC CACCAATGCTTCAGT CTTCTCAGTTAATCG
    CCATGGTGGAGAACG ACCAATGCTTCAGTT TTCTCAGTTAATCGT
    CATGGTGGAGAACGA CCAATGCTTCAGTTC TCTCAGTTAATCGTG
    ATGGTGGAGAACGAC CAATGCTTCAGTTCC CTCAGTTAATCGTGA
    TGGTGGAGAACGACC AATGCTTCAGTTCCT TCAGTTAATCGTGAA
    GGTGGAGAACGACCA ATGCTTCAGTTCCTT CAGTTAATCGTGAAG
    GTGGAGAACGACCAT TGCTTCAGTTCCTTC AGTTAATCGTGAAGT
    TGGAGAACGACCATA GCTTCAGTTCCTTCC GTTAATCGTGAAGTG
    GGAGAACGACCATAT CTTCAGTTCCTTCCA TTAATCGTGAAGTGG
    GAGAACGACCATATC TTCAGTTCCTTCCAT TAATCGTGAAGTGGA
    AGAACGACCATATCC TCAGTTCCTTCCATT AATCGTGAAGTGGAA
    GAACGACCATATCCG CAGTTCCTTCCATTC ATCGTGAAGTGGAAC
    AACGACCATATCCGT AGTTCCTTCCATTCC TCGTGAAGTGGAACC
    ACGACCATATCCGTG GTTCCTTCCATTCCC CGTGAAGTGGAACCC
    GTGAAGTGGAACCCT CTGGCAGCGGCAGCC ACAAAATCCCCATCA
    TGAAGTGGAACCCTC TGGCAGCGGCAGCCT CAAAATCCCCATCAG
    GAAGTGGAACCCTCC GGCAGCGGCAGCCTC AAAATCCCCATCAGG
    AAGTGGAACCCTCCC GCAGCGGCAGCCTCA AAATCCCCATCAGGA
    AGTGGAACCCTCCCT CAGCGGCAGCCTCAG AATCCCCATCAGGAA
    GTGGAACCCTCCCTC AGCGGCAGCCTCAGG ATCCCCATCAGGAAG
    TGGAACCCTCCCTCT GCGGCAGCCTCAGGA TCCCCATCAGGAAGT
    GGAACCCTCCCTCTC CGGCAGCCTCAGGAC CCCCATCAGGAAGTA
    GAACCCTCCCTCTCT GGCAGCCTCAGGACG CCCATCAGGAAGTAT
    AACCCTCCCTCTCTG GCAGCCTCAGGACGG CCATCAGGAAGTATG
    ACCCTCCCTCTCTGC CAGCCTCAGGACGGC CATCAGGAAGTATGC
    CCCTCCCTCTCTGCC AGCCTCAGGACGGCT ATCAGGAAGTATGCC
    CCTCCCTCTCTGCCC GCCTCAGGACGGCTA TCAGGAAGTATGCCG
    CTCCCTCTCTGCCCA CCTCAGGACGGCTAC CAGGAAGTATGCCGA
    TCCCTCTCTGCCCAA CTCAGGACGGCTACC AGGAAGTATGCCGAC
    CCCTCTCTGCCCAAC TCAGGACGGCTACCT GGAAGTATGCCGACG
    CCTCTCTGCCCAACG CAGGACGGCTACCTT GAAGTATGCCGACGG
    CTCTCTGCCCAACGG AGGACGGCTACCTTT AAGTATGCCGACGGC
    TCTCTGCCCAACGGC GGACGGCTACCTTTA AGTATGCCGACGGCA
    CTCTGCCCAACGGCA GACGGCTACCTTTAC GTATGCCGACGGCAC
    TCTGCCCAACGGCAA ACGGCTACCTTTACC TATGCCGACGGCACC
    CTGCCCAACGGCAAC CGGCTACCTTTACCG ATGCCGACGGCACCA
    TGCCCAACGGCAACC GGCTACCTTTACCGG TGCCGACGGCACCAT
    GCCCAACGGCAACCT GCTACCTTTACCGGC GCCGACGGCACCATC
    CCCAACGGCAACCTG CTACCTTTACCGGCA CCGACGGCACCATCG
    CCAACGGCAACCTGA TACCTTTACCGGCAC CGACGGCACCATCGA
    CAACGGCAACCTGAG ACCTTTACCGGCACA GACGGCACCATCGAC
    AACGGCAACCTGAGT CCTTTACCGGCACAA ACGGCACCATCGACA
    ACGGCAACCTGAGTT CTTTACCGGCACAAT CGGCACCATCGACAT
    CGGCAACCTGAGTTA TTTACCGGCACAATT GGCACCATCGACATT
    GGCAACCTGAGTTAC TTACCGGCACAATTA GCACCATCGACATTG
    GCAACCTGAGTTACT TACCGGCACAATTAC CACCATCGACATTGA
    CAACCTGAGTTACTA ACCGGCACAATTACT ACCATCGACATTGAG
    AACCTGAGTTACTAC CCGGCACAATTACTG CCATCGACATTGAGG
    ACCTGAGTTACTACA CGGCACAATTACTGC CATCGACATTGAGGA
    CCTGAGTTACTACAT GGCACAATTACTGCT ATCGACATTGAGGAG
    CTGAGTTACTACATT GCACAATTACTGCTC TCGACATTGAGGAGG
    TGAGTTACTACATTG CACAATTACTGCTCC CGACATTGAGGAGGT
    GAGTTACTACATTGT ACAATTACTGCTCCA GACATTGAGGAGGTC
    AGTTACTACATTGTG CAATTACTGCTCCAA ACATTGAGGAGGTCA
    GTTACTACATTGTGC AATTACTGCTCCAAA CATTGAGGAGGTCAC
    TTACTACATTGTGCG ATTACTGCTCCAAAG ATTGAGGAGGTCACA
    TACTACATTGTGCGC TTACTGCTCCAAAGA TTGAGGAGGTCACAG
    ACTACATTGTGCGCT TACTGCTCCAAAGAC TGAGGAGGTCACAGA
    CTACATTGTGCGCTG ACTGCTCCAAAGACA GAGGAGGTCACAGAG
    TACATTGTGCGCTGG CTGCTCCAAAGACAA AGGAGGTCACAGAGA
    ACATTGTGCGCTGGC TGCTCCAAAGACAAA GGAGGTCACAGAGAA
    CATTGTGCGCTGGCA GCTCCAAAGACAAAA GAGGTCACAGAGAAC
    ATTGTGCGCTGGCAG CTCCAAAGACAAAAT AGGTCACAGAGAACC
    TTGTGCGCTGGCAGC TCCAAAGACAAAATC GGTCACAGAGAACCC
    TGTGCGCTGGCAGCG CCAAAGACAAAATCC GTCACAGAGAACCCC
    GTGCGCTGGCAGCGG CAAAGACAAAATCCC TCACAGAGAACCCCA
    TGCGCTGGCAGCGGC AAAGACAAAATCCCC CACAGAGAACCCCAA
    GCGCTGGCAGCGGCA AAGACAAAATCCCCA ACAGAGAACCCCAAG
    CGCTGGCAGCGGCAG AGACAAAATCCCCAT CAGAGAACCCCAAGA
    GCTGGCAGCGGCAGC GACAAAATCCCCATC AGAGAACCCCAAGAC
    GAGAACCCCAAGACT CAAAACTGAAGCCGA TTGAGAATTTCCTGC
    AGAACCCCAAGACTG AAAACTGAAGCCGAG TGAGAATTTCCTGCA
    GAACCCCAAGACTGA AAACTGAAGCCGAGA GAGAATTTCCTGCAC
    AACCCCAAGACTGAG AACTGAAGCCGAGAA AGAATTTCCTGCACA
    ACCCCAAGACTGAGG ACTGAAGCCGAGAAG GAATTTCCTGCACAA
    CCCCAAGACTGAGGT CTGAAGCCGAGAAGC AATTTCCTGCACAAC
    CCCAAGACTGAGGTG TGAAGCCGAGAAGCA ATTTCCTGCACAACT
    CCAAGACTGAGGTGT GAAGCCGAGAAGCAG TTTCCTGCACAACTC
    CAAGACTGAGGTGTG AAGCCGAGAAGCAGG TTCCTGCACAACTCC
    AAGACTGAGGTGTGT AGCCGAGAAGCAGGC TCCTGCACAACTCCA
    AGACTGAGGTGTGTG GCCGAGAAGCAGGCC CCTGCACAACTCCAT
    GACTGAGGTGTGTGG CCGAGAAGCAGGCCG CTGCACAACTCCATC
    ACTGAGGTGTGTGGT CGAGAAGCAGGCCGA TGCACAACTCCATCT
    CTGAGGTGTGTGGTG GAGAAGCAGGCCGAG GCACAACTCCATCTT
    TGAGGTGTGTGGTGG AGAAGCAGGCCGAGA CACAACTCCATCTTC
    GAGGTGTGTGGTGGG GAAGCAGGCCGAGAA ACAACTCCATCTTCG
    AGGTGTGTGGTGGGG AAGCAGGCCGAGAAG CAACTCCATCTTCGT
    GGTGTGTGGTGGGGA AGCAGGCCGAGAAGG AACTCCATCTTCGTG
    GTGTGTGGTGGGGAG GCAGGCCGAGAAGGA ACTCCATCTTCGTGC
    TGTGTGGTGGGGAGA CAGGCCGAGAAGGAG CTCCATCTTCGTGCC
    GTGTGGTGGGGAGAA AGGCCGAGAAGGAGG TCCATCTTCGTGCCC
    TGTGGTGGGGAGAAA GGCCGAGAAGGAGGA CCATCTTCGTGCCCA
    GTGGTGGGGAGAAAG GCCGAGAAGGAGGAG CATCTTCGTGCCCAG
    TGGTGGGGAGAAAGG CCGAGAAGGAGGAGG ATCTTCGTGCCCAGA
    GGTGGGGAGAAAGGG CGAGAAGGAGGAGGC TCTTCGTGCCCAGAC
    GTGGGGAGAAAGGGC GAGAAGGAGGAGGCT CTTCGTGCCCAGACC
    TGGGGAGAAAGGGCC AGAAGGAGGAGGCTG TTCGTGCCCAGACCT
    GGGGAGAAAGGGCCT GAAGGAGGAGGCTGA TCGTGCCCAGACCTG
    GGGAGAAAGGGCCTT AAGGAGGAGGCTGAA CGTGCCCAGACCTGA
    GGAGAAAGGGCCTTG AGGAGGAGGCTGAAT GTGCCCAGACCTGAA
    GAGAAAGGGCCTTGC GGAGGAGGCTGAATA TGCCCAGACCTGAAA
    AGAAAGGGCCTTGCT GAGGAGGCTGAATAC GCCCAGACCTGAAAG
    GAAAGGGCCTTGCTG AGGAGGCTGAATACC CCCAGACCTGAAAGG
    AAAGGGCCTTGCTGC GGAGGCTGAATACCG CCAGACCTGAAAGGA
    AAGGGCCTTGCTGCG GAGGCTGAATACCGC CAGACCTGAAAGGAA
    AGGGCCTTGCTGCGC AGGCTGAATACCGCA AGACCTGAAAGGAAG
    GGGCCTTGCTGCGCC GGCTGAATACCGCAA GACCTGAAAGGAAGC
    GGCCTTGCTGCGCCT GCTGAATACCGCAAA ACCTGAAAGGAAGCG
    GCCTTGCTGCGCCTG CTGAATACCGCAAAG CCTGAAAGGAAGCGG
    CCTTGCTGCGCCTGC TGAATACCGCAAAGT CTGAAAGGAAGCGGA
    CTTGCTGCGCCTGCC GAATACCGCAAAGTC TGAAAGGAAGCGGAG
    TTGCTGCGCCTGCCC AATACCGCAAAGTCT GAAAGGAAGCGGAGA
    TGCTGCGCCTGCCCC ATACCGCAAAGTCTT AAAGGAAGCGGAGAG
    GCTGCGCCTGCCCCA TACCGCAAAGTCTTT AAGGAAGCGGAGAGA
    CTGCGCCTGCCCCAA ACCGCAAAGTCTTTG AGGAAGCGGAGAGAT
    TGCGCCTGCCCCAAA CCGCAAAGTCTTTGA GGAAGCGGAGAGATG
    GCGCCTGCCCCAAAA CGCAAAGTCTTTGAG GAAGCGGAGAGATGT
    CGCCTGCCCCAAAAC GCAAAGTCTTTGAGA AAGCGGAGAGATGTC
    GCCTGCCCCAAAACT CAAAGTCTTTGAGAA AGCGGAGAGATGTCA
    CCTGCCCCAAAACTG AAAGTCTTTGAGAAT GCGGAGAGATGTCAT
    CTGCCCCAAAACTGA AAGTCTTTGAGAATT CGGAGAGATGTCATG
    TGCCCCAAAACTGAA AGTCTTTGAGAATTT GGAGAGATGTCATGC
    GCCCCAAAACTGAAG GTCTTTGAGAATTTC GAGAGATGTCATGCA
    CCCCAAAACTGAAGC TCTTTGAGAATTTCC AGAGATGTCATGCAA
    CCCAAAACTGAAGCC CTTTGAGAATTTCCT GAGATGTCATGCAAG
    CCAAAACTGAAGCCG TTTGAGAATTTCCTG AGATGTCATGCAAGT
    GATGTCATGCAAGTG CGCAGACACCTACAA TTGAGAGCAGAGTGG
    ATGTCATGCAAGTGG GCAGACACCTACAAC TGAGAGCAGAGTGGA
    TGTCATGCAAGTGGC CAGACACCTACAACA GAGAGCAGAGTGGAT
    GTCATGCAAGTGGCC AGACACCTACAACAT AGAGCAGAGTGGATA
    TCATGCAAGTGGCCA GACACCTACAACATC GAGCAGAGTGGATAA
    CATGCAAGTGGCCAA ACACCTACAACATCA AGCAGAGTGGATAAC
    ATGCAAGTGGCCAAC CACCTACAACATCAC GCAGAGTGGATAACA
    TGCAAGTGGCCAACA ACCTACAACATCACC CAGAGTGGATAACAA
    GCAAGTGGCCAACAC CCTACAACATCACCG AGAGTGGATAACAAG
    CAAGTGGCCAACACC CTACAACATCACCGA GAGTGGATAACAAGG
    AAGTGGCCAACACCA TACAACATCACCGAC AGTGGATAACAAGGA
    AGTGGCCAACACCAC ACAACATCACCGACC GTGGATAACAAGGAG
    GTGGCCAACACCACC CAACATCACCGACCC TGGATAACAAGGAGA
    TGGCCAACACCACCA AACATCACCGACCCG GGATAACAAGGAGAG
    GGCCAACACCACCAT ACATCACCGACCCGG GATAACAAGGAGAGA
    GCCAACACCACCATG CATCACCGACCCGGA ATAACAAGGAGAGAA
    CCAACACCACCATGT ATCACCGACCCGGAA TAACAAGGAGAGAAC
    CAACACCACCATGTC TCACCGACCCGGAAG AACAAGGAGAGAACT
    AACACCACCATGTCC CACCGACCCGGAAGA ACAAGGAGAGAACTG
    ACACCACCATGTCCA ACCGACCCGGAAGAG CAAGGAGAGAACTGT
    CACCACCATGTCCAG CCGACCCGGAAGAGC AAGGAGAGAACTGTC
    ACCACCATGTCCAGC CGACCCGGAAGAGCT AGGAGAGAACTGTCA
    CCACCATGTCCAGCC GACCCGGAAGAGCTG GGAGAGAACTGTCAT
    CACCATGTCCAGCCG ACCCGGAAGAGCTGG GAGAGAACTGTCATT
    ACCATGTCCAGCCGA CCCGGAAGAGCTGGA AGAGAACTGTCATTT
    CCATGTCCAGCCGAA CCGGAAGAGCTGGAG GAGAACTGTCATTTC
    CATGTCCAGCCGAAG CGGAAGAGCTGGAGA AGAACTGTCATTTCT
    ATGTCCAGCCGAAGC GGAAGAGCTGGAGAC GAACTGTCATTTCTA
    TGTCCAGCCGAAGCA GAAGAGCTGGAGACA AACTGTCATTTCTAA
    GTCCAGCCGAAGCAG AAGAGCTGGAGACAG ACTGTCATTTCTAAC
    TCCAGCCGAAGCAGG AGAGCTGGAGACAGA CTGTCATTTCTAACC
    CCAGCCGAAGCAGGA GAGCTGGAGACAGAG TGTCATTTCTAACCT
    CAGCCGAAGCAGGAA AGCTGGAGACAGAGT GTCATTTCTAACCTT
    AGCCGAAGCAGGAAC GCTGGAGACAGAGTA TCATTTCTAACCTTC
    GCCGAAGCAGGAACA CTGGAGACAGAGTAC CATTTCTAACCTTCG
    CCGAAGCAGGAACAC TGGAGACAGAGTACC ATTTCTAACCTTCGG
    CGAAGCAGGAACACC GGAGACAGAGTACCC TTTCTAACCTTCGGC
    GAAGCAGGAACACCA GAGACAGAGTACCCT TTCTAACCTTCGGCC
    AAGCAGGAACACCAC AGACAGAGTACCCTT TCTAACCTTCGGCCT
    AGCAGGAACACCACG GACAGAGTACCCTTT CTAACCTTCGGCCTT
    GCAGGAACACCACGG ACAGAGTACCCTTTC TAACCTTCGGCCTTT
    CAGGAACACCACGGC CAGAGTACCCTTTCT AACCTTCGGCCTTTC
    AGGAACACCACGGCC AGAGTACCCTTTCTT ACCTTCGGCCTTTCA
    GGAACACCACGGCCG GAGTACCCTTTCTTT CCTTCGGCCTTTCAC
    GAACACCACGGCCGC AGTACCCTTTCTTTG CTTCGGCCTTTCACA
    AACACCACGGCCGCA GTACCCTTTCTTTGA TTCGGCCTTTCACAT
    ACACCACGGCCGCAG TACCCTTTCTTTGAG TCGGCCTTTCACATT
    CACCACGGCCGCAGA ACCCTTTCTTTGAGA CGGCCTTTCACATTG
    ACCACGGCCGCAGAC CCCTTTCTTTGAGAG GGCCTTTCACATTGT
    CCACGGCCGCAGACA CCTTTCTTTGAGAGC GCCTTTCACATTGTA
    CACGGCCGCAGACAC CTTTCTTTGAGAGCA CCTTTCACATTGTAC
    ACGGCCGCAGACACC TTTCTTTGAGAGCAG CTTTCACATTGTACC
    CGGCCGCAGACACCT TTCTTTGAGAGCAGA TTTCACATTGTACCG
    GGCCGCAGACACCTA TCTTTGAGAGCAGAG TTCACATTGTACCGC
    GCCGCAGACACCTAC CTTTGAGAGCAGAGT TCACATTGTACCGCA
    CCGCAGACACCTACA TTTGAGAGCAGAGTG CACATTGTACCGCAT
    ACATTGTACCGCATC CAGCGCCTCCAACTT TTCCTGGGCCAGTGA
    CATTGTACCGCATCG AGCGCCTCCAACTTC TCCTGGGCCAGTGAC
    ATTGTACCGCATCGA GCGCCTCCAACTTCG CCTGGGCCAGTGACC
    TTGTACCGCATCGAT CGCCTCCAACTTCGT CTGGGCCAGTGACCT
    TGTACCGCATCGATA GCCTCCAACTTCGTC TGGGCCAGTGACCTG
    GTACCGCATCGATAT CCTCCAACTTCGTCT GGGCCAGTGACCTGG
    TACCGCATCGATATC CTCCAACTTCGTCTT GGCCAGTGACCTGGG
    ACCGCATCGATATCC TCCAACTTCGTCTTT GCCAGTGACCTGGGA
    CCGCATCGATATCCA CCAACTTCGTCTTTG CCAGTGACCTGGGAG
    CGCATCGATATCCAC CAACTTCGTCTTTGC CAGTGACCTGGGAGC
    GCATCGATATCCACA AACTTCGTCTTTGCA AGTGACCTGGGAGCC
    CATCGATATCCACAG ACTTCGTCTTTGCAA GTGACCTGGGAGCCA
    ATCGATATCCACAGC CTTCGTCTTTGCAAG TGACCTGGGAGCCAA
    TCGATATCCACAGCT TTCGTCTTTGCAAGG GACCTGGGAGCCAAG
    CGATATCCACAGCTG TCGTCTTTGCAAGGA ACCTGGGAGCCAAGG
    GATATCCACAGCTGC CGTCTTTGCAAGGAC CCTGGGAGCCAAGGC
    ATATCCACAGCTGCA GTCTTTGCAAGGACT CTGGGAGCCAAGGCC
    TATCCACAGCTGCAA TCTTTGCAAGGACTA TGGGAGCCAAGGCCT
    ATCCACAGCTGCAAC CTTTGCAAGGACTAT GGGAGCCAAGGCCTG
    TCCACAGCTGCAACC TTTGCAAGGACTATG GGAGCCAAGGCCTGA
    CCACAGCTGCAACCA TTGCAAGGACTATGC GAGCCAAGGCCTGAA
    CACAGCTGCAACCAC TGCAAGGACTATGCC AGCCAAGGCCTGAAA
    ACAGCTGCAACCACG GCAAGGACTATGCCC GCCAAGGCCTGAAAA
    CAGCTGCAACCACGA CAAGGACTATGCCCG CCAAGGCCTGAAAAC
    AGCTGCAACCACGAG AAGGACTATGCCCGC CAAGGCCTGAAAACT
    GCTGCAACCACGAGG AGGACTATGCCCGCA AAGGCCTGAAAACTC
    CTGCAACCACGAGGC GGACTATGCCCGCAG AGGCCTGAAAACTCC
    TGCAACCACGAGGCT GACTATGCCCGCAGA GGCCTGAAAACTCCA
    GCAACCACGAGGCTG ACTATGCCCGCAGAA GCCTGAAAACTCCAT
    CAACCACGAGGCTGA CTATGCCCGCAGAAG CCTGAAAACTCCATC
    AACCACGAGGCTGAG TATGCCCGCAGAAGG CTGAAAACTCCATCT
    ACCACGAGGCTGAGA ATGCCCGCAGAAGGA TGAAAACTCCATCTT
    CCACGAGGCTGAGAA TGCCCGCAGAAGGAG GAAAACTCCATCTTT
    CACGAGGCTGAGAAG GCCCGCAGAAGGAGC AAAACTCCATCTTTT
    ACGAGGCTGAGAAGC CCCGCAGAAGGAGCA AAACTCCATCTTTTT
    CGAGGCTGAGAAGCT CCGCAGAAGGAGCAG AACTCCATCTTTTTA
    GAGGCTGAGAAGCTG CGCAGAAGGAGCAGA ACTCCATCTTTTTAA
    AGGCTGAGAAGCTGG GCAGAAGGAGCAGAT CTCCATCTTTTTAAA
    GGCTGAGAAGCTGGG CAGAAGGAGCAGATG TCCATCTTTTTAAAG
    GCTGAGAAGCTGGGC AGAAGGAGCAGATGA CCATCTTTTTAAAGT
    CTGAGAAGCTGGGCT GAAGGAGCAGATGAC CATCTTTTTAAAGTG
    TGAGAAGCTGGGCTG AAGGAGCAGATGACA ATCTTTTTAAAGTGG
    GAGAAGCTGGGCTGC AGGAGCAGATGACAT TCTTTTTAAAGTGGC
    AGAAGCTGGGCTGCA GGAGCAGATGACATT CTTTTTAAAGTGGCC
    GAAGCTGGGCTGCAG GAGCAGATGACATTC TTTTTAAAGTGGCCG
    AAGCTGGGCTGCAGC AGCAGATGACATTCC TTTTAAAGTGGCCGG
    AGCTGGGCTGCAGCG GCAGATGACATTCCT TTTAAAGTGGCCGGA
    GCTGGGCTGCAGCGC CAGATGACATTCCTG TTAAAGTGGCCGGAA
    CTGGGCTGCAGCGCC AGATGACATTCCTGG TAAAGTGGCCGGAAC
    TGGGCTGCAGCGCCT GATGACATTCCTGGG AAAGTGGCCGGAACC
    GGGCTGCAGCGCCTC ATGACATTCCTGGGC AAGTGGCCGGAACCT
    GGCTGCAGCGCCTCC TGACATTCCTGGGCC AGTGGCCGGAACCTG
    GCTGCAGCGCCTCCA GACATTCCTGGGCCA GTGGCCGGAACCTGA
    CTGCAGCGCCTCCAA ACATTCCTGGGCCAG TGGCCGGAACCTGAG
    TGCAGCGCCTCCAAC CATTCCTGGGCCAGT GGCCGGAACCTGAGA
    GCAGCGCCTCCAACT ATTCCTGGGCCAGTG GCCGGAACCTGAGAA
    CCGGAACCTGAGAAT ACAAGTTGAGGATCA GGGCCAAGCTAAACC
    CGGAACCTGAGAATC CAAGTTGAGGATCAG GGCCAAGCTAAACCG
    GGAACCTGAGAATCC AAGTTGAGGATCAGC GCCAAGCTAAACCGG
    GAACCTGAGAATCCC AGTTGAGGATCAGCG CCAAGCTAAACCGGC
    AACCTGAGAATCCCA GTTGAGGATCAGCGA CAAGCTAAACCGGCT
    ACCTGAGAATCCCAA TTGAGGATCAGCGAG AAGCTAAACCGGCTA
    CCTGAGAATCCCAAT TGAGGATCAGCGAGA AGCTAAACCGGCTAA
    CTGAGAATCCCAATG GAGGATCAGCGAGAA GCTAAACCGGCTAAA
    TGAGAATCCCAATGG AGGATCAGCGAGAAT CTAAACCGGCTAAAC
    GAGAATCCCAATGGA GGATCAGCGAGAATG TAAACCGGCTAAACC
    AGAATCCCAATGGAT GATCAGCGAGAATGT AAACCGGCTAAACCC
    GAATCCCAATGGATT ATCAGCGAGAATGTG AACCGGCTAAACCCG
    AATCCCAATGGATTG TCAGCGAGAATGTGT ACCGGCTAAACCCGG
    ATCCCAATGGATTGA CAGCGAGAATGTGTG CCGGCTAAACCCGGG
    TCCCAATGGATTGAT AGCGAGAATGTGTGT CGGCTAAACCCGGGG
    CCCAATGGATTGATT GCGAGAATGTGTGTC GGCTAAACCCGGGGA
    CCAATGGATTGATTC CGAGAATGTGTGTCC GCTAAACCCGGGGAA
    CAATGGATTGATTCT GAGAATGTGTGTCCA CTAAACCCGGGGAAC
    AATGGATTGATTCTA AGAATGTGTGTCCAG TAAACCCGGGGAACT
    ATGGATTGATTCTAA GAATGTGTGTCCAGA AAACCCGGGGAACTA
    TGGATTGATTCTAAT AATGTGTGTCCAGAC AACCCGGGGAACTAC
    GGATTGATTCTAATG ATGTGTGTCCAGACA ACCCGGGGAACTACA
    GATTGATTCTAATGT TGTGTGTCCAGACAG CCCGGGGAACTACAC
    ATTGATTCTAATGTA GTGTGTCCAGACAGG CCGGGGAACTACACA
    TTGATTCTAATGTAT TGTGTCCAGACAGGA CGGGGAACTACACAG
    TGATTCTAATGTATG GTGTCCAGACAGGAA GGGGAACTACACAGC
    GATTCTAATGTATGA TGTCCAGACAGGAAT GGGAACTACACAGCC
    ATTCTAATGTATGAA GTCCAGACAGGAATA GGAACTACACAGCCC
    TTCTAATGTATGAAA TCCAGACAGGAATAC GAACTACACAGCCCG
    TCTAATGTATGAAAT CCAGACAGGAATACA AACTACACAGCCCGG
    CTAATGTATGAAATA CAGACAGGAATACAG ACTACACAGCCCGGA
    TAATGTATGAAATAA AGACAGGAATACAGG CTACACAGCCCGGAT
    AATGTATGAAATAAA GACAGGAATACAGGA TACACAGCCCGGATT
    ATGTATGAAATAAAA ACAGGAATACAGGAA ACACAGCCCGGATTC
    TGTATGAAATAAAAT CAGGAATACAGGAAG CACAGCCCGGATTCA
    GTATGAAATAAAATA AGGAATACAGGAAGT ACAGCCCGGATTCAG
    TATGAAATAAAATAC GGAATACAGGAAGTA CAGCCCGGATTCAGG
    ATGAAATAAAATACG GAATACAGGAAGTAT AGCCCGGATTCAGGC
    TGAAATAAAATACGG AATACAGGAAGTATG GCCCGGATTCAGGCC
    GAAATAAAATACGGA ATACAGGAAGTATGG CCCGGATTCAGGCCA
    AAATAAAATACGGAT TACAGGAAGTATGGA CCGGATTCAGGCCAC
    AATAAAATACGGATC ACAGGAAGTATGGAG CGGATTCAGGCCACA
    ATAAAATACGGATCA CAGGAAGTATGGAGG GGATTCAGGCCACAT
    TAAAATACGGATCAC AGGAAGTATGGAGGG GATTCAGGCCACATC
    AAAATACGGATCACA GGAAGTATGGAGGGG ATTCAGGCCACATCT
    AAATACGGATCACAA GAAGTATGGAGGGGC TTCAGGCCACATCTC
    AATACGGATCACAAG AAGTATGGAGGGGCC TCAGGCCACATCTCT
    ATACGGATCACAAGT AGTATGGAGGGGCCA CAGGCCACATCTCTC
    TACGGATCACAAGTT GTATGGAGGGGCCAA AGGCCACATCTCTCT
    ACGGATCACAAGTTG TATGGAGGGGCCAAG GGCCACATCTCTCTC
    CGGATCACAAGTTGA ATGGAGGGGCCAAGC GCCACATCTCTCTCT
    GGATCACAAGTTGAG TGGAGGGGCCAAGCT CCACATCTCTCTCTG
    GATCACAAGTTGAGG GGAGGGGCCAAGCTA CACATCTCTCTCTGG
    ATCACAAGTTGAGGA GAGGGGCCAAGCTAA ACATCTCTCTCTGGG
    TCACAAGTTGAGGAT AGGGGCCAAGCTAAA CATCTCTCTCTGGGA
    CACAAGTTGAGGATC GGGGCCAAGCTAAAC ATCTCTCTCTGGGAA
    TCTCTCTCTGGGAAT AACAGGATATGAAAA TGATCGTGGGAGGGT
    CTCTCTCTGGGAATG ACAGGATATGAAAAC GATCGTGGGAGGGTT
    TCTCTCTGGGAATGG CAGGATATGAAAACT ATCGTGGGAGGGTTG
    CTCTCTGGGAATGGG AGGATATGAAAACTT TCGTGGGAGGGTTGG
    TCTCTGGGAATGGGT GGATATGAAAACTTC CGTGGGAGGGTTGGT
    CTCTGGGAATGGGTC GATATGAAAACTTCA GTGGGAGGGTTGGTG
    TCTGGGAATGGGTCG ATATGAAAACTTCAT TGGGAGGGTTGGTGA
    CTGGGAATGGGTCGT TATGAAAACTTCATC GGGAGGGTTGGTGAT
    TGGGAATGGGTCGTG ATGAAAACTTCATCC GGAGGGTTGGTGATT
    GGGAATGGGTCGTGG TGAAAACTTCATCCA GAGGGTTGGTGATTA
    GGAATGGGTCGTGGA GAAAACTTCATCCAT AGGGTTGGTGATTAT
    GAATGGGTCGTGGAC AAAACTTCATCCATC GGGTTGGTGATTATG
    AATGGGTCGTGGACA AAACTTCATCCATCT GGTTGGTGATTATGC
    ATGGGTCGTGGACAG AACTTCATCCATCTG GTTGGTGATTATGCT
    TGGGTCGTGGACAGA ACTTCATCCATCTGA TTGGTGATTATGCTG
    GGGTCGTGGACAGAT CTTCATCCATCTGAT TGGTGATTATGCTGT
    GGTCGTGGACAGATC TTCATCCATCTGATC GGTGATTATGCTGTA
    GTCGTGGACAGATCC TCATCCATCTGATCA GTGATTATGCTGTAC
    TCGTGGACAGATCCT CATCCATCTGATCAT TGATTATGCTGTACG
    CGTGGACAGATCCTG ATCCATCTGATCATC GATTATGCTGTACGT
    GTGGACAGATCCTGT TCCATCTGATCATCG ATTATGCTGTACGTC
    TGGACAGATCCTGTG CCATCTGATCATCGC TTATGCTGTACGTCT
    GGACAGATCCTGTGT CATCTGATCATCGCT TATGCTGTACGTCTT
    GACAGATCCTGTGTT ATCTGATCATCGCTC ATGCTGTACGTCTTC
    ACAGATCCTGTGTTC TCTGATCATCGCTCT TGCTGTACGTCTTCC
    CAGATCCTGTGTTCT CTGATCATCGCTCTG GCTGTACGTCTTCCA
    AGATCCTGTGTTCTT TGATCATCGCTCTGC CTGTACGTCTTCCAT
    GATCCTGTGTTCTTC GATCATCGCTCTGCC TGTACGTCTTCCATA
    ATCCTGTGTTCTTCT ATCATCGCTCTGCCC GTACGTCTTCCATAG
    TCCTGTGTTCTTCTA TCATCGCTCTGCCCG TACGTCTTCCATAGA
    CCTGTGTTCTTCTAT CATCGCTCTGCCCGT ACGTCTTCCATAGAA
    CTGTGTTCTTCTATG ATCGCTCTGCCCGTC CGTCTTCCATAGAAA
    TGTGTTCTTCTATGT TCGCTCTGCCCGTCG GTCTTCCATAGAAAG
    GTGTTCTTCTATGTC CGCTCTGCCCGTCGC TCTTCCATAGAAAGA
    TGTTCTTCTATGTCC GCTCTGCCCGTCGCT CTTCCATAGAAAGAG
    GTTCTTCTATGTCCA CTCTGCCCGTCGCTG TTCCATAGAAAGAGA
    TTCTTCTATGTCCAG TCTGCCCGTCGCTGT TCCATAGAAAGAGAA
    TCTTCTATGTCCAGG CTGCCCGTCGCTGTC CCATAGAAAGAGAAA
    CTTCTATGTCCAGGC TGCCCGTCGCTGTCC CATAGAAAGAGAAAT
    TTCTATGTCCAGGCC GCCCGTCGCTGTCCT ATAGAAAGAGAAATA
    TCTATGTCCAGGCCA CCCGTCGCTGTCCTG TAGAAAGAGAAATAA
    CTATGTCCAGGCCAA CCGTCGCTGTCCTGT AGAAAGAGAAATAAC
    TATGTCCAGGCCAAA CGTCGCTGTCCTGTT GAAAGAGAAATAACA
    ATGTCCAGGCCAAAA GTCGCTGTUCTGTTG AAAGAGAAATAACAG
    TGTCCAGGCCAAAAC TCGCTGTCCTGTTGA AAGAGAAATAACAGC
    GTCCAGGCCAAAACA CGCTGTCCTGTTGAT AGAGAAATAACAGCA
    TCCAGGCCAAAACAG GCTGTCCTGTTGATC GAGAAATAACAGCAG
    CCAGGCCAAAACAGG CTGTCCTGTTGATCG AGAAATAACAGCAGG
    CAGGCCAAAACAGGA TGTCCTGTTGATCGT GAAATAACAGCAGGC
    AGGCCAAAACAGGAT GTCCTGTTGATCGTG AAATAACAGCAGGCT
    GGCCAAAACAGGATA TCCTGTTGATCGTGG AATAACAGCAGGCTG
    GCCAAAACAGGATAT CCTGTTGATCGTGGG ATAACAGCAGGCTGG
    CCAAAACAGGATATG CTGTTGATCGTGGGA TAACAGCAGGCTGGG
    CAAAACAGGATATGA TGTTGATCGTGGGAG AACAGCAGGCTGGGG
    AAAACAGGATATGAA GTTGATCGTGGGAGG ACAGCAGGCTGGGGA
    AAACAGGATATGAAA TTGATCGTGGGAGGG CAGCAGGCTGGGGAA
    AGCAGGCTGGGGAAT TGCTGATGTGTACGT GCCGGGAACTTGGGC
    GCAGGCTGGGGAATG GCTGATGTGTACGTT CCGGGAACTTGGGCA
    CAGGCTGGGCAATGG CTGATGTGTACGTTC CGGGAACTTGGGCAG
    AGGCTGGGGAATGGA TGATGTGTACGTTCC GGGAACTTGGGCAGG
    GGCTGGGGAATGGAG GATGTGTACGTTCCT GGAACTTGGGCAGGG
    GCTGGGGAATGGAGT ATGTGTACGTTCCTG GAACTTGGGCAGGGG
    CTGGGGAATGGAGTG TGTGTACGTTCCTGA AACTTGGGCAGGGGT
    TGGGGAATGGAGTGC GTGTACGTTCCTGAT ACTTGGGCAGGGGTC
    GGGGAATGGAGTGCT TGTACGTTCCTGATG CTTGGGCAGGGGTCG
    GGGAATGGAGTGCTG GTACGTTCCTGATGA TTGGGCAGGGGTCGT
    GGAATGGAGTGCTGT TACGTTCCTGATGAG TGGGCAGGGGTCGTT
    GAATGGAGTGCTGTA ACGTTCCTGATGAGT GGGCAGGGGTCGTTT
    AATGGAGTGCTGTAT CGTTCCTGATGAGTG GGCAGGGGTCGTTTG
    ATGGAGTGCTGTATG GTTCCTGATGAGTGG GCAGGGGTCGTTTGG
    TGGAGTGCTGTATGC TTCCTGATGAGTGGG CAGGGGTCGTTTGGG
    GGAGTGCTGTATGCC TCCTGATGAGTGGGA AGGGGTCGTTTGGGA
    GAGTGCTGTATGCCT CCTGATGAGTGGGAG GGGGTCGTTTGGGAT
    AGTGCTGTATGCCTC CTGATGAGTGGGAGG GGGTCGTTTGGGATG
    GTGCTGTATGCCTCT TGATGAGTGGGAGGT GGTCGTTTGGGATGG
    TGCTGTATGCCTCTG GATGAGTGGGAGGTG GTCGTTTGGGATGGT
    GCTGTATGCCTCTGT ATGAGTGGGAGGTGG TCGTTTGGGATGGTC
    CTGTATGCCTCTGTG TGAGTGGGAGGTGGC CGTTTGGGATGGTCT
    TGTATGCCTCTGTGA GAGTGGGAGGTGGCT GTTTGGGATGGTCTA
    GTATGCCTCTGTGAA AGTGGGAGGTGGCTC TTTGGGATGGTCTAT
    TATGCCTCTGTGAAC GTGGGAGGTGGCTCG TTGGGATGGTCTATG
    ATGCCTCTGTGAACC TGGGAGGTGGCTCGG TGGGATGGTCTATGA
    TGCCTCTGTGAACCC GGGAGGTGGCTCGGG GGGATGGTCTATGAA
    GCCTCTGTGAACCCG GGAGGTGGCTCGGGA GGATGGTCTATGAAG
    CCTCTGTGAACCCGG GAGGTGGCTCGGGAG GATGGTCTATGAAGG
    CTCTGTGAACCCGGA AGGTGGCTCGGGAGA ATGGTCTATGAAGGA
    TCTGTGAACCCGGAG GGTGGCTCGGGAGAA TGGTCTATGAAGGAG
    CTGTGAACCCGGAGT GTGGCTCGGGAGAAG GGTCTATGAAGGAGT
    TGTGAACCCGGAGTA TGGCTCGGGAGAAGA GTCTATGAAGGAGTT
    GTGAACCCGGAGTAC GGCTCGGGAGAAGAT TCTATGAAGGAGTTG
    TGAACCCGGAGTACT GCTCGGGAGAAGATC CTATGAAGGAGTTGC
    GAACCCGGAGTACTT CTCGGGAGAAGATCA TATGAAGGAGTTGCC
    AACCCGGAGTACTTC TCGGGAGAAGATCAC ATGAAGGAGTTGCCA
    ACCCGGAGTACTTCA CGGGAGAAGATCACC TGAAGGAGTTGCCAA
    CCCGGAGTACTTCAG GGGAGAAGATCACCA GAAGGAGTTGCCAAG
    CCGGAGTACTTCAGC GGAGAAGATCACCAT AAGGAGTTGCCAAGG
    CGGAGTACTTCAGCG GAGAAGATCACCATG AGGAGTTGCCAAGGG
    GGAGTACTTCAGCGC AGAAGATCACCATGA GGAGTTGCCAAGGGT
    GAGTACTTCAGCGCT GAAGATCACCATGAG GAGTTGCCAAGGGTG
    AGTACTTCAGCGCTG AAGATCACCATGAGC AGTTGCCAAGGGTGT
    GTACTTCAGCGCTGC AGATCACCATGAGCC GTTGCCAAGGGTGTG
    TACTTCAGCGCTGCT GATCACCATGAGCCG TTGCCAAGGGTGTGG
    ACTTCAGCGCTGCTG ATCACCATGAGCCGG TGCCAAGGGTGTGGT
    CTTCAGCGCTGCTGA TCACCATGAGCCGGG GCCAAGGGTGTGGTG
    TTCAGCGCTGCTGAT CACCATGAGCCGGGA CCAAGGGTGTGGTGA
    TCAGCGCTGCTGATG ACCATGAGCCGGGAA CAAGGGTGTGGTGAA
    CAGCGCTGCTGATGT CCATGAGCCGGGAAC AAGGGTGTGGTGAAA
    AGCGCTGCTGATGTG CATGAGCCGGGAACT AGGGTGTGGTGAAAG
    GCGCTGCTGATGTGT ATGAGCCGGGAACTT GGGTGTGGTGAAAGA
    CGCTGCTGATGTGTA TGAGCCGGGAACTTG GGTGTGGTGAAAGAT
    GCTGCTGATGTGTAC GAGCCGGGAACTTGG GTGTGGTGAAAGATG
    CTGCTGATGTGTACG AGCCGGGAACTTGGG TGTGGTGAAAGATGA
    GTGGTGAAAGATCAA AAGCATGCGTGAGAG ATTGTCACCATGTGG
    TGGTGAAAGATGAAC AGCATGCGTGAGAGG TTGTCACCATGTGGT
    GGTGAAAGATGAACC GCATGCGTGAGAGGA TGTCACCATGTGGTG
    GTGAAAGATGAACCT CATGCGTGAGAGGAT GTCACCATGTGGTGC
    TGAAAGATGAACCTG ATGCGTGAGAGGATT TCACCATGTGGTGCG
    GAAAGATGAACCTGA TGCGTGAGAGGATTG CACCATGTGGTGCGA
    AAAGATGAACCTGAA GCGTGAGAGGATTGA ACCATGTGGTGCGAT
    AAGATGAACCTGAAA CGTGAGAGGATTGAG CCATGTGGTGCGATT
    AGATGAACCTGAAAC GTGAGAGGATTGAGT CATGTGGTGCGATTG
    GATGAACCTGAAACC TGAGAGGATTGAGTT ATGTGGTGCGATTGC
    ATGAACCTGAAACCA GAGAGGATTGAGTTT TGTGGTGCGATTGCT
    TGAACCTGAAACCAG AGAGGATTGAGTTTC GTGGTGCGATTGCTG
    GAACCTGAAACCAGA GAGGATTGAGTTTCT TGGTGCGATTGCTGG
    AACCTGAAACCAGAG AGGATTGAGTTTCTC GGTGCGATTGCTGGG
    ACCTGAAACCAGAGT GGATTGAGTTTCTCA GTGCGATTGCTGGGT
    CCTGAAACCAGAGTG GATTGAGTTTCTCAA TGCGATTGCTGGGTG
    CTGAAACCAGAGTGG ATTGAGTTTCTCAAC GCGATTGCTGGGTGT
    TGAAACCAGAGTGGC TTGAGTTTCTCAACG CGATTGCTGGGTGTG
    GAAACCAGAGTGGCC TGAGTTTCTCAACGA GATTGCTGGGTGTGG
    AAACCAGAGTGGCCA GAGTTTCTCAACGAA ATTGCTGGGTGTGGT
    AACCAGAGTGGCCAT AGTTTCTCAACGAAG TTGCTGGGTGTGGTG
    ACCAGAGTGGCCATT GTTTCTCAACGAAGC TGCTGGGTGTGGTGT
    CCAGAGTGGCCATTA TTTCTCAACGAAGCT GCTGGGTGTGGTGTC
    CAGAGTGGCCATTAA TTCTCAACGAAGCTT CTGGGTGTGGTGTCC
    AGAGTGGCCATTAAA TCTCAACGAAGCTTC TGGGTGTGGTGTCCC
    GAGTGGCCATTAAAA CTCAACGAAGCTTCT GGGTGTGGTGTCCCA
    AGTGGCCATTAAAAC TCAACGAAGCTTCTG GGTGTGGTGTCCCAA
    GTGGCCATTAAAACA CAACGAAGCTTCTGT GTGTGGTGTCCCAAG
    TGGCCATTAAAACAG AACGAAGCTTCTGTG TGTGGTGTCCCAAGG
    GGCCATTAAAACAGT ACGAAGCTTCTGTGA GTGGTGTCCCAAGGC
    GCCATTAAAACAGTG CGAAGCTTCTGTGAT TGGTGTCCCAAGGCC
    CCATTAAAACAGTGA GAAGCTTCTGTGATG GGTGTCCCAAGGCCA
    CATTAAAACAGTGAA AAGCTTCTGTGATGA GTGTCCCAAGGCCAG
    ATTAAAACAGTGAAC AGCTTCTGTGATGAA TGTCCCAAGGCCAGC
    TTAAAACAGTGAACG GCTTCTGTGATGAAG GTCCCAAGGCCAGCC
    TAAAACAGTGAACGA CTTCTGTGATGAAGG TCCCAAGGCCAGCCA
    AAAACAGTGAACGAG TTCTGTGATGAAGGA CCCAAGGCCAGCCAA
    AAACAGTGAACGAGG TCTGTGATGAAGGAG CCAAGGCCAGCCAAC
    AACAGTGAACGAGGC CTGTGATGAAGGAGT CAAGGCCAGCCAACA
    ACAGTGAACGAGGCC TGTGATGAAGGAGTT AAGGCCAGCCAACAC
    CAGTGAACGAGGCCG GTGATGAAGGAGTTC AGGCCAGCCAACACT
    AGTGAACGAGGCCGC TGATGAAGGAGTTCA GGCCAGCCAACACTG
    GTGAACGAGGCCGCA GATGAAGGAGTTCAA GCCAGCCAACACTGG
    TGAACGAGGCCGCAA ATGAAGGAGTTCAAT CCAGCCAACACTGGT
    GAACGAGGCCGCAAG TGAAGGAGTTCAATT CAGCCAACACTGGTC
    AACGAGGCCGCAAGC GAAGGAGTTCAATTG AGCCAACACTGGTCA
    ACGAGGCCGCAAGCA AAGGAGTTCAATTGT GCCAACACTGGTCAT
    CGAGGCCGCAAGCAT AGGAGTTCAATTGTC CCAACACTGGTCATC
    GAGGCCGCAAGCATG GGAGTTCAATTGTCA CAACACTGGTCATCA
    AGGCCGCAAGCATGC GAGTTCAATTGTCAC AACACTGGTCATCAT
    GGCCGCAAGCATGCG AGTTCAATTGTCACC ACACTGGTCATCATG
    GCCGCAAGCATGCGT GTTCAATTGTCACCA CACTGGTCATCATGG
    CCGCAAGCATGCGTG TTCAATTGTCACCAT ACTGGTCATCATGGA
    CGCAAGCATGCGTGA TCAATTGTCACCATG CTGGTCATCATGGAA
    GCAAGCATGCGTGAG CAATTGTCACCATGT TGGTCATCATGGAAC
    CAAGCATGCGTGAGA AATTGTCACCATGTG GGTCATCATGGAACT
    GTCATCATGGAACTG GCCAGAAATGGAGAA AGATGGCCGGAGAGA
    TCATCATGGAACTGA CCAGAAATGGAGAAT GATGGCCGGAGAGAT
    CATCATGGAACTGAT CAGAAATGGAGAATA ATGGCCGGAGAGATT
    ATCATGGAACTGATG AGAAATGGAGAATAA TGGCCGGAGAGATTG
    TCATGGAACTGATGA GAAATGGAGAATAAT GGCCGGAGAGATTGC
    CATGGAACTGATGAC AAATGGAGAATAATC GCCGGAGAGATTGCA
    ATGGAACTGATGACA AATGGAGAATAATCC CCGGAGAGATTGCAG
    TGGAACTGATGACAC ATGGAGAATAATCCA CGGAGAGATTGCAGA
    GGAACTGATGACACG TGGAGAATAATCCAG GGAGAGATTGCAGAC
    GAACTGATGACACGG GGAGAATAATCCAGT GAGAGATTGCAGACG
    AACTGATGACACGGG GAGAATAATCCAGTC AGAGATTGCAGACGG
    ACTGATGACACGGGG AGAATAATCCAGTCC GAGATTGCAGACGGC
    CTGATGACACGGGGC GAATAATCCAGTCCT AGATTGCAGACGGCA
    TGATGACACGGGGCG AATAATCCAGTCCTA GATTGCAGACGGCAT
    GATGACACGGGGCGA ATAATCCAGTCCTAG ATTGCAGACGGCATG
    ATGACACGGGGCGAT TAATCCAGTCCTAGC TTGCAGACGGCATGG
    TGACACGGGGCGATC AATCCAGTCCTAGCA TGCAGACGGCATGGC
    GACACGGGGCGATCT ATCCAGTCCTAGCAC GCAGACGGCATGGCA
    ACACGGGGCGATCTC TCCAGTCCTAGCACC CAGACGGCATGGCAT
    CACGGGGCGATCTCA CCAGTCCTAGCACCT AGACGGCATGGCATA
    ACGGGGCGATCTCAA CAGTCCTAGCACCTC GACGGCATGGCATAC
    CGGGGCGATCTCAAA AGTCCTAGCACCTCC ACGGCATGGCATACC
    GGGGCGATCTCAAAA GTCCTAGCACCTCCA CGGCATGGCATACCT
    GGGCGATCTCAAAAG TCCTAGCACCTCCAA GGCATGGCATACCTC
    GGCGATCTCAAAAGT CCTAGCACCTCCAAG GCATGGCATACCTCA
    GCGATCTCAAAAGTT CTAGCACCTCCAAGC CATGGCATACCTCAA
    CGATCTCAAAAGTTA TAGCACCTCCAAGCC ATGGCATACCTCAAC
    GATCTCAAAAGTTAT AGCACCTCCAAGCCT TGGCATACCTCAACG
    ATCTCAAAAGTTATC GCACCTCCAAGCCTG GGCATACCTCAACGC
    TCTCAAAAGTTATCT CACCTCCAAGCCTGA GCATACCTCAACGCC
    CTCAAAAGTTATCTC ACCTCCAAGCCTGAG CATACCTCAACGCCA
    TCAAAAGTTATCTCC CCTCCAAGCCTGAGC ATACCTCAACGCCAA
    CAAAAGTTATCTCCG CTCCAAGCCTGAGCA TACCTCAACGCCAAT
    AAAAGTTATCTCCGG TCCAAGCCTGAGCAA ACCTCAACGCCAATA
    AAAGTTATCTCCGGT CCAAGCCTGAGCAAG CCTCAACGCCAATAA
    AAGTTATCTCCGGTC CAAGCCTGAGCAAGA CTCAACGCCAATAAG
    AGTTATCTCCGGTCT AAGCCTGAGCAAGAT TCAACGCCAATAAGT
    GTTATCTCCGGTCTC AGCCTGAGCAAGATG CAACGCCAATAAGTT
    TTATCTCCGGTCTCT GCCTGAGCAAGATGA AACGCCAATAAGTTC
    TATCTCCGGTCTCTG CCTGAGCAAGATGAT ACGCCAATAAGTTCG
    ATCTCCGGTCTCTGA CTGAGCAAGATGATT CGCCAATAAGTTCGT
    TCTCCGGTCTCTGAG TGAGCAAGATGATTC GCCAATAAGTTCGTC
    CTCCGGTCTCTGAGG GAGCAAGATGATTCA CCAATAAGTTCGTCC
    TCCGGTCTCTGAGGC AGCAAGATGATTCAG CAATAAGTTCGTCCA
    CCGGTCTCTGAGGCC GCAAGATGATTCAGA AATAAGTTCGTCCAC
    CGGTCTCTGAGGCCA CAAGATGATTCAGAT ATAAGTTCGTCCACA
    GGTCTCTGAGGCCAG AAGATGATTCAGATG TAAGTTCGTCCACAG
    GTCTCTGAGGCCAGA AGATGATTCAGATGG AAGTTCGTCCACAGA
    TCTCTGAGGCCAGAA GATGATTCAGATGGC AGTTCGTCCACAGAG
    CTCTGAGGCCAGAAA ATGATTCAGATGGCC GTTCGTCCACAGAGA
    TCTGAGGCCAGAAAT TGATTCAGATGGCCG TTCGTCCACAGAGAC
    CTGAGGCCAGAAATG GATTCAGATGGCCGG TCGTCCACAGAGACC
    TGAGGCCAGAAATGG ATTCAGATGGCCGGA CGTCCACAGAGACCT
    GAGGCCAGAAATGGA TTCAGATGGCCGGAG GTCCACAGAGACCTT
    AGGCCAGAAATGGAG TCAGATGGCCGGAGA TCCACAGAGACCTTG
    GGCCAGAAATGGAGA CAGATGGCCGGAGAG CCACAGAGACCTTGC
    CACAGAGACCTTGCT CGGAGATTTTGGTAT GCAAAGGGCTGCTGC
    ACAGAGACCTTGCTG GGAGATTTTGGTATG CAAAGGGCTGCTGCC
    CAGAGACCTTGCTGC GAGATTTTGGTATGA AAAGGGCTGCTGCCC
    AGAGACCTTGCTGCC AGATTTTGGTATGAC AAGGGCTGCTGCCCG
    GAGACCTTGCTGCCC GATTTTGGTATGACG AGGGCTGCTGCCCGT
    AGACCTTGCTGCCCG ATTTTGGTATGACGC GGGCTGCTGCCCGTG
    GACCTTGCTGCCCGG TTTTGGTATGACGCG GGCTGCTGCCCGTGC
    ACCTTGCTGCCCGGA TTTGGTATGACGCGA GCTGCTGCCCGTGCG
    CCTTGCTGCCCGGAA TTGGTATGACGCGAG CTGCTGCCCGTGCGC
    CTTGCTGCCCGGAAT TGGTATGACGCGAGA TGCTGCCCGTGCGCT
    TTGCTGCCCGGAATT GGTATGACGCGAGAT GCTGCCCGTGCGCTG
    TGCTGCCCGGAATTG GTATGACGCGAGATA CTGCCCGTGCGCTGG
    GCTGCCCGGAATTGC TATGACGCGAGATAT TGCCCGTGCGCTGGA
    CTGCCCGGAATTGCA ATGACGCGAGATATC GCCCGTGCGCTGGAT
    TGCCCGGAATTGCAT TGACGCGAGATATCT CCCGTGCGCTGGATG
    GCCCGGAATTGCATG GACGCGAGATATCTA CCGTGCGCTGGATGT
    CCCGGAATTGCATGG ACGCGAGATATCTAT CGTGCGCTGGATGTC
    CCGGAATTGCATGGT CGCGAGATATCTATG GTGCGCTGGATGTCT
    CGGAATTGCATGGTA GCGAGATATCTATGA TGCGCTGGATGTCTC
    GGAATTGCATGGTAG CGAGATATCTATGAG GCGCTGGATGTCTCC
    GAATTGCATGGTAGC GAGATATCTATGAGA CGCTGGATGTCTCCT
    AATTGCATGGTAGCC AGATATCTATGAGAC GCTGGATGTCTCCTG
    ATTGCATGGTAGCCG GATATCTATGAGACA CTGGATGTCTCCTGA
    TTGCATGGTAGCCGA ATATCTATGAGACAG TGGATGTCTCCTGAG
    TGCATGGTAGCCGAA TATCTATGAGACAGA GGATGTCTCCTGAGT
    GCATGGTAGCCGAAG ATCTATGAGACAGAC GATGTCTCCTGAGTC
    CATGGTAGCCGAAGA TCTATGAGACAGACT ATGTCTCCTGAGTCC
    ATGGTAGCCGAAGAT CTATGAGACAGACTA TGTCTCCTGAGTCCC
    TGGTAGCCGAAGATT TATGAGACAGACTAT GTCTCCTGAGTCCCT
    GGTAGCCGAAGATTT ATGAGACAGACTATT TCTCCTGAGTCCCTC
    GTAGCCGAAGATTTC TGAGACAGACTATTA CTCCTGAGTCCCTCA
    TAGCCGAAGATTTCA GAGACAGACTATTAC TCCTGAGTCCCTCAA
    AGCCGAAGATTTCAC AGACAGACTATTACC CCTGAGTCCCTCAAG
    GCCGAAGATTTCACA GACAGACTATTACCG CTGAGTCCCTCAAGG
    CCGAAGATTTCACAG ACAGACTATTACCGG TGAGTCCCTCAAGGA
    CGAAGATTTCACAGT CAGACTATTACCGGA GAGTCCCTCAAGGAT
    GAAGATTTCACAGTC AGACTATTACCGGAA AGTCCCTCAAGGATG
    AAGATTTCACAGTCA GACTATTACCGGAAA GTCCCTCAAGGATGG
    AGATTTCACAGTCAA ACTATTACCGGAAAG TCCCTCAAGGATGGA
    GATTTCACAGTCAAA CTATTACCGGAAAGG CCCTCAAGGATGGAG
    ATTTCACAGTCAAAA TATTACCGGAAAGGA CCTCAAGGATGGAGT
    TTTCACAGTCAAAAT ATTACCGGAAAGGAG CTCAAGGATGGAGTC
    TTCACAGTCAAAATC TTACCGGAAAGGAGG TCAAGGATGGAGTCT
    TCACAGTCAAAATCG TACCGGAAAGGAGGC CAAGGATGGAGTCTT
    CACAGTCAAAATCGG ACCGGAAAGGAGGCA AAGGATGGAGTCTTC
    ACAGTCAAAATCGGA CCGGAAAGGAGGCAA AGGATGGAGTCTTCA
    CAGTCAAAATCGGAG CGGAAAGGAGGCAAA GGATGGAGTCTTCAC
    AGTCAAAATCGGAGA GGAAAGGAGGCAAAG GATGGAGTCTTCACC
    GTCAAAATCGGAGAT GAAAGGAGGCAAAGG ATGGAGTCTTCACCA
    TCAAAATCGGAGATT AAAGGAGGCAAAGGG TGGAGTCTTCACCAC
    CAAAATCGGAGATTT AAGGAGGCAAAGGGC GGAGTCTTCACCACT
    AAAATCGGAGATTTT AGGAGGCAAAGGGCT GAGTCTTCACCACTT
    AAATCGGAGATTTTG GGAGGCAAAGGGCTG AGTCTTCACCACTTA
    AATCGGAGATTTTGG GAGGCAAAGGGCTGC GTCTTCACCACTTAC
    ATCGGAGATTTTGGT AGGCAAAGGGCTGCT TCTTCACCACTTACT
    TCGGAGATTTTGGTA GGCAAAGGGCTGCTG CTTCACCACTTACTC
    TTCACCACTTACTCG ACTGGCCGAGCAGCC TGGAGGGCGGCCTTC
    TCACCACTTACTCGG CTGGCCGAGCAGCCC GGAGGGCGGCCTTCT
    CACCACTTACTCGGA TGGCCGAGCAGCCCT GAGGGCGGCCTTCTG
    ACCACTTACTCGGAC GGCCGAGCAGCCCTA AGGGCGGCCTTCTGG
    CCACTTACTCGGACG GCCGAGCAGCCCTAC GGGCGGCCTTCTGGA
    CACTTACTCGGACGT CCGAGCAGCCCTACC GGCGGCCTTCTGGAC
    ACTTACTCGGACGTC CGAGCAGCCCTACCA GCGGCCTTCTGGACA
    CTTACTCGGACGTCT GAGCAGCCCTACCAG CGGCCTTCTGGACAA
    TTACTCGGACGTCTG AGCAGCCCTACCAGG GGCCTTCTGGACAAG
    TACTCGGACGTCTGG GCAGCCCTACCAGGG GCCTTCTGGACAAGC
    ACTCGGACGTCTGGT CAGCCCTACCAGGGC CCTTCTGGACAAGCC
    CTCGGACGTCTGGTC AGCCCTACCAGGGCT CTTCTGGACAAGCCA
    TCGGACGTCTGGTCC GCCCTACCAGGGCTT TTCTGGACAAGCCAG
    CGGACGTCTGGTCCT CCCTACCAGGGCTTG TCTGGACAAGCCAGA
    GGACGTCTGGTCCTT CCTACCAGGGCTTGT CTGGACAAGCCAGAC
    GACGTCTGGTCCTTC CTACCAGGGCTTGTC TGGACAAGCCAGACA
    ACGTCTGGTCCTTCG TACCAGGGCTTGTCC GGACAAGCCAGACAA
    CGTCTGGTCCTTCGG ACCAGGGCTTGTCCA GACAAGCCAGACAAC
    GTCTGGTCCTTCGGG CCAGGGCTTGTCCAA ACAAGCCAGACAACT
    TCTGGTCCTTCGCGG CAGGGCTTGTCCAAC CAAGCCAGACAACTG
    CTGGTCCTTCGGGGT AGGGCTTGTCCAACG AAGCCAGACAACTGT
    TGGTCCTTCGGGGTC GGGCTTGTCCAACGA AGCCAGACAACTGTC
    GGTCCTTCGGGGTCG GGCTTGTCCAACGAG GCCAGACAACTGTCC
    GTCCTTCGGGGTCGT GCTTGTCCAACGAGC CCAGACAACTGTCCT
    TCCTTCGGGGTCGTC CTTGTCCAACGAGCA CAGACAACTGTCCTG
    CCTTCGGGGTCGTCC TTGTCCAACGAGCAA ACACAACTGTCCTGA
    CTTCGGGGTCGTCCT TGTCCAACGAGCAAG GACAACTGTCCTGAC
    TTCGGGGTCGTCCTC GTCCAACGAGCAAGT ACAACTGTCCTGACA
    TCGGGGTCGTCCTCT TCCAACGAGCAAGTC CAACTGTCCTGACAT
    CGGGGTCGTCCTCTG CCAACGAGCAAGTCC AACTGTCCTGACATG
    GGGGTCGTCCTCTGG CAACGAGCAAGTCCT ACTGTCCTGACATGC
    GGGTCGTCCTCTGGG AACGAGCAAGTCCTT CTGTCCTGACATGCT
    GGTCGTCCTCTGGGA ACGAGCAAGTCCTTC TGTCCTGACATGCTG
    GTCGTCCTCTGGGAG CGAGCAAGTCCTTCG GTCCTGACATGCTGT
    TCGTCCTCTGGGAGA GAGCAAGTCCTTCGC TCCTGACATGCTGTT
    CGTCCTCTGGGAGAT AGCAAGTCCTTCGCT CCTGACATGCTGTTT
    GTCCTCTGGGAGATC GCAAGTCCTTCGCTT CTGACATGCTGTTTG
    TCCTCTGGGAGATCG CAAGTCCTTCGCTTC TGACATGCTGTTTGA
    CCTCTGGGAGATCGC AAGTCCTTCGCTTCG GACATGCTGTTTGAA
    CTCTGGGAGATCGCC AGTCCTTCGCTTCGT ACATGCTGTTTGAAC
    TCTGGGAGATCGCCA GTCCTTCGCTTCGTC CATGCTGTTTGAACT
    CTGGGAGATCGCCAC TCCTTCGCTTCGTCA ATGCTGTTTGAACTG
    TGGGAGATCGCCACA CCTTCGCTTCGTCAT TGCTGTTTGAACTGA
    GGGAGATCGCCACAC CTTCGCTTCGTCATG GCTGTTTGAACTGAT
    GGAGATCGCCACACT TTCGCTTCGTCATGG CTGTTTGAACTGATG
    GAGATCGCCACACTG TCGCTTCGTCATGGA TGTTTGAACTGATGC
    AGATCGCCACACTGG CGCTTCGTCATGGAG GTTTGAACTGATGCG
    GATCGCCACACTGGC GCTTCGTCATGGAGG TTTGAACTGATGCGC
    ATCGCCACACTGGCC CTTCGTCATGGAGGG TTGAACTGATGCGCA
    TCGCCACACTGGCCG TTCGTCATGGAGGGC TGAACTGATGCGCAT
    CGCCACACTGGCCGA TCGTCATGGAGGGCG GAACTGATGCGCATG
    GCCACACTGGCCGAG CGTCATGGAGGGCGG AACTGATGCGCATGT
    CCACACTGGCCGAGC GTCATGGAGGGCGGC ACTGATGCGCATGTG
    CACACTGGCCGAGCA TCATGGAGGGCGGCC CTGATGCGCATGTGC
    ACACTGGCCGAGCAG CATGGAGGGCGGCCT TGATGCGCATGTGCT
    CACTGGCCGAGCAGC ATGGAGGGCGGCCTT GATGCGCATGTGCTG
    ATGCGCATGTGCTGG CAGCAGCATCAAAGA GCGAGGAGAACAAGC
    TGCGCATGTGCTGGC AGCAGCATCAAAGAG CGAGGAGAACAAGCT
    GCGCATGTGCTGGCA GCAGCATCAAAGAGG GAGGAGAACAAGCTG
    CGCATGTGCTGGCAG CAGCATCAAAGAGGA AGGAGAACAAGCTGC
    GCATGTGCTGGCAGT AGCATCAAAGAGGAG GGAGAACAAGCTGCC
    CATGTGCTGGCAGTA GCATCAAAGAGGAGA GAGAACAAGCTGCCC
    ATGTGCTGGCAGTAT CATCAAAGAGGAGAT AGAACAAGCTGCCCG
    TGTGCTGGCAGTATA ATCAAAGAGGAGATG GAACAAGCTGCCCGA
    GTGCTGGCAGTATAA TCAAAGAGGAGATGG AACAAGCTGCCCGAG
    TGCTGGCAGTATAAC CAAAGAGGAGATGGA ACAAGCTGCCCGAGC
    GCTGGCAGTATAACC AAAGAGGAGATGGAG CAAGCTGCCCGAGCC
    CTGGCAGTATAACCC AAGAGGAGATGGAGC AAGCTGCCCGAGCCG
    TGGCAGTATAACCCC AGAGGAGATGGAGCC AGCTGCCCGAGCCGG
    GGCAGTATAACCCCA GAGGAGATGGAGCCT GCTGCCCGAGCCGGA
    GCAGTATAACCCCAA AGGAGATGGAGCCTG CTGCCCGAGCCGGAG
    CAGTATAACCCCAAG GGAGATGGAGCCTGG TGCCCGAGCCGGAGG
    AGTATAACCCCAAGA GAGATGGAGCCTGGC GCCCGAGCCGGAGGA
    GTATAACCCCAAGAT AGATGGAGCCTGGCT CCCGAGCCGGAGGAG
    TATAACCCCAAGATG GATGGAGCCTGGCTT CCGAGCCGGAGGAGC
    ATAACCCCAAGATGA ATGGAGCCTGGCTTC CGAGCCGGAGGAGCT
    TAACCCCAAGATGAG TGGAGCCTGGCTTCC GAGCCGGAGGAGCTG
    AACCCCAAGATGAGG GGAGCCTGGCTTCCG AGCCGGAGGAGCTGG
    ACCCCAAGATGAGGC GAGCCTGGCTTCCGG GCCGGAGGAGCTGGA
    CCCCAAGATGAGGCC AGCCTGGCTTCCGGG CCGGAGGAGCTGGAC
    CCCAAGATGAGGCCT GCCTGGCTTCCGGGA CGGAGGAGCTGGACC
    CCAAGATGAGGCCTT CCTGGCTTCCGGGAG GGAGGAGCTGGACCT
    CAAGATGAGGCCTTC CTGGCTTCCGGGAGG GAGGAGCTGGACCTG
    AAGATGAGGCCTTCC TGGCTTCCGGGAGGT AGGAGCTGGACCTGG
    AGATGAGGCCTTCCT GGCTTCCGGGAGGTC GGAGCTGGACCTGGA
    GATGAGGCCTTCCTT GCTTCCGGGAGGTCT GAGCTGGACCTGGAG
    ATGAGGCCTTCCTTC CTTCCGGGAGGTCTC AGCTGGACCTGGAGC
    TGAGGCCTTCCTTCC TTCCGGGAGGTCTCC GCTGGACCTGGAGCC
    GAGGCCTTCCTTCCT TCCGGGAGGTCTCCT CTGGACCTGGAGCCA
    AGGCCTTCCTTCCTG CCGGGAGGTCTCCTT TGGACCTGGAGCCAG
    GGCCTTCCTTCCTGG CGGGAGGTCTCCTTC GGACCTGGAGCCAGA
    GCCTTCCTTCCTGGA GGGAGGTCTCCTTCT GACCTGGAGCCAGAG
    CCTTCCTTCCTGGAG GGAGGTCTCCTTCTA ACCTGGAGCCAGAGA
    CTTCCTTCCTGGAGA GAGGTCTCCTTCTAC CCTGGAGCCAGAGAA
    TTCCTTCCTGGAGAT AGGTCTCCTTCTACT CTGGAGCCAGAGAAC
    TCCTTCCTGGAGATC GGTCTCCTTCTACTA TGGAGCCAGAGAACA
    CCTTCCTGGAGATCA GTCTCCTTCTACTAC GGAGCCAGAGAACAT
    CTTCCTGGAGATCAT TCTCCTTCTACTACA GAGCCAGAGAACATG
    TTCCTGGAGATCATC CTCCTTCTACTACAG AGCCAGAGAACATGG
    TCCTGGAGATCATCA TCCTTCTACTACAGC GCCAGAGAACATGGA
    CCTGGAGATCATCAG CCTTCTACTACAGCG CCAGAGAACATGGAG
    CTGGAGATCATCAGC CTTCTACTACAGCGA CAGAGAACATGGAGA
    TGGAGATCATCAGCA TTCTACTACAGCGAG AGAGAACATGGAGAG
    GGAGATCATCAGCAG TCTACTACAGCGAGG GAGAACATGGAGAGC
    GAGATCATCAGCAGC CTACTACAGCGAGGA AGAACATGGAGAGCG
    AGATCATCAGCAGCA TACTACAGCGAGGAG GAACATGGAGAGCGT
    GATCATCAGCAGCAT ACTACAGCGAGGAGA AACATGGAGAGCGTC
    ATCATCAGCAGCATC CTACAGCGAGGAGAA ACATGGAGAGCGTCC
    TCATCAGCAGCATCA TACAGCGAGGAGAAC CATGGAGAGCGTCCC
    CATCAGCAGCATCAA ACAGCGAGGAGAACA ATGGAGAGCGTCCCC
    ATCAGCAGCATCAAA CAGCGAGGAGAACAA TGGAGAGCGTCCCCC
    TCAGCAGCATCAAAG AGCGAGGAGAACAAG GGAGAGCGTCCCCCT
    GAGAGCGTCCCCCTG ACACTCAGGACACAA CCAGCTTCGACGAGA
    AGAGCGTCCCCCTGG CACTCAGGACACAAG CAGCTTCGACGAGAG
    GAGCGTCCCCCTGGA ACTCAGGACACAAGG AGCTTCGACGAGAGA
    AGCGTCCCCCTGGAC CTCAGGACACAAGGC GCTTCGACGAGAGAC
    GCGTCCCCCTGGACC TCAGGACACAAGGCC CTTCGACGAGAGACA
    CGTCCCCCTGGACCC CAGGACACAAGGCCG TTCGACGAGAGACAG
    GTCCCCCTGGACCCC AGGACACAAGGCCGA TCGACGAGAGACAGC
    TCCCCCTGGACCCCT GGACACAAGGCCGAG CGACGAGAGACAGCC
    CCCCCTGGACCCCTC GACACAAGGCCGAGA GACGAGAGACAGCCT
    CCCCTGGACCCCTCG ACACAAGGCCGAGAA ACGAGAGACAGCCTT
    CCCTGGACCCCTCGG CACAAGGCCGAGAAC CGAGAGACAGCCTTA
    CCTGGACCCCTCGGC ACAAGGCCGAGAACG GAGAGACAGCCTTAC
    CTGGACCCCTCGGCC CAAGGCCGAGAACGG AGAGACAGCCTTACG
    TGGACCCCTCGGCCT AAGGCCGAGAACGGC GAGACAGCCTTACGC
    GGACCCCTCGGCCTC AGGCCGAGAACGGCC AGACAGCCTTACGCC
    GACCCCTCGGCCTCC GGCCGAGAACGGCCC GACAGCCTTACGCCC
    ACCCCTCGGCCTCCT GCCGAGAACGGCCCC ACAGCCTTACGCCCA
    CCCCTCGGCCTCCTC CCGAGAACGGCCCCG CAGCCTTACGCCCAC
    CCCTCGGCCTCCTCG CGAGAACGGCCCCGG AGCCTTACGCCCACA
    CCTCGGCCTCCTCGT GAGAACGGCCCCGGC GCCTTACGCCCACAT
    CTCGGCCTCCTCGTC AGAACGGCCCCGGCC CCTTACGCCCACATG
    TCGGCCTCCTCGTCC GAACGGCCCCGGCCC CTTACGCCCACATGA
    CGGCCTCCTCGTCCT AACGGCCCCGGCCCT TTACGCCCACATGAA
    GGCCTCCTCGTCCTC ACGGCCCCGGCCCTG TACGCCCACATGAAC
    GCCTCCTCGTCCTCC CGGCCCCGGCCCTGG ACGCCCACATGAACG
    CCTCCTCGTCCTCCC GGCCCCGGCCCTGGG CGCCCACATGAACGG
    CTCCTCGTCCTCCCT GCCCCGGCCCTGGGG GCCCACATGAACGGG
    TCCTCGTCCTCCCTG CCCCGGCCCTGGGGT CCCACATGAACGGGG
    CCTCGTCCTCCCTGC CCCGGCCCTGGGGTG CCACATGAACGGGGG
    CTCGTCCTCCCTGCC CCGGCCCTGGGGTGC CACATGAACGGGGGC
    TCGTCCTCCCTGCCA CGGCCCTGGGGTGCT ACATGAACGGGGGCC
    CGTCCTCCCTGCCAC GGCCCTGGGGTGCTG CATGAACGGGGGCCG
    GTCCTCCCTGCCACT GCCCTGGGGTGCTGG ATGAACGGGGGCCGC
    TCCTCCCTGCCACTG CCCTGGGGTGCTGGT TGAACGGGGGCCGCA
    CCTCCCTGCCACTGC CCTGGGGTGCTGGTC GAACGGGGGCCGCAA
    CTCCCTGCCACTGCC CTGGGGTGCTGGTCC AACGGGGGCCGCAAG
    TCCCTGCCACTGCCC TGGGGTGCTGGTCCT ACGGGGGCCGCAAGA
    CCCTGCCACTGCCCG GGGGTGCTGGTCCTC CGGGGGCCGCAAGAA
    CCTGCCACTGCCCGA GGGTGCTGGTCCTCC GGGGGCCGCAAGAAC
    CTGCCACTGCCCGAC GGTGCTGGTCCTCCG GGGGCCGCAAGAACG
    TGCCACTGCCCGACA GTGCTGGTCCTCCGC GGGCCGCAAGAACGA
    GCCACTGCCCGACAG TGCTGGTCCTCCGCG GGCCGCAAGAACGAG
    CCACTGCCCGACAGA GCTGGTCCTCCGCGC GCCGCAAGAACGAGC
    CACTGCCCGACAGAC CTGGTCCTCCGCGCC CCGCAAGAACGAGCG
    ACTGCCCGACAGACA TGGTCCTCCGCGCCA CGCAAGAACGAGCGG
    CTGCCCGACAGACAC GGTCCTCCGCGCCAG GCAAGAACGAGCGGG
    TGCCCGACAGACACT GTCCTCCGCGCCAGC CAAGAACGAGCGGGC
    GCCCGACAGACACTC TCCTCCGCGCCAGCT AAGAACGAGCGGGCC
    CCCGACAGACACTCA CCTCCGCGCCAGCTT AGAACGAGCGGGCCT
    CCGACAGACACTCAG CTCCGCGCCAGCTTC GAACGAGCGGGCCTT
    CGACAGACACTCAGG TCCGCGCCAGCTTCG AACGAGCGGGCCTTG
    GACAGACACTCAGGA CCGCGCCAGCTTCGA ACGAGCGGGCCTTGC
    ACAGACACTCAGGAC CGCGCCAGCTTCGAC CGAGCGGGCCTTGCC
    CAGACACTCAGGACA GCGCCAGCTTCGACG GAGCGGGCCTTGCCG
    AGACACTCAGGACAC CGCCAGCTTCGACGA AGCGGGCCTTGCCGC
    GACACTCAGGACACA GCCAGCTTCGACGAG GCGGCCCTTGCCGCT
    CGGGCCTTGCCGCTG GCAAACAGTAACGTG CAATCCATTCACAAG
    GGGCCTTGCCGCTGC CAAACAGTAACGTGT AATCCATTCACAAGC
    GGCCTTGCCGCTGCC AAACAGTAACGTGTG ATCCATTCACAAGCC
    GCCTTGCCGCTGCCC AACAGTAACGTGTGC TCCATTCACAAGCCT
    CCTTGCCGCTGCCCC ACAGTAACGTGTGCG CCATTCACAAGCCTC
    CTTGCCGCTGCCCCA CAGTAACGTGTGCGC CATTCACAAGCCTCC
    TTGCCGCTGCCCCAG AGTAACGTGTGCGCA ATTCACAAGCCTCCT
    TGCCGCTGCCCCAGT GTAACGTGTGCGCAC TTCACAAGCCTCCTG
    GCCGCTGCCCCAGTC TAACGTGTGCGCACG TCACAAGCCTCCTGT
    CCGCTGCCCCAGTCT AACGTGTGCGCACGC CACAAGCCTCCTGTA
    CGCTGCCCCAGTCTT ACGTGTGCGCACGCG ACAAGCCTCCTGTAC
    GCTGCCCCAGTCTTC CGTGTGCGCACGCGC CAAGCCTCCTGTACC
    CTGCCCCAGTCTTCG GTGTGCGCACGCGCA AAGCCTCCTGTACCT
    TGCCCCAGTCTTCGA TGTGCGCACGCGCAG AGCCTCCTGTACCTC
    GCCCCAGTCTTCGAC GTGCGCACGCGCAGC GCCTCCTGTACCTCA
    CCCCAGTCTTCGACC TGCGCACGCGCAGCG CCTCCTGTACCTCAG
    CCCAGTCTTCGACCT GCGCACGCGCAGCGG CTCCTGTACCTCAGT
    CCAGTCTTCGACCTG CGCACGCGCAGCGGG TCCTGTACCTCAGTG
    CAGTCTTCGACCTGC GCACGCGCAGCGGGG CCTGTACCTCAGTGG
    AGTCTTCGACCTGCT CACGCGCAGCGGGGT CTGTACCTCAGTGGA
    GTCTTCGACCTGCTG ACGCGCAGCGGGGTG TGTACCTCAGTGGAT
    TCTTCGACCTGCTGA CGCGCAGCGGGGTGG GTACCTCAGTGGATC
    CTTCGACCTGCTGAT GCGCAGCGGGGTGGG TACCTCAGTGGATCT
    TTCGACCTGCTGATC CGCAGCGGGGTGGGG ACCTCAGTGGATCTT
    TCGACCTGCTGATCC GCAGCGGGGTGGGGG CCTCAGTGGATCTTC
    CGACCTGCTGATCCT CAGCGGGGTGGGGGG CTCAGTGGATCTTCA
    GACCTGCTGATCCTT AGCGGGGTGGGGGGG TCAGTGGATCTTCAG
    ACCTGCTGATCCTTG GCGGGGTGGGGGGGG CAGTGGATCTTCAGT
    CCTGCTGATCCTTGG CGGGGTGGGGGGGGA AGTGGATCTTCAGTT
    CTGCTGATCCTTGGA GGGGTGGGGGGGGAG GTGGATCTTCAGTTC
    TGCTGATCCTTGGAT GGGTGGGGGGGGAGA TGGATCTTCAGTTCT
    GCTGATCCTTGGATC GGTGGGGGGGGAGAG GGATCTTCAGTTCTG
    CTGATCCTTGGATCC GTGGGGGGGGAGAGA GATCTTCAGTTCTGC
    TGATCCTTGGATCCT TGGGGGGGGAGAGAG ATCTTCAGTTCTGCC
    GATCCTTGGATCCTG GGGGGGGGAGAGAGA TCTTCAGTTCTGCCC
    ATCCTTGGATCCTGA GGGGGGGAGAGAGAG CTTCAGTTCTGCCCT
    TCCTTGGATCCTGAA GGGGGGAGAGAGAGT TTCAGTTCTGCCCTT
    CCTTGGATCCTGAAT GGGGGAGAGAGAGTT TCAGTTCTGCCCTTG
    CTTGGATCCTGAATC GGGGAGAGAGAGTTT CAGTTCTGCCCTTGC
    TTGGATCCTGAATCT GGGAGAGAGAGTTTT AGTTCTGCCCTTGCT
    TGGATCCTGAATCTG GGAGAGAGAGTTTTA GTTCTGCCCTTGCTG
    GGATCCTGAATCTGT GAGAGAGAGTTTTAA TTCTGCCCTTGCTGC
    GATCCTGAATCTGTG AGAGAGAGTTTTAAC TCTGCCCTTGCTGCC
    ATCCTGAATCTGTGC GAGAGAGTTTTAACA CTGCCCTTGCTGCCC
    TCCTGAATCTGTGCA AGAGAGTTTTAACAA TGCCCTTGCTGCCCG
    CCTGAATCTGTGCAA GAGAGTTTTAACAAT GCCCTTGCTGCCCGC
    CTGAATCTGTGCAAA AGAGTTTTAACAATC CCCTTGCTGCCCGCG
    TGAATCTGTGCAAAC GAGTTTTAACAATCC CCTTGCTGCCCGCGG
    GAATCTGTGCAAACA AGTTTTAACAATCCA CTTGCTGCCCGCGGG
    AATCTGTGCAAACAG GTTTTAACAATCCAT TTGCTGCCCGCGGGA
    ATCTGTGCAAACAGT TTTTAACAATCCATT TGCTGCCCGCGGGAG
    TCTGTGCAAACAGTA TTTAACAATCCATTC GCTGCCCGCGGGAGA
    CTGTGCAAACAGTAA TTAACAATCCATTCA CTGCCCGCGGGAGAC
    TGTGCAAACAGTAAC TAACAATCCATTCAC TGCCCGCGGGAGACA
    GTGCAAACAGTAACG AACAATCCATTCACA GCCCGCGGGAGACAG
    TGCAAACAGTAACGT ACAATCCATTCACAA CCCGCGGGAGACAGC
    CCGCGGGAGACAGCT ATGCAAGCAGCTTTT ACCTTAATGACAACA
    CGCGGGAGACAGCTT TGCAAGCAGCTTTTT CCTTAATGACAACAC
    GCGGGAGACAGCTTC GCAAGCAGCTTTTTA CTTAATGACAACACT
    CGGGAGACAGCTTCT CAAGCAGCTTTTTAT TTAATGACAACACTT
    GGGAGACAGCTTCTC AAGCAGCTTTTTATT TAATGACAACACTTA
    GGAGACAGCTTCTCT AGCAGCTTTTTATTC AATGACAACACTTAA
    GAGACAGCTTCTCTG GCAGCTTTTTATTCC ATGACAACACTTAAT
    AGACAGCTTCTCTGC CAGCTTTTTATTCCC TGACAACACTTAATA
    GACAGCTTCTCTGCA AGCTTTTTATTCCCT GACAACACTTAATAG
    ACAGCTTCTCTGCAG GCTTTTTATTCCCTG ACAACACTTAATAGC
    CAGCTTCTCTGCAGT CTTTTTATTCCCTGC CAACACTTAATAGCA
    AGCTTCTCTGCAGTA TTTTTATTCCCTGCC AACACTTAATAGCAA
    GCTTCTCTGCAGTAA TTTTATTCCCTGCCC ACACTTAATAGCAAC
    CTTCTCTGCAGTAAA TTTATTCCCTGCCCA CACTTAATAGCAACA
    TTCTCTGCAGTAAAA TTATTCCCTGCCCAA ACTTAATAGCAACAG
    TCTCTGCAGTAAAAC TATTCCCTGCCCAAA CTTAATAGCAACAGA
    CTCTGCAGTAAAACA ATTCCCTGCCCAAAC TTAATAGCAACAGAG
    TCTGCAGTAAAACAC TTCCCTGCCCAAACC TAATAGCAACAGAGC
    CTGCAGTAAAACACA TCCCTGCCCAAACCC AATAGCAACAGAGCA
    TGCAGTAAAACACAT CCCTGCCCAAACCCT ATAGCAACAGAGCAC
    GCAGTAAAACACATT CCTGCCCAAACCCTT TAGCAACAGAGCACT
    CAGTAAAACACATTT CTGCCCAAACCCTTA AGCAACAGAGCACTT
    AGTAAAACACATTTG TGCCCAAACCCTTAA GCAACAGAGCACTTG
    GTAAAACACATTTGG GCCCAAACCCTTAAC CAACAGAGCACTTGA
    TAAAACACATTTGGG CCCAAACCCTTAACT AACAGAGCACTTGAG
    AAAACACATTTGGGA CCAAACCCTTAACTG ACAGAGCACTTGAGA
    AAACACATTTGGGAT CAAACCCTTAACTGA CAGAGCACTTGAGAA
    AACACATTTGGGATG AAACCCTTAACTGAC AGAGCACTTGAGAAC
    ACACATTTGGGATGT AACCCTTAACTGACA GAGCACTTGAGAACC
    CACATTTGGGATGTT ACCCTTAACTGACAT AGCACTTGAGAACCA
    ACATTTGGGATGTTC CCCTTAACTGACATG GCACTTGAGAACCAG
    CATTTGGGATGTTCC CCTTAACTGACATGG CACTTGAGAACCAGT
    ATTTGGGATGTTCCT CTTAACTGACATGGG ACTTGAGAACCAGTC
    TTTGGGATGTTCCTT TTAACTGACATGGGC CTTGAGAACCAGTCT
    TTGGGATGTTCCTTT TAACTGACATGGGCC TTGAGAACCAGTCTC
    TGGGATGTTCCTTTT AACTGACATGGGCCT TGAGAACCAGTCTCC
    GGGATGTTCCTTTTT ACTGACATGGGCCTT GAGAACCAGTCTCCT
    GGATGTTCCTTTTTT CTGACATGGGCCTTT AGAACCAGTCTCCTC
    GATGTTCCTTTTTTC TGACATGGGCCTTTA GAACCAGTCTCCTCA
    ATGTTCCTTTTTTCA GACATGGGCCTTTAA AACCAGTCTCCTCAC
    TGTTCCTTTTTTCAA ACATGGGCCTTTAAG ACCAGTCTCCTCACT
    GTTCCTTTTTTCAAT CATGGGCCTTTAAGA CCAGTCTCCTCACTC
    TTCCTTTTTTCAATA ATGGGCCTTTAAGAA CAGTCTCCTCACTCT
    TCCTTTTTTCAATAT TGGGCCTTTAAGAAC AGTCTCCTCACTCTG
    CCTTTTTTCAATATG GGGCCTTTAAGAACC GTCTCCTCACTCTGT
    CTTTTTTCAATATGC GGCCTTTAAGAACCT TCTCCTCACTCTGTC
    TTTTTTCAATATGCA GCCTTTAAGAACCTT CTCCTCACTCTGTCC
    TTTTTCAATATGCAA CCTTTAAGAACCTTA TCCTCACTCTGTCCC
    TTTTCAATATGCAAG CTTTAAGAACCTTAA CCTCACTCTGTCCCT
    TTTCAATATGCAAGC TTTAAGAACCTTAAT CTCACTCTGTCCCTG
    TTCAATATGCAAGCA TTAAGAACCTTAATG TCACTCTGTCCCTGT
    TCAATATGCAAGCAG TAAGAACCTTAATGA CACTCTGTCCCTGTC
    CAATATGCAAGCAGC AAGAACCTTAATGAC ACTCTGTCCCTGTCC
    AATATGCAAGCAGCT AGAACCTTAATGACA CTCTGTCCCTGTCCT
    ATATGCAAGCAGCTT GAACCTTAATGACAA TCTGTCCCTGTCCTT
    TATGCAAGCAGCTTT AACCTTAATGACAAC CTGTCCCTGTCCTTC
    TGTCCCTGTCCTTCC AATAATTGCCACAAG GTCCCTGTGGCCCCA
    GTCCCTGTCCTTCCC ATAATTGCCACAAGT TCCCTGTGGCCCCAT
    TCCCTGTCCTTCCCT TAATTGCCACAAGTC CCCTGTGGCCCCATC
    CCCTGTCCTTCCCTG AATTGCCACAAGTCC CCTGTGGCCCCATCC
    CCTGTCCTTCCCTGT ATTGCCACAAGTCCA CTGTGGCCCCATCCA
    CTGTCCTTCCCTGTT TTGCCACAAGTCCAG TGTGGCCCCATCCAA
    TGTCCTTCCCTGTTC TGCCACAAGTCCAGC GTGGCCCCATCCAAC
    GTCCTTCCCTGTTCT GCCACAAGTCCAGCT TGGCCCCATCCAACC
    TCCTTCCCTGTTCTC CCACAAGTCCAGCTG GGCCCCATCCAACCA
    CCTTCCCTGTTCTCC CACAAGTCCAGCTGG GCCCCATCCAACCAC
    CTTCCCTGTTCTCCC ACAAGTCCAGCTGGG CCCCATCCAACCACT
    TTCCCTGTTCTCCCT CAAGTCCAGCTGGGA CCCATCCAACCACTG
    TCCCTGTTCTCCCTT AAGTCCAGCTGGGAA CCATCCAACCACTGT
    CCCTGTTCTCCCTTT AGTCCAGCTGGGAAG CATCCAACCACTGTA
    CCTGTTCTCCCTTTC GTCCAGCTGGGAAGC ATCCAACCACTGTAC
    CTGTTCTCCCTTTCT TCCAGCTGGGAAGCC TCCAACCACTGTACA
    TGTTCTCCCTTTCTC CCAGCTGGGAAGCCC CCAACCACTGTACAC
    GTTCTCCCTTTCTCT CAGCTGGGAAGCCCT CAACCACTGTACACA
    TTCTCCCTTTCTCTC AGCTGGGAAGCCCTT AACCACTGTACACAC
    TCTCCCTTTCTCTCT GCTGGGAAGCCCTTT ACCACTGTACACACC
    CTCCCTTTCTCTCTC CTGGGAAGCCCTTTT CCACTGTACACACCC
    TCCCTTTCTCTCTCC TGGGAAGCCCTTTTT CACTGTACACACCCG
    CCCTTTCTCTCTCCT GGGAAGCCCTTTTTA ACTGTACACACCCGC
    CCTTTCTCTCTCCTC GGAAGCCCTTTTTAT CTGTACACACCCGCC
    CTTTCTCTCTCCTCT GAAGCCCTTTTTATC TGTACACACCCGCCT
    TTTCTCTCTCCTCTC AAGCCCTTTTTATCA GTACACACCCGCCTG
    TTCTCTCTCCTCTCT AGCCCTTTTTATCAG TACACACCCGCCTGA
    TCTCTCTCCTCTCTG GCCCTTTTTATCAGT ACACACCCGCCTGAC
    CTCTCTCCTCTCTGC CCCTTTTTATCAGTT CACACCCGCCTGACA
    TCTCTCCTCTCTGCT CCTTTTTATCAGTTT ACACCCGCCTGACAC
    CTCTCCTCTCTGCTT CTTTTTATCAGTTTG CACCCGCCTGACACC
    TCTCCTCTCTGCTTC TTTTTATCAGTTTGA ACCCGCCTGACACCG
    CTCCTCTCTGCTTCA TTTTATCAGTTTGAG CCCGCCTGACACCGT
    TCCTCTCTGCTTCAT TTTATCAGTTTGAGG CCGCCTGACACCGTG
    CCTCTCTGCTTCATA TTATCAGTTTGAGGA CGCCTGACACCGTGG
    CTCTCTGCTTCATAA TATCAGTTTGAGGAA GCCTGACACCGTGGG
    TCTCTGCTTCATAAC ATCAGTTTGAGGAAG CCTGACACCGTGGGT
    CTCTGCTTCATAACG TCAGTTTGAGGAAGT CTGACACCGTGGGTC
    TCTGCTTCATAACGG CAGTTTGAGGAAGTG TGACACCGTGGGTCA
    CTGCTTCATAACGGA AGTTTGAGGAAGTGG GACACCGTGGGTCAT
    TGCTTCATAACGGAA GTTTGAGGAAGTGGC ACACCGTGGGTCATT
    GCTTCATAACGGAAA TTTGAGGAAGTGGCT CACCGTGGGTCATTA
    CTTCATAACGGAAAA TTGAGGAAGTGGCTG ACCGTGGGTCATTAC
    TTCATAACGGAAAAA TGAGGAAGTGGCTGT CCGTGGGTCATTACA
    TCATAACGGAAAAAT GAGGAAGTGGCTGTC CGTGGGTCATTACAA
    CATAACGGAAAAATA AGGAAGTGGCTGTCC GTGGGTCATTACAAA
    ATAACGGAAAAATAA GGAAGTGGCTGTCCC TGGGTCATTACAAAA
    TAACGGAAAAATAAT GAAGTGGCTGTCCCT GGGTCATTACAAAAA
    AACGGAAAAATAATT AAGTGGCTGTCCCTG GGTCATTACAAAAAA
    ACGGAAAAATAATTG AGTGGCTGTCCCTGT GTCATTACAAAAAAA
    CGGAAAAATAATTGC GTGGCTGTCCCTGTG TCATTACAAAAAAAC
    GGAAAAATAATTGCC TGGCTGTCCCTGTGG CATTACAAAAAAACA
    GAAAAATAATTGCCA GGCTGTCCCTGTGGC ATTACAAAAAAACAC
    AAAAATAATTGCCAC GCTGTCCCTGTGGCC TTACAAAAAAACACG
    AAAATAATTGCCACA CTGTCCCTGTGGCCC TACAAAAAAACACGT
    AAATAATTGCCACAA TGTCCCTGTGGCCCC ACAAAAAAACACGTG
    CAAAAAAACACGTGG ATGAAATTTACAAAG TAATTTTGCCAAAAT
    AAAAAAACACGTGGA TGAAATTTACAAAGG AATTTTGCCAAAATC
    AAAAAACACGTGGAG GAAATTTACAAAGGG ATTTTGCCAAAATCC
    AAAAACACGTGGAGA AAATTTACAAAGGGC TTTTGCCAAAATCCT
    AAAACACGTGGAGAT AATTTACAAAGGGCC TTTGCCAAAATCCTG
    AAACACGTGGAGATG ATTTACAAAGGGCCA TTGCCAAAATCCTGA
    AACACGTGGAGATGG TTTACAAAGGGCCAT TGCCAAAATCCTGAA
    ACACGTGGAGATGGA TTACAAAGGGCCATC GCCAAAATCCTGAAC
    CACGTGGAGATGGAA TACAAAGGGCCATCG CCAAAATCCTGAACT
    ACGTGGAGATGGAAA ACAAAGGGCCATCGT CAAAATCCTGAACTT
    CGTGGAGATGGAAAT CAAAGGGCCATCGTT AAAATCCTGAACTTT
    GTGGAGATGGAAATT AAAGGGCCATCGTTC AAATCCTGAACTTTC
    TGGAGATGGAAATTT AAGGGCCATCGTTCA AATCCTGAACTTTCT
    GGAGATGGAAATTTT AGGGCCATCGTTCAT ATCCTGAACTTTCTC
    GAGATGGAAATTTTT GGGCCATCGTTCATC TCCTGAACTTTCTCC
    AGATGGAAATTTTTA GGCCATCGTTCATCC CCTGAACTTTCTCCC
    GATGGAAATTTTTAC GCCATCGTTCATCCA CTGAACTTTCTCCCT
    ATGGAAATTTTTACC CCATCGTTCATCCAA TGAACTTTCTCCCTC
    TGGAAATTTTTACCT CATCGTTCATCCAAG GAACTTTCTCCCTCA
    GGAAATTTTTACCTT ATCGTTCATCCAAGG AACTTTCTCCCTCAT
    GAAATTTTTACCTTT TCGTTCATCCAAGGC ACTTTCTCCCTCATC
    AAATTTTTACCTTTA CGTTCATCCAAGGCT CTTTCTCCCTCATCG
    AATTTTTACCTTTAT GTTCATCCAAGGCTG TTTCTCCCTCATCGG
    ATTTTTACCTTTATC TTCATCCAAGGCTGT TTCTCCCTCATCGGC
    TTTTTACCTTTATCT TCATCCAAGGCTGTT TCTCCCTCATCGGCC
    TTTTACCTTTATCTT CATCCAAGGCTGTTA CTCCCTCATCGGCCC
    TTTACCTTTATCTTT ATCCAAGGCTGTTAC TCCCTCATCGGCCCG
    TTACCTTTATCTTTC TCCAAGGCTGTTACC CCCTCATCGGCCCGG
    TACCTTTATCTTTCA CCAAGGCTGTTACCA CCTCATCGGCCCGGC
    ACCTTTATCTTTCAC CAAGGCTGTTACCAT CTCATCGGCCCGGCG
    CCTTTATCTTTCACC AAGGCTGTTACCATT TCATCGGCCCGGCGC
    CTTTATCTTTCACCT AGGCTGTTACCATTT CATCGGCCCGGCGCT
    TTTATCTTTCACCTT GGCTGTTACCATTTT ATCGGCCCGGCGCTG
    TTATCTTTCACCTTT GCTGTTACCATTTTA TCGGCCCGGCGCTGA
    TATCTTTCACCTTTC CTGTTACCATTTTAA CGGCCCGGCGCTGAT
    ATCTTTCACCTTTCT TGTTACCATTTTAAC GGCCCGGCGCTGATT
    TCTTTCACCTTTCTA GTTACCATTTTAACG GCCCGGCGCTGATTC
    CTTTCACCTTTCTAG TTACCATTTTAACGC CCCGGCGCTGATTCC
    TTTCACCTTTCTAGG TACCATTTTAACGCT CCGGCGCTGATTCCT
    TTCACCTTTCTAGGG ACCATTTTAACGCTG CGGCGCTGATTCCTC
    TCACCTTTCTAGGGA CCATTTTAACGCTGC GGCGCTGATTCCTCG
    CACCTTTCTAGGGAC CATTTTAACGCTGCC GCGCTGATTCCTCGT
    ACCTTTCTAGGGACA ATTTTAACGCTGCCT CGCTGATTCCTCGTG
    CCTTTCTAGGGACAT TTTTAACGCTGCCTA GCTGATTCCTCGTGT
    CTTTCTAGGGACATG TTTAACGCTGCCTAA CTGATTCCTCGTGTC
    TTTCTAGGGACATGA TTAACGCTGCCTAAT TGATTCCTCGTGTCC
    TTCTAGGGACATGAA TAACGCTGCCTAATT GATTCCTCGTGTCCG
    TCTAGGGACATGAAA AACGCTGCCTAATTT ATTCCTCGTGTCCGG
    CTAGGGACATGAAAT ACGCTGCCTAATTTT TTCCTCGTGTCCGGA
    TAGGGACATGAAATT CCCTGCCTAATTTTG TCCTCGTGTCCGGAG
    AGGGACATGAAATTT GCTGCCTAATTTTGC CCTCGTGTCCGGAGG
    GGGACATGAAATTTA CTGCCTAATTTTGCC CTCGTGTCCGGAGGC
    GGACATGAAATTTAC TGCCTAATTTTGCCA TCGTGTCCGGAGGCA
    GACATGAAATTTACA GCCTAATTTTGCCAA CGTGTCCGGAGGCAT
    ACATGAAATTTACAA CCTAATTTTGCCAAA GTGTCCGGAGGCATG
    CATGAAATTTACAAA CTAATTTTGCCAAAA TGTCCGGAGGCATGG
    GTCCGGAGGCATGGG CGACACACTCCGTCC CAGGTCTCATTGCTT
    TCCGGAGGCATGGGT GACACACTCCGTCCA AGGTCTCATTGCTTC
    CCGGAGGCATGGGTG ACACACTCCGTCCAT GGTCTCATTGCTTCT
    CGGAGGCATGGGTGA CACACTCCGTCCATC GTCTCATTGCTTCTG
    GGAGGCATGGGTGAG ACACTCCGTCCATCC TCTCATTGCTTCTGA
    GAGGCATGGGTGAGC CACTCCGTCCATCCG CTCATTGCTTCTGAC
    AGGCATGGGTGAGCA ACTCCGTCCATCCGA TCATTGCTTCTGACT
    GGCATGGGTGAGCAT CTCCGTCCATCCGAC CATTGCTTCTGACTA
    GCATGGGTGAGCATG TCCGTCCATCCGACT ATTGCTTCTGACTAG
    CATGGGTGAGCATGG CCGTCCATCCGACTG TTGCTTCTGACTAGA
    ATGGGTGAGCATGGC CGTCCATCCGACTGC TGCTTCTGACTAGAT
    TGGGTGAGCATGGCA GTCCATCCGACTGCC GCTTCTGACTAGATT
    GGGTGAGCATGGCAG TCCATCCGACTGCCC CTTCTGACTAGATTA
    GGTGAGCATGGCAGC CCATCCGACTGCCCC TTCTGACTAGATTAT
    GTGAGCATGGCAGCT CATCCGACTGCCCCT TCTGACTAGATTATT
    TGAGCATGGCAGCTG ATCCGACTGCCCCTG CTGACTAGATTATTA
    GAGCATGGCAGCTGG TCCGACTGCCCCTGC TGACTAGATTATTAT
    AGCATGGCAGCTGGT CCGACTGCCCCTGCT GACTAGATTATTATT
    GCATGGCAGCTGGTT CGACTGCCCCTGCTG ACTAGATTATTATTT
    CATGGCAGCTGGTTG GACTGCCCCTGCTGT CTAGATTATTATTTG
    ATGGCAGCTGGTTGC ACTGCCCCTGCTGTG TAGATTATTATTTGG
    TGGCAGCTGGTTGCT CTGCCCCTGCTGTGC AGATTATTATTTGGG
    GGCAGCTGGTTGCTC TGCCCCTGCTGTGCT GATTATTATTTGGGG
    GCAGCTGGTTGCTCC GCCCCTGCTGTGCTG ATTATTATTTGGGGG
    CAGCTGGTTGCTCCA CCCCTGCTGTGCTGC TTATTATTTGGGGGA
    AGCTGGTTGCTCCAT CCCTGCTGTGCTGCT TATTATTTGGGGGAA
    GCTGGTTGCTCCATT CCTGCTGTGCTGCTC ATTATTTGGGGGAAC
    CTGGTTGCTCCATTT CTGCTGTGCTGCTCA TTATTTGGGGGAACT
    TGGTTGCTCCATTTG TGCTGTGCTGCTCAA TATTTGGGGGAACTG
    GGTTGCTCCATTTGA GCTGTGCTGCTCAAG ATTTGGGGGAACTGG
    GTTGCTCCATTTGAG CTGTGCTGCTCAAGG TTTGGGGGAACTGGA
    TTGCTCCATTTGAGA TGTGCTGCTCAAGGC TTGGGGGAACTGGAC
    TGCTCCATTTGAGAG GTGCTGCTCAAGGCC TGGGGGAACTGGACA
    GCTCCATTTGAGAGA TGCTGCTCAAGGCCA GGGGGAACTGGACAC
    CTCCATTTGAGAGAC GCTGCTCAAGGCCAC GGGGAACTGGACACA
    TCCATTTGAGAGACA CTGCTCAAGGCCACA GGGAACTGGACACAA
    CCATTTGAGAGACAC TGCTCAAGGCCACAG GGAACTGGACACAAT
    CATTTGAGAGACACG GCTCAAGGCCACAGG GAACTGGACACAATA
    ATTTGAGAGACACGC CTCAAGGCCACAGGC AACTGGACACAATAG
    TTTGAGAGACACGCT TCAAGGCCACAGGCA ACTGGACACAATAGG
    TTGAGAGACACGCTG CAAGGCCACAGGCAC CTGGACACAATAGGT
    TGAGAGACACGCTGG AAGGCCACAGGCACA TGGACACAATAGGTC
    GAGAGACACGCTGGC AGGCCACAGGCACAC GGACACAATAGGTCT
    AGAGACACGCTGGCG GGCCACAGGCACACA GACACAATAGGTCTT
    GAGACACGCTGGCGA GCCACAGGCACACAG ACACAATAGGTCTTT
    AGACACGCTGGCGAC CCACAGGCACACAGG CACAATAGGTCTTTC
    GACACGCTGGCGACA CACAGGCACACAGGT ACAATAGGTCTTTCT
    ACACGCTGGCGACAC ACAGGCACACAGGTC CAATAGGTCTTTCTC
    CACGCTGGCGACACA CAGGCACACAGGTCT AATAGGTCTTTCTCT
    ACGCTGGCGACACAC AGGCACACAGGTCTC ATAGGTCTTTCTCTC
    CGCTGGCGACACACT GGCACACAGGTCTCA TAGGTCTTTCTCTCA
    GCTGGCGACACACTC GCACACAGGTCTCAT AGGTCTTTCTCTCAG
    CTGGCGACACACTCC CACACAGGTCTCATT GGTCTTTCTCTCAGT
    TGGCGACACACTCCG ACACAGGTCTCATTG GTCTTTCTCTCAGTG
    GGCGACACACTCCGT CACAGGTCTCATTGC TCTTTCTCTCAGTGA
    GCGACACACTCCGTC ACAGGTCTCATTGCT CTTTCTCTCAGTGAA
    TTTCTCTCAGTGAAG
    TTCTCTCAGTGAAGG
    TCTCTCAGTGAAGGT
    CTCTCAGTGAAGGTG
    TCTCAGTGAAGGTGG
    CTCAGTGAAGGTGGG
    TCAGTGAAGGTGGGG
    CAGTGAAGGTGGGGA
    AGTGAAGGTGGGGAG
    GTGAAGGTGGGGAGA
    TGAAGGTGGGGAGAA
    GAAGGTGGGGAGAAG
    AAGGTGGGGAGAAGC
    AGGTGGGGAGAAGCT
    GGTGGGGAGAAGCTG
    GTGGGGAGAAGCTGA
    TGGGGAGAAGCTGAA
    GGGGAGAAGCTGAAC
    GGGAGAAGCTGAACC
    GGAGAAGCTGAACCG
    GAGAAGCTGAACCGG
    AGAAGCTGAACCGGC
    • EXAMPLE 9 Inhibition of IGF-I Binding by Antisense Oligonucleotides to IGf-I Receptor
  • Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR.AS (antisense: 5′-ATCTCTCCGCTTCCTTT-3′; [SEQ ID NO. 10]; ref 13) and IGFR.S (sense control: 5′-GAAAGGAAGCGGAGAGAT-3′; [SEQ ID NO. 11]; Ref 13) IGF-I binding to the cell monolayers was then measured as [0059] 125I-IGF-I.
    • EXAMPLE 10 Inhibition of IGFBP-3 Production Using Antisense Oligonucleotides
  • The results of this experiment are shown in FIGS. 7 and 8. [0060]
  • HaCaT cells were initially plated in DMEM with 10% v/v serum, then AS oligo experiments were performed in complete “Keratinocyte-SFM” (Gibco) to exclude the influence of exogenous IGFBPs. Oligos were synthesised as phosphorothioate (nuclease-resistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, 5′-GCGCCCGCTGCATGACGCCTCAAC-3′ (IGFBP-3 start codon); control AS2NS, 5′-CGGAGATGCCGCATGCCAGCGCAGG-3′; AS4, 5′-AGGCGGCTGACGGCACTA-3′; AS4NS, 5′-GACAGCGTCGGAGCGATC-3′; IGFRAS, 5′-ATCTCTCCGCTTCCTTTC-3′; IGFRS, 5′-GAAAGGAAGCGGAGAGAT-3′. Oligos to IGFBP-3 were based on the published sequence of Spratt et al [12]. AS oligos were added to HaCaT monolayers in 0.5 ml medium in 24-well plates at the concentrations and addition frequencies indicated. IGFBP-3 measured in cell-conditioned medium using a dot-blot assay, adapted from the Western ligand blot method of Hossenlopp et al [11], in which 100 μl of conditioned medium was applied to nitrocellulose filters with a vacuum dot-blot apparatus. After drying the membranes at 37° C., relative amounts of IGFBP are determined by [0061] 125I-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in FIG. 7, where duplicate wells were measured as shown) were analysed and corrected for changes in cell number per well. Relative cell number per well was determined using an amido black dye method, developed specifically for cultured monolayers of HaCaT cells (14). Cell numbers differed by less than 10% after treatment. For oligos to the IGF receptor, receptor quantitation in intact HaCaT monolayers was by overnight incubation with 125I-IGF-I (30,000 cpm/well) at 4° C.
    • EXAMPLE11 Inhibition of IGFBP-2 Production Using Ribozymes
  • Experiments involving ribozymes are generally conducted as described in Internaitonal Patent Application No. WO 89/05852 and in Haselhoff and Gerlach [8]. Ribozymes are constructed with a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA which, in this case, encodes IGFBP-2. Activity of ribozymes is measurable on, for example, Northern blots or using animal models such as in the nude mouse model ([0062] 15; 16) or the “flaky skin” mouse model (17; 18).
    • EXAMPLE 12 Inhibition of IGFBP-3 Production Using Ribozymes
  • The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11. [0063]
    • EXAMPLE 13 Inhibition of IGF-1 Production Using Ribozymes
  • The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11. [0064]
    • EXAMPLE 14 Inhibition of IGF-1 Receptor Production Using Ribozymes
  • The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11 [0065]
  • Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. [0066]
  • References: [0067]
  • 1. Sara V [0068] Physiological Reviews 70: 591-614, 1990.
  • 2. Rechler M M and Brown A L [0069] Growth Regulation 2: 55-68, 1992.
  • 3. Clemmons D R [0070] Growth Regn 2: 80, 1992.
  • 4. Oakes S R, K M Haynes, M J Waters, A C Herington and G A Werther [0071] J. Clin Endocrinol Metab 73: 1368-1373, 1992.
  • 5. Camacho-Hubner C et al. [0072] J Biol Chem 267: 11949-11956, 1992.
  • 6. Neely K E et al. [0073] J Inv Derm 96: 104, 1991.
  • 7. Ts'O POP; Aurelian L, Chang E and Miller P S. Nonionic oligonucleotide analogs (Matagen TM) as anticodic agents in duplex and triplex formation. in “Antisense Strategies”, Annals of the New York Academy of Sciences 660:159-177 (Baserga R and Denhardt D T, eds.), 1993. [0074]
  • 8. Haseloff J and Gerlach L [0075] Nature 334: 586-591, 1988.
  • 9. Boukamp P, Petrussevska R T, Breitkreuz D, Hornung J, Markham A, Fusenig N E. [0076] J Cell Biol 106: 761-771, 1988.
  • 10. Rheinwald and Green Cell 6: 331-344, 1975. [0077]
  • 11. Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S, Binoux M. [0078] Anal Biochem 154: 138-143, 1986.
  • 12. Spratt S K, Tatsuno G P, Yamanaka M K, Ark B C, Detmer J, Mascarenhas D, Flynn J, Talkington-Verser C, Spencer E M. [0079] Growth Factors 3: 63-72, 1990.
  • 13. Pietrzkowski, Z, Sell C, Lammers R, Ullrich A and Baserga R. [0080] Mol. Cell. Biol. 12: 3883-3889, 1992.
  • 14. Schulz J, Dettlaff S, Fritzsche U, Harms U, Schiebel H, Derer W, Fusenig N E, Hulsen A and Bohm M. [0081] J. Immunol Meth. 167: 1-13, 1994.
  • 15. Baker B S, Brent L, Valdimarsson H, Powles A V, Al-Imara L, Walker M and Fry L. Brit. [0082] J Bermatol 126: 105-110, 1992.
  • 16. Nanney L B et al [0083] J Invest. Bermatol 98: 296-301, 1992.
  • 17. Sundberg J P et al [0084] Immunol. Investigations 22: 389401, 1993.
  • 18. Sundberg J P et al [0085] J Invest. Dermatol 102: 781-788, 1994.
  • 0
    SEQUENCE LISTING
    (1) GENERAL INFORMATION:
    (iii) NUMBER OF SEQUENCES: 11
    (2) INFORMATION FOR SEQ ID NO: 1:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 1433 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (B) CLONE: Cloning, sequence analysis and expression...
    (ix) FEATURE:
    (A) NAME/KEY: Coding Sequence
    (B) LOCATION: 118...1101
    (D) OTHER INFORMATION:
    (x) PUBLICATION INFORMATION:
    (A) AUTHORS: Binkert, C., et al.
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
    ATTCGGGGCG AGGGAGGAGG AAGAAGCGGA GGAGGCGGCT CCCGCTCGCA GGGCCGTGCA 60
    CCTGCCCGCC CGCCCGCTCG CTCGCTCGCC CGCCGCGCCG CGCTGCCGAC CGCCAGC ATG 120
    Met
    1
    CTG CCG AGA GTG GGC TGC CCC GCG CTG CCG CTG CCG CCG CCG CCG CTG 168
    Leu Pro Arg Val Gly Cys Pro Ala Leu Pro Leu Pro Pro Pro Pro Leu
    5 10 15
    CTG CCG CTG CTG CCG CTG CTG CTG CTG CTA CTG GGC GCG AGT GGC GGC 216
    Leu Pro Leu Leu Pro Leu Leu Leu Leu Leu Leu Gly Ala Ser Gly Gly
    20 25 30
    GGC GGC GGG GCG CGC GCG GAG GTG CTG TTC CGC TGC CCG CCC TGC ACA 264
    Gly Gly Gly Ala Arg Ala Glu Val Leu Phe Arg Cys Pro Pro Cys Thr
    35 40 45
    CCC GAG CGC CTG GCC GCC TGC GGG CCC CCG CCG GTT GCG CCG CCC GCC 312
    Pro Glu Arg Leu Ala Ala Cys Gly Pro Pro Pro Val Ala Pro Pro Ala
    50 55 60 65
    GCG GTG GCC GCA GTG GCC GGA GGC GCC CGC ATG CCA TGC GCG GAG CTC 360
    Ala Val Ala Ala Val Ala Gly Gly Ala Arg Met Pro Cys Ala Glu Leu
    70 75 80
    GTC CGG GAG CCG GGC TGC GGC TGC TGC TCG GTG TGC GCC CGG CTG GAG 408
    Val Arg Glu Pro Gly Cys Gly Cys Cys Ser Val Cys Ala Arg Leu Glu
    85 90 95
    GGC GAG GCG TGC GGC GTC TAC ACC CCG CGC TGC GGC CAG GGG CTG CGC 456
    Gly Glu Ala Cys Gly Val Tyr Thr Pro Arg Cys Gly Gln Gly Leu Arg
    100 105 110
    TGC TAT CCC CAC CCG GGC TCC GAG CTG CCC CTG CAG GCG CTG GTC ATG 504
    Cys Tyr Pro His Pro Gly Ser Glu Leu Pro Leu Gln Ala Leu Val Met
    115 120 125
    GGC GAG GGC ACT TGT GAG AAG CGC CGG GAC GCC GAG TAT GGC GCC AGC 552
    Gly Glu Gly Thr Cys Glu Lys Arg Arg Asp Ala Glu Tyr Gly Ala Ser
    130 135 140 145
    CCG GAG CAG GTT GCA GAC AAT GGC GAT GAC CAC TCA GAA GGA GGC CTG 600
    Pro Glu Gln Val Ala Asp Asn Gly Asp Asp His Ser Glu Gly Gly Leu
    150 155 160
    GTG GAG AAC CAC GTG GAC AGC ACC ATG AAC ATG TTG GGC GGG GGA GGC 648
    Val Glu Asn His Val Asp Ser Thr Met Asn Met Leu Gly Gly Gly Gly
    165 170 175
    AGT GCT GGC CGG AAG CCC CTC AAG TCG GGT ATG AAG GAG CTG GCC GTG 696
    Ser Ala Gly Arg Lys Pro Leu Lys Ser Gly Met Lys Glu Leu Ala Val
    180 185 190
    TTC CGG GAG AAG GTC ACT GAG CAG CAC CGG CAG ATG GGC AAG GGT GGC 744
    Phe Arg Glu Lys Val Thr Glu Gln His Arg Gln Met Gly Lys Gly Gly
    195 200 205
    AAG CAT CAC CTT GGC CTG GAG GAG CCC AAG AAG CTG CGA CCA CCC CCT 792
    Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg Pro Pro Pro
    210 215 220 225
    GCC AGG ACT CCC TGC CAA CAG GAA CTG GAC CAG GTC CTG GAG CGG ATC 840
    Ala Arg Thr Pro Cys Gln Gln Glu Leu Asp Gln Val Leu Glu Arg Ile
    230 235 240
    TCC ACC ATG CGC CTT CCG GAT GAG CGG GGC CCT CTG GAG CAC CTC TAC 888
    Ser Thr Met Arg Leu Pro Asp Glu Arg Gly Pro Leu Glu His Leu Tyr
    245 250 255
    TCC CTG CAC ATC CCC AAC TGT GAC AAG CAT GGC CTG TAC AAC CTC AAA 936
    Ser Leu His Ile Pro Asn Cys Asp Lys His Gly Leu Tyr Asn Leu Lys
    260 265 270
    CAG TGC AAG ATG TCT CTG AAC GGG CAG CGT GGG GAG TGC TGG TGT GTG 984
    Gln Cys Lys Met Ser Leu Asn Gly Gln Arg Gly Glu Cys Trp Cys Val
    275 280 285
    AAC CCC AAC ACC GGG AAG CTG ATC CAG GGA GCC CCC ACC ATC CGG GGG 1032
    Asn Pro Asn Thr Gly Lys Leu Ile Gln Gly Ala Pro Thr Ile Arg Gly
    290 295 300 305
    GAC CCC GAG TGT CAT CTC TTC TAC AAT GAG CAG CAG GAG GCT TGC GGG 1080
    Asp Pro Glu Cys His Leu Phe Tyr Asn Glu Gln Gln Glu Ala Cys Gly
    310 315 320
    GTG CAC ACC CAG CGG ATG CAG TAGACCGCAG CCAGCCGGTG CCTGGCGCCC CTGC 1135
    Val His Thr Gln Arg Met Gln
    325
    CCCCCGCCCC TCTCCAAACA CCGGCAGAAA ACGGAGAGTG CTTGGGTGGT GGGTGCTGGA 1195
    GGATTTTCCA GTTCTGACAC ACGTATTTAT ATTTGGAAAG AGACCAGCAC CGAGCTCGGC 1255
    ACCTCCCCGG CCTCTCTCTT CCCAGCTGCA GATGCCACAC CTGCTCCTTC TTGCTTTCCC 1315
    CGGGGGAGGA AGGGGGTTGT GGTCGGGGAG CTGGGGTACA GGTTTGGGGA GGGGGAAGAG 1375
    AAATTTTTAT TTTTGAACCC CTGTGTCCCT TTTGCATAAG ATTAAAGGAA GGAAAAGT 1433
    (2) INFORMATION FOR SEQ ID NO: 2:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 2474 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (B) CLONE: Cloning and expression of the growth...
    (ix) FEATURE:
    (A) NAME/KEY: Coding Sequence
    (B) LOCATION: 110...982
    (D) OTHER INFORMATION:
    (x) PUBLICATION INFORMATION:
    (A) AUTHORS: Wood, W.I., et al.
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
    CTCAGCGCCC AGCCGCTTCC TGCCTGGATT CCACAGCTTC GCGCCGTGTA CTGTCGCCCC 60
    ATCCCTGCGC GCCCAGCCTG CCAAGCAGCG TGCCCCGGTT GCAGGCGTC ATG CAG CGG 118
    Met Gln Arg
    1
    GCG CGA CCC ACG CTC TGG GCC GCT GCG CTG ACT CTG CTG GTG CTG CTC 166
    Ala Arg Pro Thr Leu Trp Ala Ala Ala Leu Thr Leu Leu Val Leu Leu
    5 10 15
    CGC GGG CCG CCG GTG GCG CGG GCT GGC GCG AGC TCG GGG GGC TTG GGT 214
    Arg Gly Pro Pro Val Ala Arg Ala Gly Ala Ser Ser Gly Gly Leu Gly
    20 25 30 35
    CCC GTG GTG CGC TGC GAG CCG TGC GAC GCG CGT GCA CTG GCC CAG TGC 262
    Pro Val Val Arg Cys Glu Pro Cys Asp Ala Arg Ala Leu Ala Gln Cys
    40 45 50
    GCG CCT CCG CCC GCC GTG TGC GCG GAG CTG GTG CGC GAG CCG GGC TGC 310
    Ala Pro Pro Pro Ala Val Cys Ala Glu Leu Val Arg Glu Pro Gly Cys
    55 60 65
    GGC TGC TGC CTG ACG TGC GCA CTG AGC GAG GGC CAG CCG TGC GGC ATC 358
    Gly Cys Cys Leu Thr Cys Ala Leu Ser Glu Gly Gln Pro Cys Gly Ile
    70 75 80
    TAC ACC GAG CGC TGT GGC TCC GGC CTT CGC TGC CAG CCG TCG CCC GAC 406
    Tyr Thr Glu Arg Cys Gly Ser Gly Leu Arg Cys Gln Pro Ser Pro Asp
    85 90 95
    GAG GCG CGA CCG CTG CAG GCG CTG CTG GAC GGC CGC GGG CTC TGC GTC 454
    Glu Ala Arg Pro Leu Gln Ala Leu Leu Asp Gly Arg Gly Leu Cys Val
    100 105 110 115
    AAC GCT AGT GCC GTC AGC CGC CTG CGC GCC TAC CTG CTG CCA GCG CCG 502
    Asn Ala Ser Ala Val Ser Arg Leu Arg Ala Tyr Leu Leu Pro Ala Pro
    120 125 130
    CCA GCT CCA GGA AAT GCT AGT GAG TCG GAG GAA GAC CGC AGC GCC GGC 550
    Pro Ala Pro Gly Asn Ala Ser Glu Ser Glu Glu Asp Arg Ser Ala Gly
    135 140 145
    AGT GTG GAG AGC CCG TCC GTC TCC AGC ACG CAC CGG GTG TCT GAT CCC 598
    Ser Val Glu Ser Pro Ser Val Ser Ser Thr His Arg Val Ser Asp Pro
    150 155 160
    AAG TTC CAC CCC CTC CAT TCA AAG ATA ATC ATC ATC AAG AAA GGG CAT 646
    Lys Phe His Pro Leu His Ser Lys Ile Ile Ile Ile Lys Lys Gly His
    165 170 175
    GCT AAA GAC AGC CAG CGC TAC AAA GTT GAC TAC GAG TCT CAG AGC ACA 694
    Ala Lys Asp Ser Gln Arg Tyr Lys Val Asp Tyr Glu Ser Gln Ser Thr
    180 185 190 195
    GAT ACC CAG AAC TTC TCC TCC GAG TCC AAG CGG GAG ACA GAA TAT GGT 742
    Asp Thr Gln Asn Phe Ser Ser Glu Ser Lys Arg Glu Thr Glu Tyr Gly
    200 205 210
    CCC TGC CGT AGA GAA ATG GAA GAC ACA CTG AAT CAC CTG AAG TTC CTC 790
    Pro Cys Arg Arg Glu Met Glu Asp Thr Leu Asn His Leu Lys Phe Leu
    215 220 225
    AAT GTG CTG AGT CCC AGG GGT GTA CAC ATT CCC AAC TGT GAC AAG AAG 838
    Asn Val Leu Ser Pro Arg Gly Val His Ile Pro Asn Cys Asp Lys Lys
    230 235 240
    GGA TTT TAT AAG AAA AAG CAG TGT CGC CCT TCC AAA GGC AGG AAG CGG 886
    Gly Phe Tyr Lys Lys Lys Gln Cys Arg Pro Ser Lys Gly Arg Lys Arg
    245 250 255
    GGC TTC TGC TGG TGT GTG GAT AAG TAT GGG CAG CCT CTC CCA GGC TAC 934
    Gly Phe Cys Trp Cys Val Asp Lys Tyr Gly Gln Pro Leu Pro Gly Tyr
    260 265 270 275
    ACC ACC AAG GGG AAG GAG GAC GTG CAC TGC TAC AGC ATG CAG AGC AAG T 983
    Thr Thr Lys Gly Lys Glu Asp Val His Cys Tyr Ser Met Gln Ser Lys
    280 285 290
    AGACGCCTGC CGCAAGTTAA TGTGGAGCTC AAATATGCCT TATTTTGCAC AAAAGACTGC 1043
    CAAGGACATG ACCAGCAGCT GGCTACAGCC TCGATTTATA TTTCTGTTTG TGGTGAACTG 1103
    ATTTTTTTTA AACCAAAGTT TAGAAAGAGG TTTTTGAAAT GCCTATGGTT TCTTTGAATG 1163
    GTAAACTTGA GCATCTTTTC ACTTTCCAGT AGTCAGCAAA GAGCAGTTTG AATTTTCTTG 1223
    TCGCTTCCTA TCAAAATATT CAGAGACTCG AGCACAGCAC CCAGACTTCA TGCGCCCGTG 1283
    GAATGCTCAC CACATGTTGG TCGAAGCGGC CGACCACTGA CTTTGTGACT TAGGCGGCTG 1343
    TGTTGCCTAT GTAGAGAACA CGCTTCACCC CCACTCCCCG TACAGTGCGC ACAGGCTTTA 1403
    TCGAGAATAG GAAAACCTTT AAACCCCGGT CATCCGGACA TCCCAACGCA TGCTCCTGGA 1463
    GCTCACAGCC TTCTGTGGTG TCATTTCTGA AACAAGGGCG TGGATCCCTC AACCAAGAAG 1523
    AATGTTTATG TCTTCAAGTG ACCTGTACTG CTTGGGGACT ATTGGAGAAA ATAAGGTGGA 1583
    GTCCTACTTG TTTAAAAAAT ATGTATCTAA GAATGTTCTA GGGCACTCTG GGAACCTATA 1643
    AAGGCAGGTA TTTCGGGCCC TCCTCTTCAG GAATCTTCCT GAAGACATGG CCCAGTCGAA 1703
    GGCCCAGGAT GGCTTTTGCT GCGGCCCCGT GGGGTAGGAG GGACAGAGAG ACGGGAGAGT 1763
    CAGCCTCCAC ATTCAGAGGC ATCACAAGTA ATGGCACAAT TCTTCGGATG ACTGCAGAAA 1823
    ATAGTGTTTT GTAGTTCAAC AACTCAAGAC GAAGCTTATT TCTGAGGATA AGCTCTTTAA 1883
    AGGCAAAGCT TTATTTTCAT CTCTCATCTT TTGTCCTCCT TAGCACAATG TAAAAAAGAA 1943
    TAGTAATATC AGAACAGGAA GGAGGAATGG CTTGCTGGGG AGCCCATCCA GGACACTGGG 2003
    AGCACATAGA GATTCACCCA TGTTTGTTGA ACTTAGAGTC ATTCTCATGC TTTTCTTTAT 2063
    AATTCACACA TATATGCAGA GAAGATATGT TCTTGTTAAC ATTGTATACA ACATAGCCCC 2123
    AAATATAGTA AGATCTATAC TAGATAATCC TAGATGAAAT GTTAGAGATG CTATATGATA 2183
    CAACTGTGGC CATGACTGAG GAAAGGAGCT CACGCCCAGA GACTGGGCTG CTCTCCCGGA 2243
    GGCCAAACCC AAGAAGGTCT GGCAAAGTCA GGCTCAGGGA GACTCTGCCC TGCTGCAGAC 2303
    CTCGGTGTGG ACACACGCTG CATAGAGCTC TCCTTGAAAA CAGAGGGGTC TCAAGACATT 2363
    CTGCCTACCT ATTAGCTTTT CTTTATTTTT TTAACTTTTT GGGGGGAAAA GTATTTTTGA 2423
    GAAGTTTGTC TTGCAATGTA TTTATAAATA GTAAATAAAG TTTTTACCAT T 2474
    (2) INFORMATION FOR SEQ ID NO: 3:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 4989 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (x) PUBLICATION INFORMATION:
    (A) AUTHORS: Ullrich, A., et al.
    (B) TITLE: Insulin-like growth factor I receptor...
    (C) JOURNAL: EMBO J.
    (D) VOLUME: 5
    (E) ISSUE: 1986
    (F) PAGES: 2503-2512
    (G) DATE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:
    TTTTTTTTTT TTTTGAGAAA GGGAATTTCA TCCCAAATAA AAGGAATGAA GTCTGGCTCC 60
    GGAGGAGGGT CCCCGACCTC GCTGTGGGGG CTCCTGTTTC TCTCCGCCGC GCTCTCGCTC 120
    TGGCCGACGA GTGGAGAAAT CTGCGGGCCA GGCATCGACA TCCGCAACGA CTATCAGCAG 180
    CTGAAGCGCC TGGAGAACTG CACGGTGATC GAGGGCTACC TCCACATCCT GCTCATCTCC 240
    AAGGCCGAGG ACTACCGCAG CTACCGCTTC CCCAAGCTCA CGGTCATTAC CGAGTACTTG 300
    CTGCTGTTCC GAGTGGCTGG CCTCGAGAGC CTCGGAGACC TCTTCCCCAA CCTCACGGTC 360
    ATCCGCGGCT GGAAACTCTT CTACAACTAC GCCCTGGTCA TCTTCGAGAT GACCAATCTC 420
    AAGGATATTG GGCTTTACAA CCTGAGGAAC ATTACTCGGG GGGCCATCAG GATTGAGAAA 480
    AATGCTGACC TCTGTTACCT CTCCACTGTG GACTGGTCCC TGATCCTGGA TGCGGTGTCC 540
    AATAACTACA TTGTGGGGAA TAAGCCCCCA AAGGAATGTG GGGACCTGTG TCCAGGGACC 600
    ATGGAGGAGA AGCCGATGTG TGAGAAGACC ACCATCAACA ATGAGTACAA CTACCGCTGC 660
    TGGACCACAA ACCGCTGCCA GAAAATGTGC CCAAGCACGT GTGGGAAGCG GGCGTGCACC 720
    GAGAACAATG AGTGCTGCCA CCCCGAGTGC CTGGGCAGCT GCAGCGCGCC TGACAACGAC 780
    ACGGCCTGTG TAGCTTGCCG CCACTACTAC TATGCCGGTG TCTGTGTGCC TGCCTGCCCG 840
    CCCAACACCT ACAGGTTTGA GGGCTGGCGC TGTGTGGACC GTGACTTCTG CGCCAACATC 900
    CTCAGCGCCG AGAGCAGCGA CTCCGAGGGG TTTGTGATCC ACGACGGCGA GTGCATGCAG 960
    GAGTGCCCCT CGGGCTTCAT CCGCAACGGC AGCCAGAGCA TGTACTGCAT CCCTTGTGAA 1020
    GGTCCTTGCC CGAAGGTCTG TGAGGAAGAA AAGAAAACAA AGACCATTGA TTCTGTTACT 1080
    TCTGCTCAGA TGCTCCAAGG ATGCACCATC TTCAAGGGCA ATTTGCTCAT TAACATCCGA 1140
    CGGGGGAATA ACATTGCTTC AGAGCTGGAG AACTTCATGG GGCTCATCGA GGTGGTGACG 1200
    GGCTACGTGA AGATCCGCCA TTCTCATGCC TTGGTCTCCT TGTCCTTCCT AAAAAACCTT 1260
    CGCCTCATCC TAGGAGAGGA GCAGCTAGAA GGGAATTACT CCTTCTACGT CCTCGACAAC 1320
    CAGAACTTGC AGCAACTGTG GGACTGGGAC CACCGCAACC TGACCATCAA AGCAGGGAAA 1380
    ATGTACTTTG CTTTCAATCC CAAATTATGT GTTTCCGAAA TTTACCGCAT GGAGGAAGTG 1440
    ACGGGGACTA AAGGGCGCCA AAGCAAAGGG GACATAAACA CCAGGAACAA CGGGGAGAGA 1500
    GCCTCCTGTG AAAGTGACGT CCTGCATTTC ACCTCCACCA CCACGTCGAA GAATCGCATC 1560
    ATCATAACCT GGCACCGGTA CCGGCCCCCT GACTACAGGG ATCTCATCAG CTTCACCGTT 1620
    TACTACAAGG AAGCACCCTT TAAGAATGTC ACAGAGTATG ATGGGCAGGA TGCCTGCGGC 1680
    TCCAACAGCT GGAACATGGT GGACGTGGAC CTCCCGCCCA ACAAGGACGT GGAGCCCGGC 1740
    ATCTTACTAC ATGGGCTGAA GCCCTGGACT CAGTACGCCG TTTACGTCAA GGCTGTGACC 1800
    CTCACCATGG TGGAGAACGA CCATATCCGT GGGGCCAAGA GTGAGATCTT GTACATTCGC 1860
    ACCAATGCTT CAGTTCCTTC CATTCCCTTG GACGTTCTTT CAGCATCGAA CTCCTCTTCT 1920
    CAGTTAATCG TGAAGTGGAA CCCTCCCTCT CTGCCCAACG GCAACCTGAG TTACTACATT 1980
    GTGCGCTGGC AGCGGCAGCC TCAGGACGGC TACCTTTACC GGCACAATTA CTGCTCCAAA 2040
    GACAAAATCC CCATCAGGAA GTATGCCGAC GGCACCATCG ACATTGAGGA GGTCACAGAG 2100
    AACCCCAAGA CTGAGGTGTG TGGTGGGGAG AAAGGGCCTT GCTGCGCCTG CCCCAAAACT 2160
    GAAGCCGAGA AGCAGGCCGA GAAGGAGGAG GCTGAATACC GCAAAGTCTT TGAGAATTTC 2220
    CTGCACAACT CCATCTTCGT GCCCAGACCT GAAAGGAAGC GGAGAGATGT CATGCAAGTG 2280
    GCCAACACCA CCATGTCCAG CCGAAGCAGG AACACCACGG CCGCAGACAC CTACAACATC 2340
    ACCGACCCGG AAGAGCTGGA GACAGAGTAC CCTTTCTTTG AGAGCAGAGT GGATAACAAG 2400
    GAGAGAACTG TCATTTCTAA CCTTCGGCCT TTCACATTGT ACCGCATCGA TATCCACAGC 2460
    TGCAACCACG AGGCTGAGAA GCTGGGCTGC AGCGCCTCCA ACTTCGTCTT TGCAAGGACT 2520
    ATGCCCGCAG AAGGAGCAGA TGACATTCCT GGGCCAGTGA CCTGGGAGCC AAGGCCTGAA 2580
    AACTCCATCT TTTTAAAGTG GCCGGAACCT GAGAATCCCA ATGGATTGAT TCTAATGTAT 2640
    GAAATAAAAT ACGGATCACA AGTTGAGGAT CAGCGAGAAT GTGTGTCCAG ACAGGAATAC 2700
    AGGAAGTATG GAGGGGCCAA GCTAAACCGG CTAAACCCGG GGAACTACAC AGCCCGGATT 2760
    CAGGCCACAT CTCTCTCTGG GAATGGGTCG TGGACAGATC CTGTGTTCTT CTATGTCCAG 2820
    GCCAAAACAG GATATGAAAA CTTCATCCAT CTGATCATCG CTCTGCCCGT CGCTGTCCTG 2880
    TTGATCGTGG GAGGGTTGGT GATTATGCTG TACGTCTTCC ATAGAAAGAG AAATAACAGC 2940
    AGGCTGGGGA ATGGAGTGCT GTATGCCTCT GTGAACCCGG AGTACTTCAG CGCTGCTGAT 3000
    GTGTACGTTC CTGATGAGTG GGAGGTGGCT CGGGAGAAGA TCACCATGAG CCGGGAACTT 3060
    GGGCAGGGGT CGTTTGGGAT GGTCTATGAA GGAGTTGCCA AGGGTGTGGT GAAAGATGAA 3120
    CCTGAAACCA GAGTGGCCAT TAAAACAGTG AACGAGGCCG CAAGCATGCG TGAGAGGATT 3180
    GAGTTTCTCA ACGAAGCTTC TGTGATGAAG GAGTTCAATT GTCACCATGT GGTGCGATTG 3240
    CTGGGTGTGG TGTCCCAAGG CCAGCCAACA CTGGTCATCA TGGAACTGAT GACACGGGGC 3300
    GATCTCAAAA GTTATCTCCG GTCTCTGAGG CCAGAAATGG AGAATAATCC AGTCCTAGCA 3360
    CCTCCAAGCC TGAGCAAGAT GATTCAGATG GCCGGAGAGA TTGCAGACGG CATGGCATAC 3420
    CTCAACGCCA ATAAGTTCGT CCACAGAGAC CTTGCTGCCC GGAATTGCAT GGTAGCCGAA 3480
    GATTTCACAG TCAAAATCGG AGATTTTGGT ATGACGCGAG ATATCTATGA GACAGACTAT 3540
    TACCGGAAAG GAGGCAAAGG GCTGCTGCCC GTGCGCTGGA TGTCTCCTGA GTCCCTCAAG 3600
    GATGGAGTCT TCACCACTTA CTCGGACGTC TGGTCCTTCG GGGTCGTCCT CTGGGAGATC 3660
    GCCACACTGG CCGAGCAGCC CTACCAGGGC TTGTCCAACG AGCAAGTCCT TCGCTTCGTC 3720
    ATGGAGGGCG GCCTTCTGGA CAAGCCAGAC AACTGTCCTG ACATGCTGTT TGAACTGATG 3780
    CGCATGTGCT GGCAGTATAA CCCCAAGATG AGGCCTTCCT TCCTGGAGAT CATCAGCAGC 3840
    ATCAAAGAGG AGATGGAGCC TGGCTTCCGG GAGGTCTCCT TCTACTACAG CGAGGAGAAC 3900
    AAGCTGCCCG AGCCGGAGGA GCTGGACCTG GAGCCAGAGA ACATGGAGAG CGTCCCCCTG 3960
    GACCCCTCGG CCTCCTCGTC CTCCCTGCCA CTGCCCGACA GACACTCAGG ACACAAGGCC 4020
    GAGAACGGCC CCGGCCCTGG GGTGCTGGTC CTCCGCGCCA GCTTCGACGA GAGACAGCCT 4080
    TACGCCCACA TGAACGGGGG CCGCAAGAAC GAGCGGGCCT TGCCGCTGCC CCAGTCTTCG 4140
    ACCTGCTGAT CCTTGGATCC TGAATCTGTG CAAACAGTAA CGTGTGCGCA CGCGCAGCGG 4200
    GGTGGGGGGG GAGAGAGAGT TTTAACAATC CATTCACAAG CCTCCTGTAC CTCAGTGGAT 4260
    CTTCAGTTCT GCCCTTGCTG CCCGCGGGAG ACAGCTTCTC TGCAGTAAAA CACATTTGGG 4320
    ATGTTCCTTT TTTCAATATG CAAGCAGCTT TTTATTCCCT GCCCAAACCC TTAACTGACA 4380
    TGGGCCTTTA AGAACCTTAA TGACAACACT TAATAGCAAC AGAGCACTTG AGAACCAGTC 4440
    TCCTCACTCT GTCCCTGTCC TTCCCTGTTC TCCCTTTCTC TCTCCTCTCT GCTTCATAAC 4500
    GGAAAAATAA TTGCCACAAG TCCAGCTGGG AAGCCCTTTT TATCAGTTTG AGGAAGTGGC 4560
    TGTCCCTGTG GCCCCATCCA ACCACTGTAC ACACCCGCCT GACACCGTGG GTCATTACAA 4620
    AAAAACACGT GGAGATGGAA ATTTTTACCT TTATCTTTCA CCTTTCTAGG GACATGAAAT 4680
    TTACAAAGGG CCATCGTTCA TCCAAGGCTG TTACCATTTT AACGCTGCCT AATTTTGCCA 4740
    AAATCCTGAA CTTTCTCCCT CATCGGCCCG GCGCTGATTC CTCGTGTCCG GAGGCATGGG 4800
    TGAGCATGGC AGCTGGTTGC TCCATTTGAG AGACACGCTG GCGACACACT CCGTCCATCC 4860
    GACTGCCCCT GCTGTGCTGC TCAAGGCCAC AGGCACACAG GTCTCATTGC TTCTGACTAG 4920
    ATTATTATTT GGGGGAACTG GACACAATAG GTCTTTCTCT CAGTGAAGGT GGGGAGAAGC 4980
    TGAACCGGC 4989
    (2) INFORMATION FOR SEQ ID NO: 4:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 25 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:
    GCGCCCGCTG CATGACGCCT GCAAC 25
    (2) INFORMATION FOR SEQ ID NO: 5:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 24 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
    CGGGCGGCTC ACCTGGAGCT GGCG 24
    (2) INFORMATION FOR SEQ ID NO: 6:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 18 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:
    AGGCGGCTGA CGGCACTA 18
    (2) INFORMATION FOR SEQ ID NO: 7:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 19 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:
    CAGGCGTCAT GCAGCGGGC 19
    (2) INFORMATION FOR SEQ ID NO: 8:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 25 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8:
    CGGAGATGCC GCATGCCAGC GCAGG 25
    (2) INFORMATION FOR SEQ ID NO: 9:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 18 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:
    GACAGCGTCG GAGCGATC 18
    (2) INFORMATION FOR SEQ ID NO: 10:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 18 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:
    ATCTCTCCGC TTCCTTTC 18
    (2) INFORMATION FOR SEQ ID NO: 11:
    (i) SEQUENCE CHARACTERISTICS:
    (A) LENGTH: 18 base pairs
    (B) TYPE: nucleic acid
    (C) STRANDEDNESS: single
    (D) TOPOLOGY: linear
    (ii) MOLECULE TYPE: cDNA
    (iii) HYPOTHETICAL: NO
    (iv) ANTI-SENSE: NO
    (v) FRAGMENT TYPE: <Unknown>
    (vi) ORIGINAL SOURCE:
    (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:
    GAAAGGAAGC GGAGAGAT 18

Claims (29)

1. A method for ameliorating the effects of a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing growth factor mediated cell proliferation and/or inflammation.
2. A method according to claim 1 wherein cell proliferation and/or inflammation is mediated by at least one of insulin-like growth factor I (IGF-I ), keratinocyte growth factor (KGF), transforming growth factor-α (TGFα), tumour necrosis factor-α (TNFα), interleukin (IL)-1 (IL-1), IL-4, IL-6, IL-8 and/or basic fibroblast growth factor (bFGF).
3. A method according to claim 2 wherein cell proliferation and/or inflammation is mediated by IGF-I.
4. A method according to claim 1 wherein the nucleic acid molecule inhibits or otherwise reduces IGF-I mediated cell proliferation and/or inflammation.
5. A method according to claim 1 wherein the proliferative or inflammatory skin disorder is psoriasis, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths or cancers of the skin.
6. A method according to claim 5 wherein the skin condition is psoriasis.
7. A method according to claim 1 or 4 or 6 wherein the mammal is a human.
8. A method according to claim 1 or 4 or 6 wherein the nucleic acid molecule is capable of inhibiting, reducing or otherwise interfering with IGF-I-interaction with its receptor.
9. A method according to claim 8 wherein the nucleic acid molecule is an antisense molecule capable of reducing expression of a gene encoding IGF-I, IGF-I-receptor or an IGF binding protein (IGFBP).
10. A method according to claim 9 wherein the nucleic acid molecule is an antisense molecule capable of reducing expression of a gene encoding IGFBP-2, -3, -4, -5 or -6.
11. A method according to claim 10 wherein the nucleic acid molecule is an antisense molecule capable of reducing expression of a gene encoding IGFBP-2 or IGFBP-3.
12. A method according to claim 11 wherein the antisense molecule is at least about 15 nucleotides in length and is capable of interacting with at least one sequence selected from the list set forth in Example 6 or Example 7.
13. A method according to claim 11 wherein the antisense molecule comprises the nucleotide sequence:
5′-ATCTCTCCGCTTCCTTTC-3′. [SEQ ID NO:10]
14. A nucleic acid molecule comprising at least about 10 nucleotides capable of hybridising to or forming a heteroduplex or otherwise interacting with an RNA molecule directed from a gene corresponding to a genomic form of SEQ ID NO: 1 and/or SEQ ID NO: 2 and which thereby reduces or inhibits translation of said RNA molecule.
15. A nucleic acid molecule according to claim 14 wherein said molecule comprises at least about 15 nucleotides.
16. A nucleic acid molecule according to claim 15 wherein said molecule is capable of interacting with at least one nucleotide sequence selected from the list set forth in Example 6 and Example 7.
17. A nucleic acid molecule according to claim 15 or 16 comprising the nucleotide sequence:
5′-ATCTCTCCGCTTCCTTTC-3′. [SEQ ID NO:10]
18. A method of ameliorating the effects of psoriasis, said method comprising contacting proliferating skin or skin capable of proliferation with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP.
19. A method according to claim 18 wherein the IGFBP is IGFBP-2 or IGFBP-3.
20. A method according to claim 18 or 19 wherein the mammal is a human.
21. A method according to claim 20 wherein the nucleic acid molecule is capable of interacting with a nucleotide sequence selected from the list set forth in Example 6 or Example 7.
22. A method according to claim 18 wherein the nucleic acid molecule comprises the nucleotide sequence:
5′-ATCTCTCCGCTTCCTTTC-3′. [SEQ ID NO:10]
23. A pharmaceutical composition for topical administration said composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation said composition further comprising one or more pharmaceutically acceptable carriers and/or diluents.
24. A pharmaceutical composition according to claim 23 wherein the nucleic acid molecule is an antisense molecule to a gene encoding IGF-I, IGF-I-receptor or an IGFBP.
25. A pharmaceutical composition according to claim 24 wherein the nucleic acid molecule is capable of targeting a gene encoding IGFBP-2 and/or IGFBP-3.
26. A pharmaceutical composition according to claim 24 capable of interacting with at least one nucleotide sequence set forth in Example 6 or Example 7.
27. Use of a nucleic acid molecule in the manufacture of a medicament for the treatment of a proliferative and/or inflammatory skin disorder mediated by IGF-I.
28. Use according to claim 27 wherein the skin disorder is psoriasis.
29. A ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to SEQ ID NO: 1or SEQ ID NO: 2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation or inflammation.
US09/791,196 1994-07-08 2001-02-23 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders Abandoned US20030096769A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US09/791,196 US20030096769A1 (en) 1994-07-08 2001-02-23 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
AUPM6725/94 1994-07-08
AUPM6725A AUPM672594A0 (en) 1994-07-08 1994-07-08 A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
US08/666,392 US5929040A (en) 1994-07-08 1995-07-06 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
US09/199,926 US6284741B1 (en) 1994-07-08 1998-11-25 Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders
US09/791,196 US20030096769A1 (en) 1994-07-08 2001-02-23 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/199,926 Continuation US6284741B1 (en) 1994-07-08 1998-11-25 Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders

Publications (1)

Publication Number Publication Date
US20030096769A1 true US20030096769A1 (en) 2003-05-22

Family

ID=3781291

Family Applications (3)

Application Number Title Priority Date Filing Date
US08/666,392 Expired - Fee Related US5929040A (en) 1994-07-08 1995-07-06 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
US09/199,926 Expired - Fee Related US6284741B1 (en) 1994-07-08 1998-11-25 Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders
US09/791,196 Abandoned US20030096769A1 (en) 1994-07-08 2001-02-23 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US08/666,392 Expired - Fee Related US5929040A (en) 1994-07-08 1995-07-06 Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
US09/199,926 Expired - Fee Related US6284741B1 (en) 1994-07-08 1998-11-25 Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders

Country Status (7)

Country Link
US (3) US5929040A (en)
EP (1) EP0776210A4 (en)
JP (1) JPH10508286A (en)
AU (1) AUPM672594A0 (en)
CA (1) CA2194366A1 (en)
NZ (2) NZ289028A (en)
WO (1) WO1996001636A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282761A1 (en) * 2003-02-28 2005-12-22 George Tachas Modulation of growth hormone receptor expression and insulin-like growth factor expression
WO2006138315A2 (en) 2005-06-15 2006-12-28 Schering Corporation Anti-igf1r antibody formulations
US20090068110A1 (en) * 2006-12-22 2009-03-12 Genentech, Inc. Antibodies to insulin-like growth factor receptor
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy
EP2281841A2 (en) 2004-12-03 2011-02-09 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
US20110092572A1 (en) * 2003-02-28 2011-04-21 Antisense Therapeutics Limited Modulation of growth hormone receptor expression and insulin-like growth factor expression

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPM672594A0 (en) * 1994-07-08 1994-08-04 Royal Children's Hospital Research Foundation A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
US6147056A (en) * 1995-06-06 2000-11-14 Trustees Of Boston University Use of locally applied DNA fragments
US20030165888A1 (en) 2001-07-18 2003-09-04 Brown Bob D. Oligonucleotide probes and primers comprising universal bases for diagnostic purposes
US6518017B1 (en) * 1997-10-02 2003-02-11 Oasis Biosciences Incorporated Combinatorial antisense library
US6020339A (en) * 1997-10-03 2000-02-01 Merck & Co., Inc. Aryl furan derivatives as PDE IV inhibitors
DE19757250A1 (en) * 1997-12-22 1999-07-01 Forssmann Wolf Georg Prof Dr Insulin-like growth factor binding protein and its use
KR100820266B1 (en) 1999-02-26 2008-04-08 더 유니버시티 오브 브리티쉬 콜롬비아 TRPM-2 antisense therapy
JP2003517283A (en) * 1999-04-08 2003-05-27 オアシス バイオサイエンシーズ インコーポレイティッド Amplification and sequencing of primer pairs and their use
KR20020013519A (en) * 1999-04-08 2002-02-20 추후제출 Antisense Oligonucleotides Comprising Universal and/or Degenerate Bases
EP2363478B1 (en) * 1999-04-21 2019-07-24 Alnylam Pharmaceuticals, Inc. Methods and compositions for inhibiting the function of polynucleotide sequences
US20040138168A1 (en) * 1999-04-21 2004-07-15 Wyeth Methods and compositions for inhibiting the function of polynucleotide sequences
JP2003502383A (en) * 1999-06-21 2003-01-21 マードック チルドレンズ リサーチ インスティチュート Method for prevention and / or treatment of medical disorders
US6900186B1 (en) * 1999-06-21 2005-05-31 Murdock Children's Research Institute Method for the prophylaxis and/or treatment of medical disorders
ATE314856T1 (en) * 1999-10-26 2006-02-15 Immusol Inc RIBOZYME THERAPY FOR THE TREATMENT OF PROLIFERATIVE EYE DISEASES
US6770633B1 (en) 1999-10-26 2004-08-03 Immusol, Inc. Ribozyme therapy for the treatment of proliferative skin and eye diseases
US7569551B2 (en) 2000-02-25 2009-08-04 The University Of British Columbia Chemo- and radiation-sensitization of cancer by antisense TRPM-2 oligodeoxynucleotides
HU229207B1 (en) * 2000-09-14 2013-09-30 Univ British Columbia Antisense insulin-like growth factor binding protein (igfbp)-2-oligodeoxynucleotides for prostate and other endocrine regulated tumor therapy
AUPR030900A0 (en) 2000-09-22 2000-10-12 Queensland University Of Technology Growth factor complex
US6861406B2 (en) * 2001-09-18 2005-03-01 Bioexpertise, Llc IGF-binding protein-derived peptide
US6914049B2 (en) * 2001-09-18 2005-07-05 Bioexpertise, Llc IGF-binding protein-derived peptide or small molecule
US6887851B2 (en) * 2001-09-18 2005-05-03 Bioexpertise, Llc IGF-binding protein-derived peptide
DE60322509D1 (en) * 2002-01-17 2008-09-11 Univ British Columbia BIS-SPECIFIC ANTISENSE OLIGONUCLEOTIDES INHIBIT THE IGFBP-2 AND IGFBP-5 AND THEIR USE
DE10233994A1 (en) * 2002-07-25 2004-02-12 Phenion Gmbh & Co. Kg Cosmetic or pharmaceutical preparations containing nucleic acids based on non-methylated CpG motifs
WO2004018675A1 (en) * 2002-08-21 2004-03-04 The University Of British Columbia Treatment of melanoma by reduction in clusterin levels
AU2007216630B2 (en) * 2002-08-21 2010-09-16 The University Of British Columbia RNAi probes targeting cancer-related proteins
CA2882443C (en) 2002-08-21 2016-12-13 The University Of British Columbia Rnai probes targeting cancer-related proteins
US20040121407A1 (en) * 2002-09-06 2004-06-24 Elixir Pharmaceuticals, Inc. Regulation of the growth hormone/IGF-1 axis
WO2004043395A2 (en) * 2002-11-14 2004-05-27 Wyeth Methods and compositions for treating neurological disorders
US20060276394A1 (en) * 2002-11-14 2006-12-07 Wyeth Methods and compositions for treating neurological disorders
US20100143442A1 (en) 2003-02-05 2010-06-10 Queensland University Of Technology Growth factor complexes and modulation of cell migration and growth
AU2003900481A0 (en) 2003-02-05 2003-02-20 Queensland University Of Technology Synthetic modulators of cell migration and growth
WO2004092378A2 (en) * 2003-04-18 2004-10-28 The University Of British Columbia Method for treatment of cancerous angiogenic disorders
JP2007523839A (en) * 2003-04-18 2007-08-23 ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア Treatment of angiogenic disorders
CA2539727C (en) * 2003-10-01 2016-11-01 The University Of British Columbia Bispecific oligonucleotide for the treatment of cns malignancies
DE10361502A1 (en) * 2003-12-23 2005-07-28 Phenion Gmbh & Co. Kg Cosmetic or pharmaceutical preparations containing superstructure-forming nucleic acid sequences
US8710020B2 (en) * 2004-04-02 2014-04-29 The University Of British Columbia Clusterin antisense therapy for treatment of cancer
WO2006056054A1 (en) * 2004-11-23 2006-06-01 The University Of British Columbia Treatment of cancer with a combination of an agent that perturbs the egf signaling pathway and an oligonucleotide that reduces clusterin levels
US8383598B2 (en) * 2005-10-12 2013-02-26 Idera Pharmaceuticals, Inc. Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response
RU2012127364A (en) 2009-11-30 2014-01-10 Квинсленд Юниверсити Оф Текнолоджи CHIMERS FIBRONECTIN: GROWTH FACTOR
WO2011139710A1 (en) * 2010-04-26 2011-11-10 Marina Biotech, Inc. Nucleic acid compounds with conformationally restricted monomers and uses thereof
ES2664237T3 (en) 2012-03-13 2018-04-18 James Cook University Ac-TMP-2 for use in the treatment of inflammation
WO2018077889A1 (en) * 2016-10-24 2018-05-03 Almirall, S.A. Compositions comprising linsitinib

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643788A (en) * 1993-03-26 1997-07-01 Thomas Jefferson University Method of inhibiting the proliferation and causing the differentiation of cells with IGF-1 receptor antisense oligonucleotides
US6284741B1 (en) * 1994-07-08 2001-09-04 Royal Children's Hospital Research Foundation Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5176996A (en) * 1988-12-20 1993-01-05 Baylor College Of Medicine Method for making synthetic oligonucleotides which bind specifically to target sites on duplex DNA molecules, by forming a colinear triplex, the synthetic oligonucleotides and methods of use
IE20010427A1 (en) * 1990-04-10 2003-03-05 Canji Inc Gene therapy for cell proliferative diseases
US5585479A (en) * 1992-07-24 1996-12-17 The United States Of America As Represented By The Secretary Of The Navy Antisense oligonucleotides directed against human ELAM-I RNA
WO1994023034A2 (en) * 1993-04-06 1994-10-13 Cedars-Sinai Medical Center Variant insulin-like growth factor i receptor subunits and methods for use thereof
AU3760595A (en) * 1994-10-04 1996-04-26 Emory University Methods for regulation of insulin-like growth factor i receptor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643788A (en) * 1993-03-26 1997-07-01 Thomas Jefferson University Method of inhibiting the proliferation and causing the differentiation of cells with IGF-1 receptor antisense oligonucleotides
US6284741B1 (en) * 1994-07-08 2001-09-04 Royal Children's Hospital Research Foundation Method for the prophylaxis and/or treatment of proliferative and /or inflammatory skin disorders

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282761A1 (en) * 2003-02-28 2005-12-22 George Tachas Modulation of growth hormone receptor expression and insulin-like growth factor expression
US20110092572A1 (en) * 2003-02-28 2011-04-21 Antisense Therapeutics Limited Modulation of growth hormone receptor expression and insulin-like growth factor expression
US8299039B2 (en) * 2003-02-28 2012-10-30 Isis Pharmaceuticals, Inc. Modulation of growth hormone receptor expression and insulin-like growth factor expression
US8623836B2 (en) 2003-02-28 2014-01-07 Isis Pharmaceuticals, Inc. Modulation of growth hormone receptor expression and insulin-like growth factor expression
US8637484B2 (en) 2003-02-28 2014-01-28 Isis Pharmaceuticals, Inc. Modulation of growth hormone receptor expression and insulin-like growth factor expression
US9371530B2 (en) 2003-02-28 2016-06-21 Antisense Therapeutics Ltd. Modulation of growth hormone receptor expression and insulin-like growth factor expression
US9988635B2 (en) 2003-02-28 2018-06-05 Antisense Therapeutics Limited Modulation of growth hormone receptor expression and insulin-like growth factor expression
EP2281841A2 (en) 2004-12-03 2011-02-09 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
EP2283831A2 (en) 2004-12-03 2011-02-16 Schering Corporation Biomakers for pre-selection of patients for anti-IGF1R therapy
WO2006138315A2 (en) 2005-06-15 2006-12-28 Schering Corporation Anti-igf1r antibody formulations
US20090068110A1 (en) * 2006-12-22 2009-03-12 Genentech, Inc. Antibodies to insulin-like growth factor receptor
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy

Also Published As

Publication number Publication date
CA2194366A1 (en) 1996-01-25
NZ329202A (en) 2001-08-31
NZ289028A (en) 1998-01-26
EP0776210A4 (en) 2000-06-07
EP0776210A1 (en) 1997-06-04
US6284741B1 (en) 2001-09-04
JPH10508286A (en) 1998-08-18
AUPM672594A0 (en) 1994-08-04
WO1996001636A1 (en) 1996-01-25
US5929040A (en) 1999-07-27

Similar Documents

Publication Publication Date Title
US20030096769A1 (en) Method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
AU768904B2 (en) A method for the prophylaxis and/or treatment of medical disorders
Resnicoff et al. Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors
Cohen et al. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice
Rabchevsky et al. A role for transforming growth factor α as an inducer of astrogliosis
Werner et al. New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia
Wu et al. Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpy Mutant
Liu et al. TIMP3: a physiological regulator of adult myogenesis
Breuhahn et al. Epidermal overexpression of granulocyte-macrophage colony-stimulating factor induces both keratinocyte proliferation and apoptosis
Finotto et al. Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma
Brossier et al. Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system
DE60038680T2 (en) ANTISENSE THERAPY FOR HORMONE-REGULATED TUMORS
Kamanga‐Sollo et al. Role of insulin‐like growth factor binding protein (IGFBP)‐3 in TGF‐β‐and GDF‐8 (myostatin)‐induced suppression of proliferation in porcine embryonic myogenic cell cultures
US20050261230A1 (en) Method for the prophylaxis and/or treatment of medical disorders
US11077110B2 (en) Compositions and methods for treating and preventing metabolic disorders
US8399421B2 (en) Treatment for neuropathic pain due to spinal cord injury
Harmancey et al. Adrenomedullin inhibits adipogenesis under transcriptional control of insulin
AU692278B2 (en) A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders
Flint et al. Prolactin inhibits cell loss and decreases matrix metalloproteinase expression in the involuting mouse mammary gland but fails to prevent cell loss in the mammary glands of mice expressing IGFBP-5 as a mammary transgene
Yang et al. Opposite regulation of IGF-I and IGF-I receptor mRNA and concomitant changes of GH receptor and IGF-II/M6P receptor mRNA in human IM-9 lymphoblasts
US20130261057A1 (en) Methods for therapeutic treatment of benign prostatic hypertrophy (bph)
Wolf et al. Increases in levels of collagen types I and IV messenger ribonucleic acid in murine kidneys after treatment with ciclosporin
US20050250123A1 (en) Reducing galectin-12 activity to reduce formation of adipocytes
KR20210090660A (en) ANGPTL4 oligonucleotides affecting the regulation of fatty acid metabolism
Esposito et al. Molecular mechanisms in chronic pancreatitis

Legal Events

Date Code Title Description
AS Assignment

Owner name: MURDOCH CHILDREN'S RESEARCH INSTITUTE, AUSTRALIA

Free format text: RELATIONSHIP AGREEMENT; ASSET AND LIABILITY TRANSFER AGREEMENT;ASSIGNOR:ROYAL CHILDREN'S HOSPITAL RESEARCH FOUNDATION;REEL/FRAME:014724/0806

Effective date: 19960820

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION