CA2518238A1

CA2518238A1 - Association of polymorphic kinase anchor proteins with cardiac phenotypes and related methods

Info

Publication number: CA2518238A1
Application number: CA002518238A
Authority: CA
Inventors: Andreas Braun; Stefan M. Kammerer
Original assignee: Sequenom, Inc.; Andreas Braun; Stefan M. Kammerer
Current assignee: Sequenom Inc
Priority date: 2003-03-07
Filing date: 2004-03-05
Publication date: 2004-09-23
Also published as: WO2004081576A2; WO2004081576A3; EP1601972A2; AU2004219665A1

Abstract

Polymorphic A-kinase anchor proteins (AKAPs) and nucleic acids encoding the proteins are provided herein. Methods of detecting polymorphic AKAPs and nucleic acids encoding the AKAPs, and kits for use in the detection methods are also provided. Further provided herein are methods of identifying subjects having or at risk of developing diseases or disorders, such as those related to signal transduction and/or cardiovascular disease. Methods of determining susceptibility to morbidity and/or increased or early mortality are also provided.

Description

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ASSOCIATION OF POLYMORPHIC KINASE ANCHOR PROTEINS WITH
CARDIAC PHENOTYPES AND RELATED METHODS
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. provisional application Serial No. 60/453,215, to Andrews Braun and Stefan Kammerer entitled "ASSOCIATION OF POLYMORPHIC KINASE ANCHOR
PROTEINS WITH CARDIAC PHENOTYPES AND RELATED METHODS", filed March 7, 2003, U.S. provisional application Serial No. 60/453,208, to Andrews Braun and Stefan Kammerer entitled "ASSOCIATION OF
POLYMORPHIC KINASE ANCHOR PROTEINS WITH CARDIAC
PHENOTYPES AND RELATED METHODS", filed March 7, 2003, and U.S.
provisional application Serial No. 50/453,350, to Andrews Braun and Stefan Kammerer entitled "ASSOCIATION OF POLYMORPHIC KINASE
ANCHOR PROTEINS WITH CARDIAC PHENOTYPES AND RELATED
METHODS", filed March 7, 2003.
Where permitted, the subject matter of each of the above-noted wpplicwtions is incorporated herein by reference. ~4lso, e~here permitted the subject mwtter and disclosure of U.S. Application Serial No.
09/834,700 to Andrews Braun entitled "POLYMORPHIC KINASE
ANCHOR PROTEINS AND NUCLEIC ACIDS ENCODING THE SAME", filed April 12, 2001, and U.S. Application Serial No. 10/428,254 to Andrews Braun, Charles Cantor, Stefan Kammerer, Susan Taylor, and Lora Burns, entitled "KINASE ANCHOR PROTEIN MUTEINS, PEPTIDES THEREOF, AND RELATED METHODS", filed May 1, 2003, are incorporated by reference.
FIELD OF THE INVENTION
Methods of identifying subjects having or at a risk of developing disorders of cellular protein phosphorylation and/or signal transduction.

Methods of determining susceptibility to morbidity and/or increased or early mortality are also provided.
BACKGROUND OF THE INVENTION
Protein phosphorylation is an important mechanism for enzyme regulation and the transduction of extracellular signals across the cell membrane in eukaryotic cells. A wide variety of cellular substrates, including enzymes, membrane receptors, ion channels and transcription factors, can be phosphorylated in response to extracellular signals that interact with cells. A key enzyme in the phosphorylation of cellular proteins in response to hormones and neurotransmitters is cyclic AMP
(cAMP)-dependent protein kinase (PKA). Upon activation by CAMP, PKA
thus mediates a variety of cellular responses to such extracellular signals.
An array of PI<A isozymes are expressed in mammalian cells. The PKAs usually exist as inactive tetrameres containing a regulatory (R) subunifi dimer and two catalytic (C) subunits. Genes encoding three C
subunits (Ca, C,r3 and Cy) and four R subunits (Rla, R1~3, Rlla and RII,~) have been identified (see Takio e~ al. (1982) Proo. f~la~l. load. Soi, ll.S.
A. ~~:2544-2548; Lee e~ al. ( 1983) Proc. f~la~'7. ~l oad. Sci. (l. S. A, 50:36~8-3612; Jahnsen et al, ( 1996) J. Siol. Chem. 26':12352-12361;
Clegg et al. ( 1988) Proe, l~latl. ~I cad, Sci. U. S. ~l. 55:3703-37~7; and Scott (1991 ) Pharmacol. Ther. 50:123-145). The type I (RI) a and type II
(R11) a subunits are distributed ubiquitously, whereas RI,~ and R11~3 are present mainly in brain (see. e.g,, Miki and Eddy (1999) J. Siol. Ohem.
274:29057-29052). The type I PKA holoenzyme (Rla and R1~3) is predominantly cytoplasmic, whereas the majority of type II PKA (Rlla and R11~3) associates with cellular structures and organelles (Scott (1991) Pharmacol. Ther, 50:123-145). Many hormones and other signals act through receptors to generate cAMP which binds to the R subunits of PKA and releases and activates the C subunits to phosphorylate proteins.

Because protein kinases and their substrates are widely distributed throughout cells, there are mechanisms in place in cells to localize protein kinase-mediated responses to different signals. One such mechanism involves subcellular targeting of PKAs through association with anchoring proteins, referred to as A-kinase anchoring proteins (AKAPs), that place PKAs in close proximity to specific organelles or cytoskeletal components and particular substrates thereby providing for more specific PKA
interactions and localized responses (see, e.g., Scott et al. (1990) J. Biol.
Chem. 265:21561-21566; Bregman et al. (1991) J. Biol. Chem.
266:7207-7213; and Miki and Eddy (1999) J. Biol. Chem. 274:29057-29062). Anchoring not only places the kinase close to preferred substrates, but also positions the PI<A holoenzyme at sites where it can optimally respond to fluctuations in the second messenger cAMP
(Mochly-Rosen ( 1995) Science 26B:247-251; Faux and Scott ( 1996) Trends Biochem. Sci. 2 7:312-315; Hubbard and Cohen ( 1993) Trends Biochem. Sci. ?B:172-177).
Up to 75~/~ of type II PKs4 is localized to various intracellular sites through association of the regulatory subunit (R11) with AKAPs (see, e.g., Hausken et' al. (1996) J. Biol. Chem. 277:29016-29022). RII subunits of PKA bind to AI<APs with nanomolar affinity (Carr et al. ( 1992) J. Biol.
Chem. 267:13376-13382), and many AKAP-RII complexes have been isolated from cell extracts. RI subunits of PKA bind to AKAPs with only micromolar affinity (Burton et al. (1997) Proc. Nat/, a4cad. Sci. U.S.~I.
94:1 1067-1 1072). Evidence of binding of a PKA RI subunit to an AKAP
has been reported (Miki and Eddy (1998) J. Biol. Chem 273:34384-34390) in which Rla-specific and Rla/Rlla dual specificity PKA anchoring domains were identified on FSC1 /AKAP82. Additional dual specific AKAPs, referred to as D-AKAP1 and D-AKAP2, which interact with the type I and type II regulatory subunits of PKA have also been reported (Huang et al. (1997) J. Biol. Chem. 272:8057-8064; Huang et al, (1997) Proc. Nat/, Acad. Sci. U.S.A, 94:11184-11189).
More than 20 AKAPs have been reported in different tissues and species. Complementary DNAs (cDNAs) encoding AKAPs have been isolated from diverse species, ranging from Caenorhabditis alegans and Drosophilia to human (see, e.g., Colledge and Scott (1999) Trends Cell Biol. 9:216-221 ). Regions within AKAPs that mediate association with RII subunits of PKA have been identified. These regions of approximately 10-18 amino acid residues vary substantially in primary sequence, but 1~ secondary structure predictions indicate that they are likely to form an amphipathic helix with hydrophobic residues aligned along one face of the helix and charged residues along the other (Cart et al. (1991 ) J. Biol.
Chem. 256:14188-14192; Carr et al, (1992) J. Biol. Chem. 267:13375-13382). Hydrophobic amino acids with a long aliphatic side chain, e.g., valine, leucine or isoleucine, can participate in binding to RII subunits (Glantz et al. (1993) J. Biol. Chem. 265:12796-12804).
f~iany AKc~Ps als~ have the ability to bind to multiple proteins, including ~ther signaling enzymes. For example, AICAP79 binds t~ PKA, protein kinase C (PI<C) and the protein phosphatase calcineurin (PP2B) 2~ (Coghlan et al. (1995) Science 257:108-1 12 and Klauck et al. (1995) Science 277:1589-1592). Therefore, the targeting of AKAP79 t~
neuronal postsynaptic membranes brings together enzymes with opposite catalytic activities in a single complex.
AKAPs thus serve as potential regulatory mechanisms that increase the selectivity and intensity of a CAMP-mediated response.
There is a need, therefore, to identify and elucidate the structural and functional properties of AKAPs in order to gain a complete understanding of the important role these proteins play in the basic functioning of cells.

SUMMARY
Provided herein are methods for indicating increased susceptibility of a subject to a disease or disorder. The methods include assessment of the presence or absence of an allele of the an AKAP gene and other aspects, including determining EKG features, or methods in which the AKAP gene is predictive of treatment outcome or response. Methods provided herein include steps of conducting an EKG examination;
determining the EKG-PR-interval in the subject. If the EKG-PR-interval is decreased, then identity of an amino acid present in the subject at position 646 of AKAP10/D-AKAP2 (SEQ ID NO:2) or a nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1 is assessed. The presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SECT ID N0:1, indicates increased susceptibility to a disease or disorder. The disease or disorder can be selected from among a variety of diseases and discorders, including, but are not limited to, cardiovascular disorders, cardiac disease, proliferative disorders, neurological disorders, neurodegenerative disorders, obesity, diabetes and peripheral refiinopathies.
Also provided are methods for indicating increased susceptibility of a subject to a disease or disorder associated with the cardiovascular system, by conducting an EI<G exam; determining the EKG-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present at position 646 of AI<AP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder associated with the cardiovascular system. The EKG-PR-interval in the subject can be compared to a predetermined age-matched standard EKG-PR-interval to determine whether it is decreased.
Also provided herein are methods of assessing the susceptibility of a subject to a disease or disorder associated with the cardiovascular system, the method comprising determining the amino acid at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G-at nucleotide position 2073 of SEQ ID NO:1, indicates increased 1~ susceptibility to a disease or disorder associated with the cardiovascular system.
Also provided herein are methods of diagnosing a disease or disorder associated with the cardiovascular system, comprising detecting the presence of Val at 646 of D-AI<AP2 (SECT ID N0:2) or the presence of a G at a nucleotide position corresponding to nucleotide 2073 of SEQ
ID N0:1, wherein the presence of Val at position 646 of SEQ ID NO:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID f~0:1, indicates the presence of a disease or disorder associated with the cardiovascular system. In these methods, fihe disease or disorder can be 2~ from among, but not limited to, one or more of the group consisting of:
atrial fibrillation, sick sinus syndrome, sudden cardiac arrest, ventricular arrythmia, ventricular fibrillation, ventricular tachycardia, Wolf-Parkinson-White (WPW) Syndrome, Lown-Ganong-Levin (LGL) Syndrome, hypertension.
Provided herein are methods for determining responsiveness of a subject to one or more /3-blocking agents, comprising detecting for the subject the presence or absence of Val at position 646 of SEQ ID
N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID

N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has a modulated response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. In one embodiment, the modulated response is a decreased response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. In another embodiment, the decreased response is a non-response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. In yet another embodiment, the modulated response is an increased response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. The ,r3-blocker can be an antagonist of a ,Q-adrenergic receptor. In another embodiment, the ,~-blocker is an agonist of a ,Q-adrenergic receptor.
Also provided herein are methods for determining responsiveness of a subject to one or more ~3-blocking agents, comprising detecting the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G-nucleotide at a positi~n corresponding to position 2073 ~f SEA ID f~0: 1, wherein the presence of a Val at position 646 of SECT ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has an increased response to one or more ,~-blocking agents compared to a subject who does not have the allelic varianfi.
Also provided herein, are methods for determining responsiveness of a subject to one or more ,~-blocking agents, comprising detecting for the subject the presence or absence of Val at position 646 of SEQ ID
N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID
N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is non-responsive to one or more ,~-_$_ blocking agents compared to a subject who does not have the allelic variant.
Also provided herein are methods for determining responsiveness of a subject to one or more ~3-blocking agents, comprising detecting the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G
nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is hyper-responsive to one or more /3-blocking agents 1 ~ compared to a subject who does not have the allelic variant.
Provided herein are methods for indicating susceptibility of a subject to acquired long Q-T syndrome, comprising detecting the presence or absence of Val at position 646 of SEQ ID N0:2 or presence or absence of a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of increased susceptibility to acquired long Q-T syndrome, compared to the susceptibility of a subject who does not have the allelic variant. In accordance with this embodiment, the detecting step can be effected by a method selected from the group consisting of allele specific hybridization, primer specific extension, oligonucleotide ligation assay, restriction enzyme site analysis and single-stranded conformation polymorphism analysis. Also provided herein, the detecting step can comprise mass spectrometry. Also provided herein, detection can be effected by detecting a signal moiety selected from the group consisting of radioisotopes, enzymes, antigens, antibodies, spectrophotometric reagents, chemiluminescent reagents, fluorescent reagents and other light producing reagents.

_g_ Also provided herein, are methods for indicating susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a subject; comprising conducting an EKG exam;
determining the EKG-PR-interval in the subject, wherein if the EKG-PR-interval is decreased; then determining the amino acid at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEO. ID N0:1, indicates increased susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a subject.
In one embodiment of each of the methods provided herein, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous !!al/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment of each of the methods provided herein, the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEO. ID 10:1 or homozygous Val/!!al at a position corresponding to position 646 of SECT ID N0:2.
Another non-synonymous D-AKAP2 variation retrieved from dbSNP
2~ has been verified. The G-A transversion in axon 4 results in an Arg to His substitution at position 249 of SEQ ID N0:2 (R249H; corresponding to a G to A transversion at nucleotide 883 of SEQ ID N0:1 encoding human D-AKAP2). The Arg at residue 249 of SEQ ID N0:2 was found to be in complete linkage disequilibrium with the Ile at position 646 of SEQ
ID N0:646, occurring together in every case, and therefore shows the same age effect. Accordingly, in the each of the methods provided herein, where a subject is assayed for the genotype at position 2073 of SEQ ID N0:1, the subject can also be assayed for the genotype at position 883 of SEQ ID N0:1. The genotype -G- at position 883 of SEQ

ID N0:1 corresponds to genotype -A- at nucleotide 2073 of SEQ ID N0:1 and vice versa. Likewise, in the methods provided herein the genotype -A- at position 883 of SEQ ID N0:1 corresponds to genotype -G- at nucleotide 2073 of SEQ ID N0:1 and vice versa. For amino acid residues, the detection of a Ile at residue 646 of SEQ ID N0:2 corresponds to detection of an Arg at residue 249 of SEQ ID N0:2 and vice versa. Likewise, the detection of a Val at residue 646 of SEQ ID
N0:2 corresponds to detection of an His at residue 249 of SEQ ID N0:2 and vice versa.
Further provided are kits for practicing the methods. The kits can include reagents for assessing genotype of an AICAP allele and also reagents and/or components for conducting an EICG and/or a ,~-blocking agent. For e~:ample, a kit for assessing genotype can include a primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 2073 of SEQ ID NO 1 or 3 of an AICAP10 allele or the complement thereof and a second primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to positions selected from the group consisting of position 83587 of SEQ ID NO 13 or 17, position 129600 of SEQ ID NO 14 or 17, and position 156,277 of SEQ ID NO 18 or 17 of an AICAP10 allele or the complement thereof. Primers include, but are not limited to, nucleic acids consisting essentially of the nucleotide sequence of SEQ ID NO: 8, SEQ ID N0: 15, SEQ ID NO: 19 and SEQ ID NO 20.
Other genotyping components of the kit can include a first primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 883 of SEQ ID NO 1 or 3 of an AKAP10 allele or the complement thereof and a second primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to positions selected from the group consisting of position 83587 of SEQ ID NO 13 or 17, position 129600 of SEQ ID NO 14 or 17, and position 156,277 of SEQ ID NO 18 or 17 of an AKAP10 allele or the complement thereof. The kits optionally contain instructions for performing assays, interpreting results or for aiding in peforming the methods. The kits also can include at least one didieoxynucleotide such as ddA, ddC, ddG.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the results of an analysis of covariance that was conducted t~ test the effect of the genotypes on PR mean levels. Age was included as a covariate in the model, which was significantly associated with PR mean up to a third order polynomial. The relationship between age and PR mean was genotype-dependent, and therefore interaction terms between genotype and age were included. The predicted values from the resulting model are shown in Figure 1 for each genotype.
DETAILED DESCRIPTION
D~fir9iti~r~~
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the inventions) belong. All patents, patent applications, published applications and publications, GENBANK
sequences, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the Internet can come and go, but equivalent information is known and can be readily accessed, such as by searching the Internet and/or appropriate databases. Reference thereto evidences the availability and public dissemination of such information.
As used herein, the phrase "EKG examination" or "ECG
examination" refers to the well-known electrocardiogram examination that generates an electrical recording of the heart and is conducted on human subjects to investigate heart function and heart disease.
As used herein, the phrase "PR-interval" or "EKG-PR-interval", in the context of an electrocardiogram (EKG or ECG) analysis, is the time (typically expressed herein in units of milliseconds) elapsed between the beginning of the P wave to the beginning of the next QRS complex. It corresponds to the time lag from the onset of atrial depolarization to the onset of ventricular depolarization. This time lag allows atrial systole to occur, filling the ventricles before ventricular systole. f~iost of the delay occurs in the Al.~ node. The PR interval is longer with high vagal tone. A
prolonged PR interval corresponds to impaired AV conduction. The normal range of PR-intervals from about 120 to 200 milliseconds. It is well-knoe~n that each sguare on a EI~G readout (graph) corresponds to 40 milliseconds.
As used herein the phrase "predetermined standard" refers to an average of a multiplicity of EKG-PR-intervals that can be empirically determined from a specifically chosen group of individuals. The group of individuals can be selected irrespective of disease status, e.g., from a healthy patient database. In another embodiment, the standard can be obtained from a group of control age-matched subjects that do not have a particular disease, such as heart disease. In another embodiment, the predetermined standard can be obtained from a known age-matched control that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2.

As used herein "age-matched standard EKG-PR-interval" refers to the average PR-interval (also referred to herein as "PRmean") for a multiplicity of subjects of the same age. In addition, the average PR-interval can be obtained from controls having the same genotype, such as -AA- homozygotes and/or -GA- heterozygotes at a position corresponding to nucleotide 2073 of SEQ ID N~:1. Accordingly, the EKG-PR-interval can be stratified by age and/or genotype. For example, the EKG-PR-interval of the subject being examined can be compared to PRmean of either: a group of control subjects of the same age having the -AA- homozygous genotype at a position corresponding to nucleotide 2073 of SEQ ID N0:1; a group of control subjects of the same age having the -GA- heterozygous genotype at a position corresponding to nucleotide 2073 of SEA ID N~:1; both groups of control subjects of the same age having either the -AA- homozygous or the -GA- homozygous genotype at a position corresponding to nucleotide 2073 of SEQ ID
N0:1. In another embodiment, the EKG-PR-interval of the subject being e;zamined can be compared to the PRmean of a group of control subjects of the same age having any genotype at a position corresponding to nucleotide 2073 of SEQ ID N~:1.
As used herein, the phrase "disease or disorders" is meant to encompass all genetic or physiological irregularities that can be attributed to a particular body organ or physiological or cellular system. As used herein, the phrase "disorder or disease associated with a decreased EKG-PR-interval" or grammatical variations thereof, refers to any disease or disorder that exhibits a decreased PR-interval as one of its characteristics. Exemplary disorders and/or diseases contemplated herein as associated with decreased EKG-PR-intervals include, but are not limited to, those involving alterations in cellular protein phosphorylation and/or signal transduction. Among such disorders and diseases are:

neurodegeneratives diseases, such as Alzheimer's Disease, cardiovascular disorders, cardiac disorders, particularly disorders associated with altered left ventricular function, cardiomyopathies, proliferative disorders, bipolar disorder and other neurological disorders, obesity, diabetes and certain peripheral retinopathies, such as retinitis pigmentosa. As used herein, cardiovascular disorders or cardiac disease collectively encompass all cardiovascular abnormalities, such as, but not limited to congenital heart disease, cardiac arrhythmia, brachycardia, atrial fibrillation, sick sinus syndrome, sudden cardiac arrest, ventricular 1 ~ arrythmia, ventricular fibrillation, ventricular tachycardia, Wolf-Parkinson-White (WPW) Syndrome, Lown-Ganong-Levin (LGL) Syndrome, hypertension, familial cardiac myxomas and Garney complex.
As used herein, a "decreased" EICG-PR-interval or grammatical variations thereof, refers to a PR-interval that is lower than the average PR-interval (e.g., PRmean) for subjects of the same age group. As set forth herein (e.g., Figure 1 ) the average PR-interval (e.g., PRmean) increases with age for subjects having either a llomozygous -A~4- or heterozygous -GA- genotype at a position corresponding t~ nucleotide 2073 of SEO. ID N0:1 encoding the AKAP10/D-AKAP2 protein. For subjects (e.g., humans) having the homozygous -GG- genotype at a position corresponding to nucleotide 2073 of SEQ ID N0:1, it has been found herein that the average PR-interval is decreased relative to subjects of the same age that have either a homozygous -AA- or heterozygous -GA- genotype. The decreased EICG-PR-interval is evident in subjects from the age of about 40 up to about 70 years of age.
In addition, although the average PR-interval for the -GA-heterozygotes increases with age as with the -AA- homozygotes, the average PR-interval (e.g., PRmean) is always lower for the -GA-heteroaygotes than for the -AA- homozygotes (see Figure 1 ).

Accordingly, in one embodiment, the EKG-PR-interval of the subject being examined is compared to the PRmean (e.g., average PR-interval) of age-matched -AA- homozygotes. This embodiment serves as a preliminary screen for subjects that have either 1 or 2 copies of the 1646V variant (e.g., screen for potential -GA- heterozygotes or -AA-homozygotes at a nucleotide position corresponding to nucleotide 2073 of SEQ ID N0:1 ). In another embodiment, the EKG-PR-interval of the subject being examined is compared to the PRmean (e.g., average PR-interval) of age-matched -GA- heterozygotes. This embodiment serves as preliminary screen for subjects that have 2 copies of the 1646V variant, e.g., subjects that are -GG- homozygotes.
In the methods provided herein, if the EKG-PR-interval is not decreased relative to the age-matched average PR-interval (PRmean) for -AA- homozygotes and/or -GA- heterozygotes at a position corresponding to nucleotide 2073 of SEQ ID N0:1, then there is no need to determine the genotype of the subject.
As used herein, a ~-T interval is the time from electrocardiogram Q
wave to the end of the T wave corresponding to electrical systole. This interval represents the time required for depolarization and repolarization to occur. In long QT syndrome, the duration of repolarization is longer than normal. Thus, the QT-interval is prolonged. An interval above 440 milliseconds (msec) is considered prolonged. An interval at or above 430 milliseconds in females or 470 milliseconds in males typically is sufficient to diagnose a subject as having long QT syndrome.
As used herein, sequencing refers to the process of determining a nucleotide sequence and can be performed using any method known to those of skill in the art. For example, if a polymorphism is identified or known, and it is desired to assess its frequency or presence in nucleic acid samples taken from the subjects that comprise the database, the region of interest from the samples can be isolated, such as by PCR or restriction fragments, hybridization or other suitable method known to those of skill in the art, and sequenced. For purposes herein, sequencing analysis can be carried out using mass spectrometry (see, e.g., U.S.
Patent Nos. 5,547,835, 5,622,824, 5,851,765, and 5,928,906).
Nucleic acids can also be sequenced by hybridization (see, e.g., U.S.
Patent Nos. 5,503,980, 5,631,134, 5,795,714) and including analysis by mass spectrometry (see, U.S. Application Serial Nos. 08/419,994 and 09/395,409). Alternatively, sequencing can be performed using other 1~ known methods, such as set forth in U.S. Patent Nos. 5,525,464;
5,695,940; 5,834,189; 5,869,242; 5,876,934; 5,908,755; 5,912,118;
5,952,174; 5,976,802; 5,981,186; 5,998,143; 6,004,744; 6,017,702;
6,018,041; 6,025,136; 6,046,005; 6,087,095; 6,1 17,634, 6,013,431, W0 98/30883; W0 98/56954; W0 99/09218; W~/00/58519, and the others.
As used herein, "polymorphism" refers to the coexistence of more than one form of a gene or portion thereof. A portion of a gene of which there are at least two different forms, i.e., two different nucleotide sequences, is referred to as a "polymorphic region of a gene". A
polymorphic region can be a single nucleotide, the identity of which differs in different alleles. A polymorphic region can also be several nucleotides in length.
As used herein, "polymorphic gene" refers to a gene having at least one polymorphic region.
As used herein, "allele", which is used interchangeably herein with "allelic variant" refers to alternative forms of a gene or portions thereof.
Alleles occupy the same locus or position on homologous chromosomes.
When a subject has two identical alleles of a gene, the subject is the to be homozygous for the gene or allele. When a subject has two different alleles of a gene, the subject is the to be heterozygous for the gene.
Alleles of a specific gene can differ from each other in a single nucleotide, or several nucleotides, and can include substitutions, deletions, and insertions of nucleotides. An allele of a gene can also be a form of a gene containing a mutation.
As used herein, "predominant allele" refers to an allele that is represented in the greatest frequency for a given population. The allele or alleles that are present in lesser frequency are referred to as allelic variants.
As used herein, "associated" refers to coincidence with the development or manifestation of a disease, condition or phenotype.
Association can be due to, but is not limited to, genes rasp~nsible for housekeeping functions wh~se alteration can provide the foundati~n for a variety of diseases and conditions, those that are part of a pathway that is involved in a specific disease, condition or phenotype and those that indirectly contribute to the manifestation of a disease, condition or phenotype.
As used herein, the term "subject" refers to mammals and in particular human beings.
~0 As used herein, the term "gene" or "recombinant gene" refers to a nucleic acid molecule comprising an open reading frame and including at least one axon and (optionally) an intron sequence. A gene can be either RNA or DNA. Genes can include regions preceding and following the coding region (leader and trailer).
As used herein, "intron" refers to a DNA sequence present in a given gene which is spliced out during mRNA maturation.
As used herein, "nucleotide sequence complementary to the nucleotide sequence set forth in SEQ ID NO: x" refers to the nucleotide sequence of the complementary strand of a nucleic acid strand having SEQ ID NO: x. The term "complementary strand" is used herein interchangeably with the term "complement". The complement of a nucleic acid strand can be the complement of a coding strand or the complement of a non-coding strand. When referring to double stranded nucleic acids, the complement of a nucleic acid having SEQ ID NO: x refers to the complementary strand of the strand having SEQ ID NO: x or to any nucleic acid having the nucleotide sequence of the complementary strand of SEQ ID NO: x. When referring to a single stranded nucleic acid having the nucleotide sequence SEQ ID NO: x, the complement of this nucleic acid is a nucleic acid having a nucleotide sequence which is complementary to that of SEQ ID NO: x.
As used herein, the term "coding sequence" refers to that portion of a gene that encodes an amino acid sequence of a protein.
As used herein, the term "sense strand" refers to that strand of a double-stranded nucleic acid molecule that has the sequence of the mRNA that encodes the amino acid sequence encoded by the double-stranded nucleic acid molecule.
As used herein, the term "antiasnsa strand" refers to that strand of a double-stranded nucleic acid molecule that is the complement of the sequence of the mRNA that encodes the amino acid sequence encoded by the double-stranded nucleic acid molecule.
As used herein, the amino acids, which occur in the various amino acid sequences appearing herein, are identified according to their well-known, three-letter or one-letter abbreviations. The nucleotides, which occur in the various DNA fragments, are designated with the standard single-letter designations used routinely in the art (see, Table 1 ).

As used herein, amino acid residue refers to an amino acid formed upon chemical digestion (hydrolysis) of a polypeptide at its peptide linkages. The amino acid residues described herein are typically in the "L" isomeric form. Residues in the "D" isomeric form can be substituted for any L-amino acid residue, as long as the desired functional property is retained by the polypeptide. NH2 refers to the free amino group present at the amino terminus of a polypeptide. COOH refers to the free carboxy group present at the carboxyl terminus of a polypeptide. In keeping with standard polypeptide nomenclature described in J. Bi~l. ahem.~
243:3552-59 (1969) and adopted at 37 C.F.R. ~ ~ 1.321 - 1.822, abbreviations for amino acid residues are shown in the following Table:
Table 1 Table of Correspondence SYIl~ 80L

1-Letter 3-Letter Af~ilf~~ ACI~

Y Tyr tyrosine G Gly glycine F Phe phenylalanine IVY f!/let methionine 2~ A Ala alanine S Ser serine I Ile isoleucine L Leu leucine T Thr threonine V Val valine P Pro proline IC Lys lysine H His histidine SYM BOL

Q Gln glutamine E Glu glutamic acid Z Glx Glu and/or Gln W Trp tryptophan R Arg arginine D Asp aspartic acid N Asn asparagine B Asx Asn and/or Asp C Cys cysteine ~0 ?~ Xaa Unknown or other It should be noted that all amino acid residue sequences represented herein by formulae have a left to right orientation in the conventional direction of amino-terminus to carboxyl-terminus. In 'i 5 addition, the phrase °°amino acid residue'° is broadly defined to include the amino acids listed in the Table of Correspondence and modified and unusual amino acids, such as those referred to in 37 C.F.R. ~ ~ 1.821-1.822, and incorporated herein by reference. Furthermore, it should be noted that a dash at the beginning or end of an amino acid residue 20 sequence indicates a peptide bond to a further sequence of one or more amino acid residues or to an amino-terminal group such as NH2 or to a carboxyl-terminal group such as COOH.
In a peptide or protein, suitable conservative substitutions of amino acids are known to those of skill in this art and can be made 25 generally without altering the biological activity of the resulting molecule.
Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin/Cummings Pub.
co., p.224).
Such substitutions are typically made in accordance with those set forth in TABLE 2 as follows:

Original residue Conservative substitution Ala (A) Gly; Ser Arg (R) Lys Asn (N) Gln; His Cys (C) Ser Gln (Q) Asn Glu (E) Asp Gly (G) Ala; Pro His (H) Asn; Gln Ile (I) Leu; !/al Leu (L) Ile; val Lys (IC) Arg; Gln; Glu Met (fVl) Leu; Tyr; Ile Phe (F) Met; Leu; Tyr Ser (S) Thr Thr (T) Ser Trp (VV) Tyr Tyr (1') Trp; Phe dal (!/) Ile; Leu Other substitutions permissible and can be determined are also empirically or in accord with known conservative substitutions.
As used herein, a DNA or nucleic acid homolog refers to a nucleic acid that includes a preselected conserved nucleotide sequence, such as a sequence encoding a therapeutic polypeptide. By the term °'substantially homologous°' is meant having at least 80%, typically at least 90%, or at least 95% homology therewith or a less percentage of homology or identity and conserved biological activity or function.
The terms "homology" and "identity" are often used interchangeably. In this regard, percent homology or identity can be determined, for example, by comparing sequence information using a GAP computer program. The GAP program uses the alignment method of Needleman and Wunsch (J. Mol. Biol. 48:443 (1970), as revised by Smith and Waterman (Adv. App/. Math. 2:482 (1981). Briefly, the GAP
program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences. The default parameters for the GAP program can include: (1) a unary comparison matrix (containing a value of 1 for identities and 0 for non-identities) and the weighted comparison matrix of Gribskov and Burgess, Nucl. Acids Res.
14:6745 (1986), as described by Schwartz and Dayhoff, eds., ATLAS
~F PR~TElN SEQUENCE AN~ STRUCTURE, National Biomedical Research Foundation, pp. 353-358 (1979); (2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap; and (3) no penalty for end gaps.
Whether any two nucleic acid molecules have nucleotide sequences that are at least 80°/~, 85°/~, 90°/~, 95°/~, 95°/~, 9%°/~, 98°/~ or 99°/~ "identical" can be determined using known computer algorithms such as the "FAST A" program, using for example, the default parameters as in Pearson and Lipman, Proe. Nat/. Acad. Sci, USA
85:2444 (1988). Alternatively the BLAST function of the National Center for Biotechnology Information database can be used to determine identity In general, sequences are aligned so that the highest order match is obtained. "Identity" per se has an art-recognized meaning and can be calculated using published techniques. (See, e.g.: Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Seguence Data, Part l, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991 ). While there exist a number of methods to measure identity between two polynucleotide or polypeptide sequences, the term "identity" is well known to skilled artisans (Carillo, H. & Lipton, D., SIAM ,J Applied Math 4B:1073 (1988)). Methods commonly employed to determine identity or similarity between two sequences include, but are not limited to, those disclosed in Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo, H. ~ Lipton, D., SIAM J Applied Math 45:1073 (1988). Methods to determine identity and similarity are codified in computer programs. Typical computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCG program package (Devereux, J., et al., Nucleic Acids Research '2(/J:387 (1984)), BLASTP, BLASTN, FASTA (Atschul, S.F., et a/.° ~d lls~~lec Biol ~~~:403 (1990)).
Therefore, as used herein, the term "identity" represents a comparison between a test and a reference polypeptide or polynucleotide. For example, a test polypeptide can be defined as any polypeptide that is 90°/~ or more identical to a reference polypeptide.
As used herein, the term at least "90°/~ identical to" refers to percent identities from 90 to 99.99 relative to the reference polypeptides. Identity at a level of 90% or more is indicative of the fact that, assuming for exemplification purposes a test and reference polypeptide length of 100 amino acids are compared. No more than 10% (i.e., 10 out of 100) amino acids in the test polypeptide differs from that of the reference polypeptides. Similar comparisons can be made between a test and reference polynucleotides. Such differences can be represented as point mutations randomly distributed over the entire length of an amino acid sequence or they can be clustered in one or more locations of varying length up to the maximum allowable, e.g.
10/100 amino acid difference (approximately 90% identity). Differences are defined as nucleic acid or amino acid substitutions, or deletions.
As used herein, stringency conditions refer to the washing conditions for removing the non-specific probes and conditions that are equivalent to either high, medium, or low stringency as described below:
1) high stringency: 0.1 x SSPE, 0.1% SDS, 65°C
2) medium stringency: 0.2 x SSPE, 0.1 % SDS, 50°C
3) low stringency: 1.0 x SSPE, 0.1 % SDS, 50°C.
It is understood that equivalent stringencies can be achieved using alternative buffers, salts and temperatures.
As used herein, "heterologous DNA" is DNA that encodes RNA
and proteins that are not normally produced in vivo by the cell in which it is expressed or that mediates or encodes mediators that alter expression of endogenous Df~A by affecting transcription, translation, or otller regulatable biochemical processes or is not present in the exact orientation or position as the counterpart DNA in a wildtype cell.
Heterologous DNA can also be referred to as foreign DNA. Any DNA
that one of skill in the art would recognize or consider as heterologous or foreign to the cell in which is expressed is herein encompassed by heterologous DNA. Examples of heterologous DNA include, but are not limited to, DNA that encodes traceable marker proteins, such as a protein that confers drug resistance, DNA that encodes therapeutically effective substances, such as anti-cancer agents, enzymes and hormones, and DNA that encodes other types of proteins, such as antibodies.
Antibodies that are encoded by heterologous DNA can be secreted or expressed on the surface of the cell in which the heterologous DNA has been introduced.
As used herein, isolated with reference to a nucleic acid molecule or polypeptide or other biomolecule means that the nucleic acid or polypeptide has separated from the genetic environment from which the polypeptide or nucleic acid were obtained. It can also mean altered from the natural state. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated", as the term is employed herein. Thus, a polypeptide or polynucleotide produced and/or contained within a recombinant host cell is considered isolated. Also intended as an "isolated polypeptide'° or an "isolated polynucleotide°' are polypeptides or polynucleotides that have been purified, partially or substantially, from a recombinant host cell or from a native source. For example, a recombinantly produced version of a compound can be substantially purified by the one-step method described in Smith and Johnson, ~eoe ~a~:~1-4~ (19~~). The terms isolated and purified are sometimes used interchangeably.
2~ Thus, by "isolated" is meant that the nucleic acid is free of the coding sequences of those genes that, in the naturally-occurring genome of the organism (if any) immediately flank the gene encoding the nucleic acid of interest. Isolated DNA can be single-stranded or double-stranded, and can be genomic DNA, cDNA, recombinant hybrid DNA, or synthetic DNA. It can be identical to a native DNA sequence, or can differ from such sequence by the deletion, addition, or substitution of one or more nucleotides.
Isolated or purified as it refers to preparations made from biological cells or hosts means any cell extract containing the indicated DNA or protein including a crude extract of the DNA or protein of interest. For example, in the case of a protein, a purified preparation can be obtained following an individual technique or a series of preparative or biochemical techniques and the DNA or protein of interest can be present at various degrees of purity in these preparations. The procedures can include for example, but are not limited to, ammonium sulfate fractionation, gel filtration, ion exchange change chromatography, affinity chromatography, density gradient centrifugation and electrophoresis.
A preparation of DNA or protein that is "substantially pure" or "isolated" should be understood to mean a preparation free from naturally occurring materials with which such DNA or protein is normally associated in nature. "Essentially pure" should be understood to mean a "highly" purified preparation that contains at least 95% of the DNA or protein of interest.
A cell extract that contains the DNA or protein of interest should be understood to mean a homogenate preparation or cell-free preparation obtained from sells that e~epress the protein or contain the DNA of interest. The term '°cell extract" is intended to include culture media, especially spent culture media from which the cells have been removed.
~~ As used herein, receptor refers to a biologically active molecule that specifically binds to (or with) other molecules. The term °'receptor protein" can be used to more specifically indicate the proteinaceous nature of a specific receptor.
As used herein, recombinant refers to any progeny formed as the result of genetic engineering.
As used herein, a promoter region refers to the portion of DNA of a gene that controls transcription of the DNA to which it is operatively linked. The promoter region includes specific sequences of DNA that are sufficient for RNA polymerise recognition, binding and transcription initiation. This portion of the promoter region is referred to as the promoter. In addition, the promoter region includes sequences that modulate this recognition, binding and transcription initiation activity of the RNA polymerase. These sequences can be cis acting or can be responsive to traps acting factors. Promoters, depending upon the nature of the regulation, can be constitutive or regulated.
As used herein, the phrase "operatively linked" generally means the sequences or segments have been covalently joined into one piece of DNA, whether in single or double stranded form, whereby control or regulatory sequences on one segment control or permit expression or replication or other such control of other segments. The two segments are not necessarily contiguous. For gene earpression a DNA sequence and a regulatory sequences) are connected in such a way to control or permit gene expression when the appropriate molecular, e.g., transcriptional activator proteins, are bound to the regulatory sequences) .
~,s used herein, production by recombinant means by using recombinant DNA methods means the use of the well known methods of molecular biology for expressing proteins encoded by cloned DNA, including cloning expression of genes and methods, such as gene shuffling and phage display with screening for desired specificities.
As used herein, the term °°conjugated" refers stable attachment, such ionic or covalent attachment.
As used herein, a composition refers to any mixture of two or more products or compounds. It can be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.

As used herein, a combination refers to any association between two or more items.
As used herein, substantially identical to a product means sufficiently similar so that the property of interest is sufficiently unchanged so that the substantially identical product can be used in place of the product.
As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
~ne typical vector is an episome, i.e., a nucleic acid capable of 1 ~ extra-chromosomal replication. Typical vectors are those capable of auton~mous replication and/or expression of nucleic acids to which they are linked. Vectors capable of directing the expression of genes t~ which they are operatively linked are referred to herein as "expression vectors".
In general, expression vectors of utility in recombinant ~f~A techniques are often in the form of "plasmids" which refer generally to circular double stranded ~IVA I~ops which, in their vector form are not bound to the chr~m~some. '°Plasmid" and "vector" are used interchangeably as the plasmid is the most commonly used f~rm of vector. ~ther such other forms of expression vectors that serve equivalent functions and that 2~ become known in the art subsequently hereto.
As used herein, "indicating" or "determining" means that the presence or absence of an allelic variant can be one of many factors that are considered when a subject's predisposition to a disease or disorder is evaluated. Thus a predisposition to a disease or disorder is not necessarily conclusively determined by only ascertaining the presence or absence of one or more allelic variants, but the presence of one of more of such variants is among a number of factors considered.
As used herein, "predisposition to develop a disease or disorder"
means that a subject having a particular genotype and/or haplotype has a higher likelihood than one not having such a genotype and/or haplotype for developing a particular disease or disorder.
As used herein, "morbidity" refers to conditions, such as diseases or disorders, that compromise the health and well-being of an organism, such as an animal. Morbidity susceptibility or morbidity-associated genes are genes that, when altered, for example, by a variation in nucleotide sequence, facilitate the expression of a specific disease clinical phenotype. Thus, morbidity susceptibility genes have the potential, upon alteration, of increasing the likelihood or general risk that an organism will develop a specific disease.
As used herein, "mortality" refers to the statistical likelihood that an organism, particularly an animal, will not survive a full predicted lifespan. Hence, a trait or a marker, such as a polymorphism, associated with increased mortality is observed at a lower frequency in older than younger segments of a population.
As used herein, "transgenic animal" refers to any animal, typically a non-human animal, e.~. a mammal, bird or an amphibian, in which one or more of the cells of the animal contain heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. This molecule can be integrated within a chromosome, or it can be extrachromosomally replicating DNA. In the typical transgenic animals described herein, the transgene causes cells to express a recombinant form of a protein. Transgenic animals in which the recombinant gene is silent are also contemplated, as for example, using the FLP or CRE
recombinase dependent constructs. Moreover, "transgenic animal" also includes those recombinant animals in which gene disruption of one or more genes is caused by human intervention, including recombination and antisense techniques.
As used herein, "target nucleic acid" refers to a nucleic acid molecule which contains all or a portion of a polymorphic region of a gene of interest.
As used herein, "signal moiety" refers to any moiety that allows for the detection of a nucleic acid molecule. Included are moieties covalently attached to nucleic acids and those that are not.
As used herein, "molecule that modulates or effects the biological activity of an AICAP10 protein" refers to any drug, small molecule, nucleic acid (sense and antiasnsa), ribozyme, protein, peptide, lipid, carbohydrate ate. or combination thereof, that directly or indirectly changes, alters, abolishes, increases or decreases a biological activity attributed to AI~AP10 protein.
As used herein, "biological activity of an AI~AP10 protein" refers to, but is not limited to, binding of AI~AP10 to protein leinase A or its subunits, localization of AICAP10 protein to a subcellular site, e.g., the mitochondria, localization of protein lcinase A to the mitochondria and binding of AICAP10 protein to other proteins including other signaling enzymes.
As used herein, "combining" refers to contacting the biologically active agent with a cell or animal such that the agent is introduced into the cell or animal. For a cell any method that results in an agent traversing the plasma membrane is useful. For an animal any of the standard routes of administration of an agent, e.g. oral, rectal, transmucosal, intestinal, intravenous, intraperitoneal, intraventricular, subcutaneous, intramuscular, ete., can be used.
As used herein, a composition refers to any mixture. It can be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.
As used herein, a combination refers to any association between two or among more items.
As used herein, "kit" refers to a package that contains a combination, such as one or more primers or probes used to amplify or detect polymorphic regions of AKAP10 genes, optionally including instructions and/or reagents for their use.
As used herein, "solid support" refers to a support substrate or matrix, such as silica, polymeric materials or glass. At least one surface of fibs support can be partially planar. Regions of the support can be physically separated, for example with trenches, grooves, well or the like. Some examples of solid supports include slides and beads.
Supports are of such composition so as to allow for the immobilization or attachment of nucleic acids and other molecules such that these molecules retain their binding ability.
As used herein, "array" refers to a collection of elements, such as nucleic acids, containing three or more members. An addressable array is one in which the members of the array are identifiable, typically by position on a solid support. Hence, in general the members of the array will be immobilized to discrete identifiable loci on the surface of a solid phase.
As used herein, "specifically hybridizes" refers to hybridization of a probe or primer only to a target sequence preferentially to a non-target sequence. Those of skill in the art are familiar with parameters that affect hybridization; such as temperature, probe or primer length and composition, buffer composition and salt concentration and can readily adjust these parameters to achieve specific hybridization of a nucleic acid to a target sequence.
As used herein "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The term should also be understood to include, as equivalents, derivatives, variants and analogs of either RNA or DNA made from nucleotide analogs, single (sense or antisense) and double-stranded polynucleotides.
Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine and deoxythymidine. For RNA, the uracil base is uridine.
As used herein, "mass spectrometry" encompasses any suitable mass spectrometric format known to those of skill in the art. Such formats include, but are not limited to, Matrix-Assisted Laser Desorption/lonization, Time-of-Flight (MALDI-TOF), Electrospray (ES), IR-MALDI (see, e.g., published International PCT Application No.
VSO 99/ 57518 and U.S. Patent i~o. 5,1 18,937) Ion Oyclotron Resonance (10R), Fourier Transform and combinations thereof. I~ALDI, particular UV
and IR, are among the typical formats.
As used herein, "at a position corresponding to" refers to a position of interest (i.e., base number or residue number) in a nucleic acid molecule or protein relative to the position in another reference nucleic acid molecule or protein. Corresponding positions can be determined by comparing and aligning sequences to maximize the number of matching nucleotides or residues, for example, such that identity between the sequences is greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. The position of interest is then given the number assigned in the reference nucleic acid molecule. For example, it is shown herein that a particular polymorphism in AKAP10 occurs at nucleotide 2073 of SEQ ID No. 1. To identify the corresponding nucleotide in another allele or isolate, the sequences are aligned and then the position that lines up with 2073 is identified. Since various alleles can be of different length, the position designate 2073 can not be nucleotide 2073, but instead is at a position that "corresponds" to the position in the reference sequence.
As used herein, "primer" and "probe" refer to a nucleic acid molecule including DNA, RNA and analogs thereof, including protein nucleic acids (PNA), and mixtures thereof. Such molecules are typically of a length such that they are statistically unique (i.e., occur only once) in the genome of interest. Generally, for a probe or primer to be unique in the human genome, it contains at least 14, 16 or contiguous nucleotides of a sequence complementary to or identical to a gene of interest. Probes and primers can be 10, 20, 30, 50, 100 or more nucleic acids long.
As used herein, "antiasnsa nucleic acid molecule" refers to a molr~cule encoding a sequence complementary to at least a portion of an RNA molecule. The sequence is sufficiently complementary to be able to hybridize with the RNA, typically under moderate or high stringency conditions to form a stable duplex. The ability to hybridize depends on the degree of complementarity and the length of the antiasnsa nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA it can contain and still form a stable duplex.
One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.
As used herein, a "variant protein" refers to a protein encoded by an allelic variant of a AKAP10 gene which results in a change of an amino acid residue at a particular position relative to that position in the protein encoded by the predominant allele.
As used herein, "signal transduction" refers to the propagation of a signal. In general, an extracellular signal is transmitted through the cell membrane to become an intracellular signal. This signal can then stimulate a cellular response. The term also encompasses signals that are propagated entirely within a cell. The polypeptide molecules involved in signal transduction processes are typically receptor and non-receptor protein kinases, receptor and non-receptor protein phosphatases, 1~ nucleotide exchange factors and transcription factors. One of the key biochemical mechanisms involved in signal transduction is protein phosphorylation. AKAP10 proteins are involved in signal transduction as they bind to protein kinase A (PKA) and are though to anchor the kinase at a location, e.g., the mitochondria, where PKA acts to phosphorylate a specific substrate. Thus, an alteration in AKAP10 binding to PKA, localization to the mitochondria, or phosphorylation by PKA, among other steps v~rill result in an alteration in signal transduction. Assays including those that determine phosphorylation by PKA, association of PKA and AKAP10 and localization of AKAP10 can be used to monitor the state of 2~ signal transduction.
As used herein, "adjacent" refers to a position 5' to the site of a single nucleotide polymorphism (SNP) such that there could be unpaired nucleotides between that position and the site of the SNP.
As used herein, "immediately adjacent" refers to a position 5' to the site of a single nucleotide polymorphism (SNP) such that there are no unpaired nucleotides between that position and the site of the SNP.
As used herein, "binding to PKA", refers to the interaction of the PKA binding domain of an AKAP10 protein and the regulatory subunits RI and/or RII of the protein kinase A holoenzyme.

B. Methods employing polymorphic AKAPs Methods herein include a step a identifying the prescence of a particular allele of an A-kinase anchoring protein (AKAP) genes.
Thus, polymorphic sequences encoding an A-kinase anchoring protein (AKAP) genes and polymorphic AKAP proteins encoded by polymorphic AKAP gene sequences are used in methods provided herein. These polymorphic sequences are based on differences in AKAP genes within and among different organisms, including humans.
Polymorphisms of the genome can lead to altered gene function, 1~ protein function or mRNA instability. AKAPs provide a mechanism for regulating ubiquitous cAMP-dependent kinase (PKA) activity by tethering PKA to specific subcellular locations thereby segregating it with particular components in a given signaling pathway and contributing to specificity in cellular responses to extracellular signals. AKAPs thus play a fundamental role in the basic functioning of cells, the response of cells to their environment and ultimately in the coordination of vital systems within an organism. Therefore, polymorphisms in AKAP gene sequences can affect the proper functioning of cells and systems within organisms and could be directly linked with certain disorders or could predispose an 2~ organism to a variety of diseases and disorders, especially those involving alterations in cellular protein phosphorylation and/or signal transduction. Among such disorders and diseases include, but are not limited to, neurodegeneratives diseases, such as Alzheimer's Disease, cardiovascular disorders, cardiac disorders, particularly disorders associated with altered left ventricular function, cardiomyopathies, proliferative disorders, bipolar disorder and other neurological disorders, obesity, diabetes and certain peripheral retinopathies, such as retinitis pigmentosa. AKAP gene polymorphisms, such as those described herein, provides for the identification and development of diagnostic and prognostic methods, also provided herein, and the development of drug therapies and treatment regimens. Furthermore, polymorphisms of AKAP
genes aid in the study of AKAP protein structure and function, which also contributes to the development of diagnostic methods and therapies.
1. AKAP10 The AKAP10 protein is primarily located in mitochondria. The sequence of a human AKAP10 cDNA (also referred to as D-AKAP2) is available in the GenBank database, at accession numbers AF037439 and NM 007202, and is provided in SEQ. ID. N0:1. The AKAP10 gene is located on chromosome 17.
The sequence of a mouse D-AKAP2 cDNA is also available in the GenBank database (see accession number AF0~1333). The mouse D-AKAP2. protein contains an RGS domain near the amino terminus that is characteristic of proteins that interact with Go° subunits and possess GTPase activating protein-like activity (Huang et al. (1997) Proc. Nat/.
~Icad. Sci. U.S.~°I. 94:11 1 B4-11 1 B9). The human AKAP10 protein also has sequences homologous to RGS domains. The carboy-terminal 40 residues of the mouse D-AI~AP~ protein are responsible for the interaction with the regulatory subunits of PKA. This sequence is fairly well conserved between the mouse D-AKAP2 and human AKAP10 proteins.
2. P~lym~rphisms ~f the human AKAP10 gene and p~lym~rphic AKAP10 proteins Polymorphisms of AKAP genes that alter gene expression, regulation, protein structure and/or protein function are more likely to have a significant effect on the regulation of enzyme (particularly PKA) activity, cellular transduction of signals and responses thereto and on the basic functioning of cells than polymorphisms that do not alter gene and/or protein function. Included in the polymorphic AKAPs provided herein are human AKAP10 proteins containing differing amino acid residues at position number 646 of SEQ. ID. No. 2.
Amino acid 646 of the human AKAP10 protein (SEQ. ID. NO: 2) is located in the carboxy-terminal region of the protein within a segment that participates in the binding of R-subunits of PKAs. This segment includes the carboxy-terminal 40 amino acids.
The amino acid residue reported for position 646 of the human AKAP10 protein is an isoleucine. Polymorphic human AKAP10 proteins provided herein have the amino acid sequence set forth in SEQ. ID. N0:
2 but contain residues other than isoleucine at amino acid position 646 of the protein. In particular embodiments of the polymorphic human AKAP10 proteins provided herein, the amino acid at position ~a4G of SEQ.
ID. NO: 2 is a valine (as set forth in SECa. ID. NO: 4), leucine or phenylalanine residue.
a. An A to G transition at nucleotide 2073 of the human AKAP10 coding sequence As described herein, an allelic variant of the human AICR~P10 gene is at the polymorphic site at position 2073 of the coding sequence (see SEQ.ID. NO: 3) and encodes a valine at position 646 of the AKAP10 protein. This allelic variant has been found to vary in frequency in DNA
samples from younger and older segments of a healthy population. This allele has the A at position 2073 of the AKAP10 gene coding sequence of SEQ. ID. NO: 1 changed to a G, giving rise to the sequence set forth in SEQ. ID. NO: 3. Consequently, the codon for amino acid 646 changes from ATT, coding for isoleucine, to GTT, coding for valine.
b. An A to C transversion at nucleotide 2073 of the human AKAP10 coding sequence In another human AKAP10 allelic variant, the nucleotide at position 2073 of the coding sequence in SEQ. ID. NO: 1 is changed from an A to a C. Thus, changing the codon for amino acid 646 from ATT, coding for isoleucine, to CTT, coding for leucine.
c. An A to T transversion at nucleotide 2073 of the human AKAP10 coding sequence In another human AKAP10 allelic variant, the nucleotide at position 2073 of the coding sequence in SEQ. ID. NO: 1 is changed from an A to a T. Thus, the codon for amino acid 646 changes from ATT, coding for isoleucine, to TTT, coding for phenylalanine.
d. Other AKAP10 polymorphisms Name GenBank Accession No. SNP Location For AKAP10-1 additional variants are represented by the presence of A or G at nucleotide position 156277 of SEQ ID NO: 17.
For AI<AP10-7 additional variants are represented by the presence of C or T at nucleotide position 129600 of SEA ID I~O: 17.
C. Association of AKAP10-5 1646V variant v~ith Cardiac Traits The SNPs found to be associated with age were analyzed for association with disease-related quantitative traits in a twin collection.
To identify traits correlated with the observed age association of the 1646V SNP, a cohort of 417 fasting Caucasian twin pairs with extensive coverage for a variety of disease-related traits was utilized. The analysis was conducted using a quantitative transmission-disequilibrium test (QTDT) as described by Abecasis et al., (Am. J. Hum. Genet., 66:279-292, 2000) to take advantage of the twin-based sample and to control for admixture and other non-genetic sources of variation. Of the 97 traits analyzed, only the PR-interval from electrocardiogram (EKG or ECG) analysis was statistically significant at a nominal level of 0.05. The PR

interval from EKG analysis is referred to herein is "EKG-PR-interval". The estimate from the QTDT model of the average effect of the G allele (Val at position 646 of SEQ ID N0:2) was to decrease the PR interval 6.3 units (P = 0.007). The genotype mean values in the subset of 207 informative twin pairs were 157 ~ 23.4, 152 ~ 26.9, and 146 ~ 25.4 (mean ~ standard deviation) for genotypes AA, GA, and GG, respectively.
An analysis of covariance was also conducted to test the effect of the genotypes on PR mean levels. Age was included as a covariate in the model, which was significantly associated with PR mean up to a third order polynomial as set forth in Figure 1. The relationship between age and PR mean was genotype-dependent, and therefore interaction terms between genotype and age were included. The predicted values from the resulting model are shown in Figure 1 for each genotype. From about the age of 30 or just beyond and up to about the age of 70, it has been found that human subjects having the -GG- genotype, on average have a lower PRmean than human subjects having an -Ad4- hommozygous genotype at a nucleotide corresponding to position 2073 of SECT ID
N0:1. From about the age of 40, it has also been found that human 2~ subjects having the -GG- genotype, on average have a lower PRmean than human subjects having either a -GA- heterozygous or -AA-homozygous genotype at a nucleotide corresponding to position 2073 of SEQ ID N0:1. Accordingly, on average a human subject about 30 years or older having a lower PRmean than an age-matched control group of -AA- homozygous at position 2073 of SEQ ID N0:1 has a higher likelihood of having either a -GA- heterozygous or a -GG- homozygous genotype at that position.
Thus, methods of comparing a subjects PR-interval to the PRmean of an age-matched control group of either one or both of an -AA-homozygous or -GA- heterozygous genotype at a nucleotide corresponding to position 2073 of SEQ ID N0:1 can identify subjects that have a higher likelihood of possessing a -GG- homozygous genotype at that position. Once a particular subject is identified as having a lower EKG-PR-interval than the PRmean from an age-matched control group, then that subject's particular genotype can be determined using the methods provided herein at a position corresponding to nucleotide 2073 of SEQ ID N0:1. As set forth herein, those subjects having the -GG-genotype have an increase susceptibility to a disease or disorder, such as a cardiovascular disease or disorder.
As also evident from Figure 1, on average a human subject at any age having a lower PRmean than an age-matched control group of an -AA- homozygous at a nucleotide corresponding to position 2073 of SEQ
ID NO:1 has a higher likelihood of having a -GA- heterozygous genotype than a -AA- homozygous genotype. Thus, for embodiments where it would be useful to identify subjects that can contain at least one "G"
allele at a nucleotide corresponding to position 2073 of SEO ID ~t0:1, methods of comparing a subjects PR-interval to the PRmean of an age-matched control group of an -AA- homozygous genotype at a nucleotide corresponding to position 2073 of SEA ID N0:1 can identify subjects that have a higher likelihood of possessing at least one -G- allele at that position.
SNPs in the D-AKAP2 gene have been identified herein that are associated with morbidity using a genome-wide association study from an age-stratified healthy population and 6,500 gene-based SNPs. The combined genetic and biochemical evidence points to the Ile/Val variant as the functional polymorphism. The Val variant is contemplated to be the deleterious allele in a Caucasian-American cohort, and this finding is replicated in Hispanic-Americans. The variant maps to the conserved AKB domain of the D-AKAP2 gene. It has been found that the 1646V
variation impacts the binding to PKA in an isoform-specific manner both in vitro and in cells. The Ile variant have been found to bind three-fold weaker to the Rla isoform than to the Val variant. At the cellular level, this affinity difference results in a dramatic decrease in compartmentalization of Rla for the Ile variant. The Ile/Val variant has been found to be critical for binding to only the Rla isoform of PKA.
Increasing evidence suggests that the RI and RII isoforms of PKA
have distinct functions. The RI isoform has been implicated in a variety of biological functions such as cell proliferation, tumor suppression, immune regulation, and embryonic levelopment. In addition, the Rla isoform plays a significant r~le in maintaining cAll~P-regulation of PI<A as evidenced by the embryonic lethality of mice deficient in the gene.
Interestingly, these mice have defects in cardiac morphogenesis.
The identified correlation of the 1646V variant (e.g., -G- at position 2073 of SEQ ID IV0:1 ) with the EKG PR interval measurement is contemplated herein to indicate that the I~a4BV polymorphism is a predisposing factor for a disease or disorder, such as a cardiovascular disease or disorder manifesting a cardiac phenotype. For example, 2~ individuals homozygous for the Val variant exhibit shorter depolarization intervals of the atrium (PR) as compared to individuals homozygous for Ile. This phenotypic correlation combined with reports in the literature supporting a role for AKAP mediated PKA signaling in normal cardiac function suggest a lead into the pathogenesis coded for by this functional variant. AKAP-mediated targeting of PKA in cardiac myocytes has been implicated in regulating cell contractility (Fink et al., Cir. /3es., 83:291-297, 2001 ). Stimulation of the f3-adrenergic signaling pathway in cardiac myocytes results in activation of PKA and phosphorylation of a variety of PKA substrates, including the sarcolemmal L-type Ca2+ channel, the ryanodine receptor (RyR), phospholamban (PLB) of the sarcoplasmic reticulum (SR), the myofibrillar proteins troponin I (Tnl) and myosin binding protein C (MBP-C) (Holroyde et al., Biochim. Biophys. Acta, 586:63-69, 1979; Kranias et al., Nature, 298:182-184, 1982; Brum et al., Pflugers Arch., 401:1 1 1-1 18, 1984; Garvey et al., Biochem. J., 249:709-714, 1988; Marx et al., Cell, 101:365-376, 1999).
Phosphorylation of these substrates acts in concert to generate both enhanced contractility and accelerated relaxation in response to (3-adrenergic stimulation.
Although PKA has broad substrate specificity, it can be highly selective by targeting of PKA to distinct subcellular locations via interaction with AI<APs (Colledge et al., Treads Cell Bi~l., 19:216-221, 1999). Three AKAPs have been shown to interact with PI<A in cardiac myocytes, muscle-selective AKAP (mAKAP), AKAP18 and Yotiao.
mAKAP targets PKA to the perinuclear region of differentiated myocytes, c~ordinating both PKA and phosphodiesterase activity in a single complex (l~apiloff ct al., J. Call Sci., 1 14:3167-3175, 2001 ). AKAP18 couples PKA fio L-type Ca2 + channels, which enhances Ca2 + influx through the channel following ,Q-adrenergic stimulati~n (Gray et al., ,l.
Bi~l. Chem., 272:6297-6302, 1997). Yotiao, previously ass~ciated with NM~A receptors, has been shown to interact with the KCNQ1-KCNE1 K+ channel subunits in human hearts (Marx et al., Science, 295:496-499, 2002). This channel is responsible for the slow delayed rectifier current that repolarizes the myocyte membrane and controls action potential duration. Mutations in this channel associated with hereditary long QT syndrome abolish Yotiao interactions with the channel, thereby attenuating PI<A regulation (Marx et al., 2002). Additionally, in cardiac myocytes the Rla subunit is the predominant isoform associated with the sarcolemma (Robinson et al., Arch. Biochem. Biophys., 330:181-187, 1996; Reinitz et al., Arch. Biochem. Biophys., 348:391-402; 1997).
Mutations in RI are associated with both familial cardiac myxomas and Carney complex, implicating this isoform in cardiac growth and differentiation (Casey et al., J. Clin. Invest., 106:831-38, 2000;
Kirschner et al., Nat. Genet., 26:89-92, 2000). Direct involvement of PKA in heart disease was also recently reported in a transgenic mice study (Antos et al., Circ. Res., 89:997-1004, 2001 ). The transgenic mice that overexpressed the catalytic subunit of PKA developed dilated cardiomyopathy with reduced cardiac contractility and increased risk of arrhythmias. These cardiac abnormalities correlated with PKA-mediated hyperphosphorylation of the ryanodine receptor and Ca2 + release from the sarcoplasmic reticulum (SR) and phospholamban, which regulates the activity of the SR Ca2+ -ATPase (Autos et al., 2001 ).
D-AI<AP2 1AKAP10-5) contains a PD2 binding motif (TKL) at the C-terminus (Fig. 3a), which is contemplated herein to serve as a targeting domain to membrane-bound receptors or ion-channels (Harris et al., J.
Cell Sci., 1 14:3219-3231, 2001 ), and two RGS domains, which are contemplated herein to coordinate upstream G alpha signaling with downstream PKA signaling. It is contemplated herein that D-AKAP2 is 2~ part of a signaling complex associated with a cardiac ion-channel. The D-AKAP2 variants is contemplated herein to impact the phosphorylation state of the ion-channel by recruiting different amounts of PKA-Rla and thereby modulate heart contraction. This model is in agreement with the observed association with an EKG phenotype. The shorter depolarization intervals for Val/Val homozygous individuals is contemplated herein to be due to increased activation of ion-channels in cardiac myocytes.
In summary, through the analysis of significant morbidity markers in a well-phenotyped healthy twin population, cardiac phenotypes have been associated to particular D-AKAP2 genotypes.

1. Method for indicating increased susceptibility of a subject to a disease or disorder Accordingly, provided herein are methods for indicating increased susceptibility of a subject to a disease or disorder, comprising:
conducting an EKG examination;
determining the EKG-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present in the subject at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position 1~ corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID NO:2 or the presence of a -G- at nucleotide position 2073 of SEC2 ID NO:1, indicates increased susceptibility to a disease or disorder. The disease or disorder can be selected from among cardiovascular disorders, cardiac disease, proliferative disorders, neurological disorders, neurodegenerative disorders, obesity, diabetes and peripheral retinopathies.
In one embodiment, the EKG-PR-interval in the subject is compared to a predetermined age-matched standard EI~G-PR-interval. The predetermined standard EKG-PR-interval can be obtained from a known 2~ age-matched control group that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control group that is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control group that is selected from either homozygous -AA-at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID
N0:2; or heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the predetermined standard EKG-PR-interval is obtained from a control age-matched subject without heart disease.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the subject is homozyg~us -GG- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Val/Val at a position corresponding to position 646 of SEA ID N0:2.
Also provided are methods for indicating increased susceptibility of a subject to a disease or disorder associated with the cardiovascular system, comprising:
conducting an EKG eacam;
determining the EI<G-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present at position 646 of AKAP10/D-AKAP2 (SEO. ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder associated with the cardiovascular system. The EKG-PR-interval in the subject can be compared to a predetermined age-matched standard EKG-PR-interval to determine whether it is decreased. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID
N0:2. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control group that is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ
ID N0:2. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control group that is selected from either homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ
ID N0:1 or homozygous Ilellle at a position corresponding to position 646 of SEQ ID N0:2; or heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Valllle at a position corresponding to position 546 of SEQ ID N0:2. In another embodiment, the predetermined standard EKG-PR-interval can be obtained from a control age-matched subject without heart disease.
In particular embodiments of the various methods provided herein, in the conteact of determining whether the EKG-PR-interval is decreased, a ~9ecreased EKG-PR-interval is less than 150 for a subject 40 or more year old. In another embodiment, a decreased EI~G-PR-interval is less than 155 for a subject 50 or more year old. In another embodiment, a decreased EI<G-PR-interval is less than 150 for a subject 50 or more year old. In another embodiment, a decreased EKG-PR-interval is less than 160 for a subject 60 or more year old. In another embodiment, a decreased EKG-PR-interval is less than 155 for a subject 60 or more year old. In another embodiment, a decreased EKG-PR-interval is less than 150 for a subject 60 or more year old.
In yet other embodiments, a decreased EKG-PR-interval for the subject is less than 146. In another embodiment, a decreased EKG-PR-interval for the subject is less than 130. In another embodiment, a decreased EKG-PR-interval for the subject is less than 120.

The disease or disorder can be selected from one or more of the group consisting of: atrial fibrillation, sick sinus syndrome, sudden cardiac arrest, ventricular arrythmia, ventricular fibrillation, ventricular tachycardia, Wolf-Parkinson-White (WPW) Syndrome, Lown-Ganong-Levin (LGL) Syndrome, hypertension. In one embodiment, the methods can further comprise monitoring the subject for cardiovascular disease.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID NO:2. In 1~ another embodiment, the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEQ ID NO:1 or homozygous Val/Val at a position corresponding to position 045 of SECT ID NO:2.
In another embodiment, the methods can further comprise administering to the subject prophylactic steps. For ea:ample, in view of developments in genetics and technology as well as epidemiology, the methods provided herein permit the determination of the probability and risk assessment for the development of disease, in particular heart disease in an individual. lJsing the genetic screening methods herein and/or family health histories, it is possible to predict the probability a particular individual has for developing any one of several types of disease, such as heart disease. Those individuals identified as being predisposed to developing a particular form of disease by using the methods provided herein, can take prophylactic steps towards reducing the risk of the particular disease, such as a heart disease. Accordingly, high-risk individuals identified herein can take one or more of the well-known prophylactic steps against the form of disease that they have a predisposition to develop.

-48_ a. Methods of assessing the susceptibility of a subject to a disease or disorder associated with the cardiovascular system Also provided herein are methods of assessing the susceptibility of a subject to a disease or disorder associated with the cardiovascular system, the method comprising determining the amino acid at position 646 of AKAP10/D-AKAP2 (SEQ fD N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G-at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder associated with the cardiovascular system.
Also provided herein are methods of diagnosing a disease or disorder associated with the cardiovascular system, comprising detecting the presence of Val at 646 of D-AKAP2 (SEQ ID N0:2) or the presence of a G at a nucleotide position corresponding to nucleotide 2073 of SEQ
ID f~0:1, wherein the presence of Val at position ~4.~ of SECT ID X10:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates the presence of a disease or disorder associated with the cardiovascular system. In these methods, the disease or disorder can be from among one or more of the group consisting of: atrial fibrillation, sick sinus syndrome, sudden cardiac arrest, ventricular arrythmia, ventricular fibrillation, ventricular tachycardia, Wolf-Parkinson-White (WPW) Syndrome, Lown-Ganong-Levin (LGL) Syndrome, hypertension.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the subject is homozygous -GG- at a position -49_ corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous VallVal at a position corresponding to position 646 of SEQ ID N0:2.
2. Methods for determining responsiveness of a subject to one or more ,l3-blocking agents The presence of the 1646V variant in a subject is contemplated herein to affect the D-AICAP2-mediated ~3-adrenergic signaling pathway.
For example, it is contemplated herein that the presence of 1 or 2 copies of the 1646V variant (e.g., a -g- at nucleotide 2073 of SEQ ID NO:1 ) in a subject renders the subject resistant to treatment with, or the effects of, 1 ~ the well-known ~3-blockers. Beta-blockers (,~-adrenergic blocking drugs) "block" the effects of adrenaline on the body's beta receptors. This slows the nerve impulses that travel through the heart. As a result, the heart does not have to work as hard because it needs less blood and oxygen. Beta-blockers also block the impulses that can cause an arrhythmia. In one embodiment, the heterozygous presence of the 1646V
variant (e.g., a -GA- heterozygous genotpye at a nucleotide corresponding t~ p~sition 2003 of SEQ ID 10:1 ) is contemplated herein to produce a ,~-blocker resistance phen~type. In another embodiment, the homozygous presence of the 1646V variant (e.g., a -GG-2~ heterozygous genotpye at a nucleotide corresponding to position 2073 of SEQ ID N0:1 ) is contemplated herein to produce the ~3-blocker resistance phenotype.
Accordingly, provided herein are methods for determining responsiveness of a subject to one or more (~-blocking agents, comprising:
detecting for the subject the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has a modulated response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. In one embodiment, the modulated response is a decreased response to one or more ~3-blocking agents compared to a subject who does not have the allelic variant. In another embodiment, the decreased response is a non-response to one or more ,~-blocking agents compared to a subject who does not have the allelic variant. In yet another embodiment, the modulated response is an increased response to one or more ,~-blocking agents compared to a subject who does not have the allelic variant. The ,~-blocker ican bean antagonist of a ~3-adrenergic receptor. In another embodiment, the ~3-blocker is an agonist of a ~3-adrenergic receptor.
Also provided herein are methods for determining responsiveness of a subject to one or more ,Q-blocking agents, comprising:
detecting the presence or absence of Val at position 646 of SEQ
ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEA ID i~~10: 1, wherein the presence of a Val at position 046 of SEr~
ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has an increased response to one or more ,Q-blocking agents compared to a subject who does not have the allelic variant. In one embodiment, the ~3-blocker is an antagonist of a ,~-adrenergic receptor. In another embodiment, the ,Q-blocker is an agonist of a /3-adrenergic receptor.
Also provided herein, are methods for determining responsiveness of a subject to one or more ~3-blocking agents, comprising:
detecting for the subject the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is non-responsive to one or more ~i-blocking agents compared to a subject who does not have the allelic variant. In one embodiment, the ~3-blocker is an antagonist of a ~3-adrenergic receptor. In another embodiment, the ~3-blocker is an agonist of a ~3-adrenergic receptor.
Also provided herein are methods for determining responsiveness of a subject to one or more ~3-blocking agents, comprising:
detecting the presence or absence of Val at position 646 of SEQ
ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 1 ~ of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ
ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is hyper-responsive to one or more ~-blocking agents compared to a subject who does not have the allelic variant. The ,~-blocker can be an antagonist of a ~3-adrenergic receptor.
In another embodiment, the ~3-blocker is an agonist of a ~3-adrenergic receptor.
Ea;emplary ,~-blockers well known in the art include, but are not limited to, 64cebutolol, atenolol, I3etae~olol, 6isoprolol, Oarteolol, Garbedilol, Esmolol, Labetolol, IVletoprolol, Nadolol, Penbutolol, Pindolol, 2~ Propranolol and Timolol. These ,Q-blocking agents are used to treat: high blood pressure, angina, abnormal heart rythms, hypertrophic cardiomyopathy, heart failure, vasovagal fainting, migraines, essential tremor, bleeding from esophageal varices, stage fright, glaucoma and to prolong survival of heart attack patients. Thus, the methods provided herein are useful to identify subjects that require or would benefit from a different treatment regimen than the use of ~3-blockers for their respective disease or disorder.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Valllle at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Val/Val at a position corresponding to position 646 of SEQ ID N0:2.
3. Method for indicating susceptibility of a subject to acquired long Q-T syndrome The long QT syndrome (LQTS) is an abnormality of the heart's electrical system. The mechanical function of the heart is entirely normal. The electrical problem is due to defects in heart muscle cell structures called ion channels. These electrical defects predispose affected persons to a very fast heart rhythm (arrhythmia) called torsade de pointer which leads t~ sudden loss of consciousness (syncope) and can cause sudden cardiac death. The syndrome can be inherited (the genetic form) or acquired. The inherited long OT Syndrome was first clearly described in 1957. There are two variants, the autosomal dominant Romano-Ward type and the autosomal recessive Jervell and Lunge f~ielren type. Even though LOTS eras described alm~rt 40 years ago, t~~ many physicians are unaware of it. Vi~hereas acquired long OT
syndrome is m~rt often due to the administration of medication. These 2~ medications are contraindicated in patients with the long OT syndrome.
There are a number of drugs which are known to prol~ng the OT-interval and to cause heart rhythm abnormalities, particularly in patients with the long OT syndrome (LQTS). Accordingly, patients with LQTS
should always inquire their physician or other health care provider about the risk of any medication suggested or prescribed for them. In addition, LQTS-patients should always inform their doctors) and dentists) about their disease and make sure they know there are many medications which are contraindicated in this condition. For example, the department of pharmacology at Georgetown university provides a complete and up-to-date list of drugs that prolong the QT-interval (external link).
The frequency is unknown but long Q-T syndrome appears to be a common cause of sudden and unexplained death in children and young adults. It is certainly much more common than previously thought. It can be as frequent as 1 in 5,000, and can cause 3,000-4,000 sudden deaths in children and young adults each year in the United States. The Jervell and Lange Nielsen form is associated with congenital deafness and is rare, but the Romano-Ward variant, with normal hearing, is being 1~ recognized with increasing frequency.
The usual symptoms are syncope (sudden loss of consciousness) or sudden death, typically occurring during physical activity or emotional upset. These most commonly begin in preteen to teenage years, but can present from a few days of age to middle age. The syncopal episodes are often misdiagnosed as the common faint (vasovagal event) or a seizure. Actual seizures are uncommon in long QT syndrome, but epilepsy is one of the comm~n errors in diagnosis. Sudden loss of consciousness during physical exertion or during emotional excitement should strongly raise the possibility of the long QT syndrome. A family 2~ history of unexplained syncope or sudden death in young people should also raise suspicion. Importantly, about one third of individuals who have the long QT syndrome never exhibit symptoms, and therefore, the lack of symptoms does not exclude a person or family from having LQTS. Any young person that has an unexplained cardiac arrest should be considered for LQTS, as well as those with unexplained syncope.
Since the electrocardiographic Q-T intervals vary in a given individual from day to day, and since Q-T prolongation in affected individuals can be mild, the diagnosis can be missed even if an EKG is performed. Therefore, because a patients can not receive an existing effective treatment in time because the condition which can kill quickly is sometimes very hard to diagnose, other methods of diagnosing long Q-T
or a predisposition for long Q-T syndrome would be very useful. It is contemplated herein that the 1646V variant in D-AKAP2 is indicative of a predisposition to the acquired form of Long Q-T syndrome. Accordingly, provided herein are methods that identify subjects who are predisposed or susceptible to acquired long Q-T syndrome. These methods are useful in identifying the class of subjects who should avoid taking particular medications, such as the well-documented group of medications that 1~ those diagnosed with long Q-T syndrome should avoid.
For example, provided herein are methods for indicating susceptibility of a subject to acquired long Q-T syndrome, comprising:
detecting the presence or absence of Val at position 646 of SEQ
ID N0:2 or presence or absence of a -Ca- nucleotide at a position corresponding to position 2073 of SEQ ID N0: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEA ID 10:1, is indicative of increased susceptibility to acquired long Q-T syndrome, compared to the susceptibility of a subject who does not have the allelic variant. The detecting step can be effected by a method 2~ selected from the group consisting of allele specific hybridization, primer specific extension, oligonucleotide ligation assay, restriction enzyme site analysis and single-stranded conformation polymorphism analysis. In addition, the detecting step can comprise mass spectrometry. The detection can be effected by detecting a signal moiety selected from the group consisting of radioisotopes, enzymes, antigens, antibodies, spectrophotometric reagents, chemiluminescent reagents, fluorescent reagents and other light producing reagents.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Val/Val at a position corresponding to position 646 of SEQ ID N0:2.
4. Methods for indicating susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a subject Also provided herein, are methods for indicating susceptibility to morbidity, increased or early mortality, or morbidity and increased or 1~ early mortality of a subject; comprising:
conducting an EKG exam;
determining the EKG-PR-interval in the subject, wherein if the EKG-PR-interval is decreased; then determining the amino acid at position 64C of AKAP10/D-AKAP2 (SEQ ID NO:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position ~a45 of SEO ID i~0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a 2~ subject. The EKG-PR-interval in the subject can be compared to a predetermined standard EKG-PR-interval. The predetermined standard EKG-PR-interval can be obtained from a known age-matched control that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2. The detecting step can be effected by a method selected from the group consisting of allele specific hybridization, primer specific extension, oligonucleotide ligation assay, restriction enzyme site analysis and single-stranded conformation polymorphism analysis. The detecting step can comprise mass spectrometry. The detection step can be effected by detecting a signal moiety selected from the group consisting of radioisotopes, enzymes, antigens, antibodies, spectrophotometric reagents, chemiluminescent reagents, fluorescent reagents and other light producing reagents.
In one embodiment, the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2. In another embodiment, the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Val/Val at a position corresponding to position 646 of SEQ ID N0:2.
D. Detecti~n of Polymorphisms in Human AKAP10 Genes I~ilethods of determining the presence or absence of allelic variants of a human AKAP10 gene are also provided. In particular methods, the detection or identification of a G, C, or T nucleotide at position 2073 of the sense strand of the human AKAP10 gene coding sequence (see SEO.
ID N0: 1 ), or the detection or identification of a C, G or A nucleotide at the same position in the antiasnsa strand of the human AI~AP10 gene coding sequence, indicates the presence of an allelic variant. In these particular methods, the detection or identification of an A nucleotide at position 2073 of the sense strand of the human AKAP10 gene coding sequence, or the detection or identification of a T nucleotide at the same position in the antisense strand of the human AKAP10 gene coding sequence, indicates the absence of polymorphism.
Other methods for determining the presence or absence of an allelic variant of the AKAP10 gene detect or identify a nucleotide other than a C at position 83587 of the SEQ ID NO: 17 or a nucleotide other than a G on the complementary strand, a nucleotide other than a G at position 129600 of the SEQ ID NO: 17 or a nucleotide other than a C on the complementary strand or a nucleotide other than T at position 156,277 of SEQ ID N0: 17 or a nucleotide other than A on the complementary strand.
1. Nucleic acid detection methods Generally, these methods are based in sequence-specific polynucleotides, oligonucleotides, probes and primers. Any method known to those of skill in the art for detecting a specific nucleotide within a nucleic acid sequence or for determining the identity of a specific nucleotide in a nucleic acid sequence is applicable to the methods of determining the presence or absence of an allelic variant of the AKAP10 gene. Such methods include, but are not limited to, techniques utilizing nucleic acid hybridization of sequence-specific probes, nucleic acid sequencing, selective amplification, analysis of restriction enzyme digests of the nucleic acid, cleavage of mismatched heteroduplexes of nucleic acid and probe, alterations of electrophoretic mobility, primer specific extension, oligonucleotide ligation assay and single-stranded conformation polymorphism analysis. In particular, primer ea~tension reactions that specifically terminate by incorporating a dideooynuoleotide are useful for detection. Several such general nucleic acid detection assays are known (see, e.g.,U.S. Patent No. 6,030,778).
2~ a. Primer extension-based methods Several primer extension-based methods for determining the identity of a particular nucleotide in a nucleic acid sequence have been reported (see, e.g., PCT Application Nos. PCT/US96/03651 (W096/29431 ), PCT/US97/20444 (WO 98/20166), PCT/US97/20194 (WO 98120019), PCT/US91 /00046 (W091 /13075), and U.S. Patent Nos.
5,547,835, 5,605,798, 5,622,824, 5,691,141, 5,872,003, 5,851,765, 5,856,092, 5,900,481, 6,043,031, 6,133,436 and 6,197,498.) In general, a primer is prepared that specifically hybridizes adjacent to a polymorphic site in a particular nucleic acid molecule. The primer is then extended in the presence of one or more dideoxynucleotides, typically with at least one of the dideoxynucleotides being the complement of the nucleotide that is polymorphic at the site. The primer and/or the dideoxynucleotides can be labeled to facilitate a determination of primer extension and identity of the extended nucleotide.
In an exemplary method, primer extension and/or the identity of the extended nucleotides) are determined by mass spectrometry (see, e.g., PCT Application Nos. PCT/US96/03651 (WO96/29431 ), PCT
Application No. PCT/US97/20444 (WO 98/20166), PCT Application No.
1 ~ PCT/US97/20194 (WO 98/20019), PCT Application No.
PCT/US91 /00046 (W091 /13075), and U.S. Patent Nos. 5,605,798, 5,622,824, 5,856,092.
b. P~lyrrr~rphisrr~-specific pr~be hybridizati~n A typical detection method is allele specific hybridization using probes overlapping the polymorphic site and having about 5, 10, 15, 20, 25, or 30 nucleotides around the polymorphic region. The probes can contain naturally occurring or modified nucleotides (see U.S. Patent No.
6,156,501). For example, oligonucleotide probes can be prepared in which the known polymorphic nucleotide is placed centrally (allele-2~ specific probes) and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al.
(1986) Nature 324:163; Saiki et al. (1989) Proc. Natl Acad. Sci USA
86:6230; and Wallace et al. (1979) Nucl. Acids Res. 6:3543). Such allele specific oligonucleotide hybridization techniques can be used for the simultaneous detection of several nucleotide changes in different polymorphic regions. For example, oligonucleotides having nucleotide sequences of specific allelic variants are attached to a hybridizing membrane and this membrane is then hybridized with labeled sample nucleic acid. Analysis of the hybridization signal will then reveal the identity of the nucleotides of the sample nucleic acid. In one embodiment, several probes capable of hybridizing specifically to allelic variants are attached to a solid phase support, e.g., a "chip".
Oligonucleotides can be bound to a solid support by a variety of processes, including lithography. For example a chip can hold up to 250,000 oligonucleotides (GeneChip, Affymetrix, Santa Clara, CA).
Mutation detection analysis using these chips comprising oligonucleotides, also termed "DNA probe arrays" is described e.g., in Cronin et al. (1996) Human Mutation 7:244 and in Kozal et al. (1996) Nature Medicine 2:753. In one embodiment, a chip includes all the allelic variants of at least one polymorphic region of a gene. The solid phase support is then contacted with a test nucleic acid and hybridization to the specific probes is detected. Accordingly, the identity of numerous allelic variants of one or more genes can be identified in a simple hybridization experiment.
c. Nucleic acid amplification-based methods In other detectican methods, it is necessary to first amplify at least a portion of an AKAP gene prior to identifying the allelic variant.
Amplification can be performed, e.g., by PCR and/or LCR, according to methods known in the art. In one embodiment, genomic DNA of a cell is exposed to two PCR primers and amplification is performed for a number of cycles sufficient to produce the required amount of amplified DNA. In typical embodiments, the primers are located between 150 and 350 base pairs apart.
Alternative amplification methods include: self sustained sequence replication (Guatelli, J. C. et al., 1990, Proc. Natl. Acad. Sci. U.S.A.
87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al., 1988, Bio/Technology 6:1 197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.
Alternatively, allele specific amplification technology, which depends on selective PCR amplification can be used in conjunction with the alleles provided herein. Oligonucleotides used as primers for specific amplification can carry the allelic variant of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. ( 1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3° end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerise extension (Prossner (1993) Tibtech 1 1:38; Newton e~ a/. (1989) Nucl. Acids Res. 17:2503). In addition it can be desirable to introduce a restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol.
Cell Probes 6:1 ).
d. h~l~cl~ic ~~ia7 ~~a~~~n~ing-5a~~d r~~tC-r~~s In one embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence at least a portion of an AKAP gene and fio detect allelic variants, e.g., mutations, by comparing the sequence of the sample sequence with the corresponding wild-type (control) sequence. Exemplary sequencing reactions include those based on techniques developed by Maxim and Gilbert (Proc. Natl. Acid. Sci.
USA (1977) 74:560) or Singer (Singer et al. (1977) Proc. Natl. Acid.
Sci 74:5463). It is also contemplated that any of a variety of automated sequencing procedures can be used when performing the subject assays (Biotechniques (1995) 19:448), including sequencing by mass spectrometry (see, for example, U.S. Patent Nos. 5,547,835, 5,691,141, and International PCT Application No. PCT/US94/00193 (WO 94/16101 ), entitled "DNA Sequencing by Mass Spectrometry" by H. Koster; U.S.
Patent Nos. 5,547,835, 5,622,824, 5,851,765, 5,872,003, 6,074,823, 6,140,053 and International PCT Application No. PCT/US94/02938 (WO 94/21822), entitled "DNA Sequencing by Mass Spectrometry Via Exonuclease Degradation" by H. Koster), and U.S. Pat. Nos. 5,605,798, 6,043,031, 6,197,498, and International Patent Application No.
PCT/US96/03651 (WO 96/29431 ) entitled "DNA Diagnostics Based on Mass Spectrometry" by H. Koster; Cohen et al. (1996) Adv Chromatography 36:127-162; and Griffin et al. (1993) Appl Biochem 1~ Biotechnol 38:147-159). It will be evident to one skilled in the art that, for certain embodiments, the occurrence of only one, two or three of the nucleic acid bases need be determined in the sequencing reaction. For instance, A-track sequencing or an equivalent, e.g., where only one nucleotide is detected, can be carried out. Other sequencing methods are known (see, e.g., in U.S. Patent No. 5,580,732 entitled "Method of DNA sequencing employing a mixed DNA-polymer chain probe" and U.S.
Patent fro. 5,5/1,575 entitled "f~lr~thod for mismatch-directed i~a ~i~r~
DNA sequencing"). .
e. Restriction enzyme digest analysis 2~ In some cases, the presence of a specific allele in nucleic acid, particularly DNA, from a subject can be shown by restriction enzyme analysis. For example, a specific nucleotide polymorphism can result in a nucleotide sequence containing a restriction site which is absent from the nucleotide sequence of another allelic variant.
f. Mismatch Cleavage Protection from cleavage agents, such as, but not limited to, a nuclease, hydroxylamine or osmium tetroxide and with piperidine, can be used to detect mismatched bases in RNA/RNA DNA/DNA, or RNA/DNA
heteroduplexes (Myers, et al. (1985) Science 230:1242). In general, the technique of "mismatch cleavage" starts by providing heteroduplexes formed by hybridizing a control nucleic acid, which is optionally labeled, e.g., RNA or DNA, comprising a nucleotide sequence of an allelic variant with a sample nucleic acid, e.g, RNA or DNA, obtained from a tissue sample. The double-stranded duplexes are treated with an agent, which cleaves single-stranded regions of the duplex such as duplexes formed based on basepair mismatches between the control and sample strands.
For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S1 nuclease to enzymatically digest the 1~ mismatched regions.
In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine whether the control and sample nucleic acids have an identical nucleotide sequence or in which nucleotides they differ (see, for eazample, C~tton e~ ~/. (1988) Proc. i~atl Acad Sci USA
85:4397; Saleeba e~ e/. 11992) Methods Enzymod. 217:286-295). The control or sample nucleic acid is labeled for detection.
g. Electrophoretic mobility alterations In other embodiments, alteration in electrophoretic mobility is used to identify the type of allelic variant in an AICAP gene. For example, single-strand conformation polymorphism (SSCP) can be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. ( 1989) Proc. Natl. Acad. Sci. USA 86:2766, see also Cotton (1993) Mutat Res 285:125-144; and Hayashi (1992) Genet Anal Tech Appl 9:73-79). Single-stranded DNA fragments of sample and control nucleic acids are denatured and allowed to renature.
The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments can be labeled or detected with labeled probes. The sensitivity of the assay can be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In another embodiment, the subject method uses heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991 ) Trends Genet 7:5).
h. Polyacrylamide Gel Electrophoresis In yet another embodiment, the identity of an allelic variant of a polymorphic region of an AKAP gene is obtained by analyzing the movement of a nucleic acid comprising the polymorphic region in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (~ilyers e~ a/. (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA
will be modified to ensure that it does not completely denature, for example by adding a GO clamp of appro~zimately 4.0 by of high-melting GG-rich DNA by POR. In a further embodiment, a temperature gradient is used in place of a denaturing agent gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:1275).
i. ~ligonucleotide ligation assay (~LA) In another embodiment, identification of the allelic variant is carried out using an oligonucleotide ligation assay (OLA), as described, e.g., in U.S. Patent No. 4,998,617 and in Landegren, U. et al., Science 241:1077-1080 (1988). The OLA protocol uses two oligonucleotides which are designed to be capable of hybridizing to abutting sequences of a single strand of a target. One of the oligonucleotides is linked to a separation marker, e.g,. biotinylated, and the other is detestably labeled.

If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate. Ligation then permits the labeled oligonucleotide to be recovered using avidin, or another biotin ligand. Nickerson, D. A. et al.
have described a nucleic acid detection assay that combines attributes of PCR and OLA (Nickerson, D. A. et al., Proc. Natl. Acad. Sci. (U.S.A.) 87:8923-8927 (1990). In this method, PCR is used to achieve the exponential amplification of target DNA, which is then detected using OLA.
Several techniques based on this OLA method have been developed and can be used to detect specific allelic variants of a polymorphic region of a gene. For example, U.S. Pat. No. 5,593,826 discloses an OLA using an oligonucleotide having 3'-amino group and a 5'- phosphorylated oligonucleotide to form a conjugate having a phosphoramidate linkage. In another variation of OLA described in Tobe et al. (1996) Nucl. Acids Res. 24: 3728), OLA combined with PCR
permits typing of te~so alleles in a single microtiter sell. By marking each of the allele-specific primers with a unique hapten, i.e. digo~;igenin and fluorescein, each OLA reaction can be detected by using hapten specific antibodies that are labeled with different enzyme reporters, alkaline phosphatase or horseradish peroxidase. This system permits the detection of the two alleles using a high throughput format that leads to the production of two different colors.
j. SNP detection methods Also provided are methods for detecting single nucleotide polymorphisms. Because single nucleotide polymorphisms constitute sites of variation flanked by regions of invariant sequence, their analysis requires no more than the determination of the identity of the single nucleotide present at the site of variation and it is unnecessary to determine a complete gene sequence for each patient. Several methods have been developed to facilitate the analysis of such single nucleotide polymorphisms.
In one embodiment, the single base polymorphism can be detected by using a specialized exonuclease-resistant nucleotide, as disclosed, e.g., in Mundy, C. R. (U.S. Patent No. 4,656,127). According to the method, a primer complementary to the allelic sequence immediately 3' to the polymorphic site is permitted to hybridize to a target molecule obtained from a particular animal or human. If the poiymorphic site on the target molecule contains a nucleotide that is complementary to the particular exonuclease-resistant nucleotide derivative present, then that derivative will be incorporated onto the end of the hybridized primer.
Such incorporation renders the primer resistant to exonuclease, and thereby permits its detection. Since the identity of the exonuclease-resistant derivative of the sample is known, a finding that the primer has become resistant to exonucleases reveals that the nucleotide present in the polymorphic site of the target molecule was complementary to that of the nucleotide derivative used in the reaction.
This method has the advantage that it does not require the determination of large amounts of extraneous sequence data.
In another embodiment, a solution-based method for determining the identity of the nucleotide of a polymorphic site is employed (Cohen, ~. et al. (French Patent 2,65~,S4~; PCT Application No. W091 /Q2~i37)).
As in the Mundy method of U.S. Patent No. 4,656,127, a primer is employed that is complementary to allelic sequences immediately 3' to a polymorphic site. The method determines the identity of the nucleotide of that site using labeled dideoxynucleotide derivatives, which, if complementary to the nucleotide of the polymorphic site will become incorporated onto the terminus of the primer.

k. Genetic Bit Analysis An alternative method, known as Genetic Bit Analysis or GBATM is described by Goelet, et al. (U.S. Patent No. 6,004,744, PCT Application No. 92/15712). The method ofi Goelet, et al. uses mixtures of labeled terminators and a primer that is complementary to the sequence 3' to a polymorphic site. The labeled terminator that is incorporated is thus determined by, and complementary to, the nucleotide present in the polymorphic site of the target molecule being evaluated. In contrast to the method of Cohen et al. (French Patent 2,650,840; PCT Application 1 ~ No. W091 /02087), the method of Goelet, et al. is typically a heterogeneous phase assay, in which the primer or the target molecule is immobilised to a solid phase.
I. Other primer-guided nucle~tide inc~rp~rati~n pr~cedures Other primer-guided nucleotide incorporation procedures for assaying polymorphic sites in DNA have been described (fComher, J. S.
et al., Nucl. Acids Res. 17:7779-7784- (1989); S~k~lov, B. P., f~l~acl.
Acids Res. 18:3561 (1990); Syvanen, A. C., anal., Genomics 8:584-692 (1990), I~uppuswamy, 1!/l. N. e~'a/., Proc. Natl. Acad. Sci. (U.S.A.) 2~ 88:1143-1147 (1991); Prezant, T. R. etal., Hum. nllutat. 1:159-164 (1992); Ugozzoli, L, et al., GATA 9:107-1 12 (1992); Nyren, P. et al., Anal. Biochem. 208:171-175 (1993)). These methods diffier from GBATM
in that they all rely on the incorporation of labeled deoxynucleotides to discriminate between bases at a polymorphie site. In such a format, since the signal is proportional to the number of deoxynucleotides incorporated, polymorphisms that occur in runs of the same nucleotide can result in signals that are proportional to the length of the run (Syvanen, A. C., et al., Amer. J. Hum. Genet. 52:46-59 (1993)).

-67_ For determining the identity of the allelic variant of a polymorphic region located in the coding region of a gene, yet other methods than those described above can be used. For example, identification of an allelic variant which encodes a mutated protein can be performed by using an antibody specifically recognizing the mutant protein in, e.g., immunohistochemistry or immunoprecipitation. Binding assays are known in the art and involve, e.g., obtaining cells from a subject, and performing binding experiments with a labeled lipid, to determine whether binding to the mutated form of the protein differs from binding t~ the 1 ~ wild-type protein.
m. Molecular structure determination If a polymorphic region is located in an axon, either in a coding or non-coding region of the gene, the identity of the allelic variant can be determined by determining the molecular structure of the mRNA, pre-mRNA, or cDNA. The molecular structure can be determined using any of the above described methods for determining the molecular structure ~f the genomic Di~A, e.g., sequencing and SSCP.
n. l~7as~ spec~:r~metric methoe~s Nucleic acids can also be analyzed by detection methods and 2~ protocols, particularly those that rely on mass spectrometry (see, e. g., U.S. Patent Nos. 5,605,798, 6,043,031, 6,197,498, and International Patent Application No. WO 96/29431, allowed co-pending U.S.
Application Serial No. 08/617,256, allowed co-pending U.S. Application Serial No. 08/744,481, U.S. Application Serial No. 08/990,851, International PCT Application No. WO 98/20019). These methods can be automated (see, e.g., co-pending U.S. Application Serial No.
09/285,481, which describes an automated process line). Among the methods of analysis herein are those involving the primer oligo base extension (PROBE) reaction with mass spectrometry for detection (see e.g., U.S. Patent Nos. 6,043,031 and 6,197,498, Patent Application Serial Nos. 09/287,681, 09/287,682, and 09/287,679, allowed co-pending U.S. Application Serial No. 081744,481, International PCT
Application No. PCT/US97/20444 (WO 98/20166), and based upon U.S.
Patent Nos. 5,900,481, 6,024,925, 6,074,823, Application Serial Nos.
08/746,055, 08/786,988, 08/933,792, 08/746,055, and 08/786,988;
see, also U.S. Application Serial No. 09/074,936, and published International PCT Application No. PCT/US97/20195 (WO 98/20020)).
A typical format for performing the analyses is a chip based format in which the biopolymer is linked to a solid support, such as a silicon or silicon-coated substrate, for example, in the form of an array. More typically, when analyses are performed using mass spectrometry, particularly MALDI, nanoliter volumes of sample are loaded on, such that the resulting spot is about, or smaller than, the size of the laser spot. It has been found that when this is achieved, the results from the mass spectrometric analysis are quantitative. The area under the peaks in the resulting mass spectra are proportional t~ concentration (when normalized and corrected for background). Methods for preparing and using such chips are described in U.S. Patent No. 6,024,925, co-pending U.S. Application Serial Nos. 08/786,988, 09/364,774, 09/371,150 and 09/297,575; see, also PCT Application No. PCT/US97/20195 (WO 98/20020). Chips and kits for performing these analyses are commercially available from SEQUENOM under the trademark MassARRAYT"". MassARRAYT"" relies on the fidelity of the enzymatic primer extension reactions combined with the miniaturized array and MALDI-TOF (Matrix-Assisted Laser Desorption Ionization-Time of Flight) mass spectrometry to deliver results rapidly. It accurately distinguishes single base changes in the size of DNA fragments relating to genetic variants without tags.

Multiplex methods allow for the simultaneous detection of more than one polymorphic region in a particular gene. This is the typical method for carrying out haplotype analysis of allelic variants of the AICAP10 gene.
Multiplexing can be achieved by several different methodologies.
For example, several mutations can be simultaneously detected on one target sequence by employing corresponding detector (probe) molecules (e.g., oligonucleotides or oligonucleotide mimetics). The molecular weight differences between the detector oligonucleotides must be large enough so that simultaneous detection (multiplexing) is possible. This can be achieved either by the sequence itself (composition or length) or by the introduction of mass-modifying functionalities into the detector oligonucleotides (see below).
Mass modifying moieties can be attached, for instance, to either the 5'-end of the oligonucleotide, to the nucleobase (or bases), to the phosphate backbone, and to the 2'-position of the nucleoside (nucleosiales) and/or to the terminal 8°-position. Examples ~f mass modifying moieties include, for eacample, a halogen, an azido, or of the type, XR, wherein X is a linking group and R is a mass-modifying functionality. The mass-modifying functionality can thus be used to introduce defined mass increments into the oligonucleotide molecule.
The mass-modifying functionality can be located at different positions within the nucleotide moiety (see, e.g., U.S. Patent No.
5,547,835 and International PCT Application No. WO 94/21822). For example, the mass-modifying moiety, M, can be attached either to the nucleobase, (in case of the c' -deazanucleosides also to C-7), to the triphosphate group at the alpha phosphate or to the 2'-position of the sugar ring of the nucleoside triphosphate. Modifications introduced at the phosphodiester bond, such as with alpha-thio nucleoside triphosphates, have the advantage that these modifications do not interfere with accurate Watson-Crick base-pairing and additionally allow for the one-step post-synthetic site-specific modification of the complete nucleic acid molecule e.g., via alkylation reactions (see, e.g., Nakamaye et al. (1988) Nucl. Acids Res. 16:9947-59). Typical mass-modifying functionalities are boron-modified nucleic acids since they are better incorporated into nucleic acids by polymerases (see, e.g., Porter et al.
(1995) Biochemistry 34:1 1963-1 1969; Hasan et al. (1996) Nucleic Acids Res. 24:2150-2157; Li et al. (1995) Nucl. Acids Res. 23:4495-4501 ).
Furthermore, the mass-modifying functionality can be added so as to affect chain termination, such as by attaching it to the 3'-position of the sugar ring in the nucleoside triphosphate. For those skilled in the art, it is clear that many combinations can be used in the methods provided herein. In the same way, those skilled in the art will recognize that chain-elongating nucleoside triphosphates can also be mass-modified in a similar fashion with numerous variations and combinations in functionality and attachment positions.
For example, without being bound to any particular theory, the mass-modification can be introduced for X in ?(R as well as using oligo-/polyethylene glycol derivatives for R. The mass-modifying increment (m) in this case is 44, i.e. five different mass-modified species can be generated by just changing m from 0 to 4 thus adding mass units of 45 (m = 0), 89 (m = 1 ), 133 (m = 2), 177 (m = 3) and 221 (m = 4) to the nucleic acid molecule (e. g., detector oligonucleotide (D) or the nucleoside triphosphates, respectively). The oligo/polyethylene glycols can also be monoalkylated by a lower alkyl such as, but are not limited to, methyl, ethyl, propyl, isopropyl and t-butyl. Other chemistries can be used in the mass-modified compounds (see, e.g., those described in Oligonucleotides and Analogues, A Practical Approach, F. Eckstein, editor, IRL Press, Oxford, 1991 ).
In yet another embodiment, various mass-modifying functionalities, R, other than oligo/polyethylene glycols, can be selected and attached via appropriate linking chemistries, X. A simple mass-modification can be achieved by substituting H for halogens, such as F, CI, Br and/or I, or pseudohalogens such as CN, SCN, NCS, or by using different alkyl, aryl or aralkyl moieties such as methyl, ethyl, propyl, isopropyl, t-butyl, hexyl, phenyl, substituted phenyl, benzyl, or functional groups such as CHEF, CHF2, CF3, Si(CH3)3, Si(CH3)2(C~HS), Si(CH3)(C2H5)2, SI(C~H5)3. Yet another mass-modification can be obtained by attaching homo- or heteropeptides through the nucleic acid molecule (e.g., detector (D)) or nucleoside triphosphates). One example, useful in generating mass-modified species with a mass increment of 57, is the attachment of oligoglycines (m) to nucleic acid molecules (r), e.g., mass-modifications of 74 (r=1, m=~), 131 (r=1, m=1), 18B (r=1, m=2), 245 (r=1, m = 3) are achieved. Simple oligoamides also can be used, e.~., mass-modifications of 74 (r =1, m = ~), 33 (r = ~, m = ~), 102 (r = 3, m=~), 116(r=4, m=~), ete. are obtainable. Variations in additions to 2~ those set forth herein will be apparent to the skilled artisan.
Different mass-modified detector oligonucleotides can be used to simultaneously detect all possible variants/mutants simultaneously.
Alternatively, all four base permutations at the site of a mutation can be detected by designing and positioning a detector oligonucleotide, so that it serves as a primer for a DNA/RNA polymerase with varying combinations of elongating and terminating nucleoside triphosphates.
For example, mass modifications also can be incorporated during the amplification process.

A different multiplex detection format is one in which differentiation is accomplished by employing different specific capture sequences which are position-specifically immobilized on a flat surface (e.g., a 'chip array'). If different target sequences T1-Tn are present, their target capture sites TCS1-TCSn will specifically interact with complementary immobilized capture sequences C1-Cn. Detection is achieved by employing appropriately mass differentiated detector oligonucleotides D1-Dn, which are mass modifying functionalities M1-Mn.
0. ~ther methods Additional methods of analyzing nucleic acids include amplification- based methods including polymerase chain reaction (PCR), ligase chain reaction (LCR), mini-PCR, rolling circle amplification, autocatalytic methods, such as those using ~J replicase, TAS, SSR, and any other suitable method known to those of skill in the art.
Other methods for analysis and identification and detection of polymorphisms, include but are not limited to, allele specific probes, Southern analyses, and other such analyses.
2. Primers, Iprobes and antiasnsa nucleic acid molecules Primers refer to nucleic acids which are capable of specifically hybridizing to a nucleic acid sequence which is adjacent to a polymorphic region of interest or to a polymorphic region and are extended. A primer can be used alone in a detection method, or a primer can be used together with at least one other primer or probe in a detection method.
Primers can also be used to amplify at least a portion of a nucleic acid.
For amplifying at least a portion of a nucleic acid, a forward primer (i.e., 5' primer) and a reverse primer (i.e., 3' primer) will typically be used.
Forward and reverse primers hybridize to complementary stands of a double stranded nucleic acid, such that upon extension from each primer, a double stranded nucleic acid is amplified.
Probes refer to nucleic acids which hybridize to the region of interest and which are not further extended. For example, a probe is a nucleic acid which hybridizes adjacent to or at a polymorphic region of an AICAP gene and which by hybridization or absence of hybridization to the DNA of a subject will be indicative of the identity of the allelic variant of the polymorphic region of the gene. Typical probes have a number of nucleotides sufficient to allow specific hybridization to the target nucleotide sequence. Where the target nucleotide sequence is present in a large fragment of DNA, such as a genomic DNA fragment of several tens or hundreds of kilobases, the size of a probe can have to be longer to provide sufficiently specific hybridization, as compared to a probe which is used to detect a target sequence which is present in a shorter fragment of DNA. For example, in some diagnostic methods, a portion of an AICAP gene can first be amplified and thus isolated from the rest of the chromosomal Df~A and then hybridized to a probe. In sucll a situation, a shorter probe will likely provide sufficient specificity of hybridization. For example, a probe having a nucleotide sequence of ~0 about 1 ~ nucleotides can be sufficient.
Primers and probes (RNA, DNA (single-stranded or double-stranded), PNA and their analogs) described herein can be labeled with any detectable reporter or signal moiety including, but not limited to radioisotopes, enzymes, antigens, antibodies, spectrophotometric reagents, chemiluminescent reagents, fluorescent and any other light producing chemicals. Additionally, these probes can be modified without changing the substance of their purpose by terminal addition of nucleotides designed to incorporate restriction sites or other useful sequences, proteins, signal generating ligands such as acridinium esters, and/or paramagnetic particles.
These probes can also be modified by the addition of a capture moiety (including, but not limited to para-magnetic particles, biotin, fluorescein, dioxigenin, antigens, antibodies) or attached to the walls of microtiter trays to assist in the solid phase capture and purification of these probes and any DNA or RNA hybridized to these probes.
Fluorescein can be used as a signal moiety as well as a capture moiety, the latter by interacting with an anti-fluorescein antibody.
Any probe, primer or antisense molecule can be prepared according to methods well known in the art and described, e.g., in Sambrook, J. Fritsch, E.F., and Maniatis, T. (1989( M~lecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. For example, discrete fragments of the DNA can be prepared and cloned using restriction enzymes. Alternatively, probes and primers can be prepared using the Polymerase Chain Reaction (PCR) using primers having an appropriate sequence.
0ligonucleotides can be synthesized by standard methods known in the art, e. g. by use of an automated DNA synthesizer (such as are commercially available from 8iosearch (Novato, CA); Applied 8iosystems (Foster City, CA) and other methods). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides, for example, can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451 ) .
Probes and primers used in the methods of detecting allelic variants in human AICAP10 genes are of sufficient length to specifically hybridize to portions of AICAP10 gene at polymorphic sites. Typically such lengths depend upon the complexity of the source organism genome. For humans such lengths are at least 14-16 nucleotides, and typically can be 20, 30, 50, 100 or more nucleotides.
The methods of detecting polymorphisms in human AKAP10 genes provided herein, probes and primers include the following:
(1) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein nucleic acid molecule includes at least 5 contiguous nucleotides from nucleotide 2069 to nucleotide 2077 of SEQ.
ID. N~: 3;
(2) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein the nucleic acid includes the nucleotide at position 2073 of SE(~ ID No. 1 replaced with G, G or T.
(3) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein the nucleic acid molecule includes at least 5 contiguous nucleotides from nucleotide 129556 to nucleotide 129604 of SEQ. ID. N~: 14;
(4) at least 14 or 16 contiguous nucleotides of the AICd4P10 allele or complement thereof, wherein the nucleic acid includes the nucleotide at position 129600 of SEQ ID No. 17 replaced with A, G or T;
2~ (5) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein the nucleic acid molecule includes at least 5 contiguous nucleotides from nucleotide 83583 to nucleotide 83591 of SEQ.. ID. N~: 13;
(6) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein the nucleic acid includes the nucleotide at position 83587 of SEQ ID No. 17 replaced with G, A or T;
(7) at least 14 or 16 contiguous nucleotides of the AKAP10 allele or complement thereof, wherein the nucleic acid molecule includes at least 5 contiguous nucleotides from nucleotide 156,273 to nucleotide 156281 of SEQ. ID. NO: 18;

(8) at least 14 or 16 contiguous nucleotides of the AfCAP10 allele or complement thereof, wherein the nucleic acid includes the nucleotide at position 156277 of SEQ ID No. 17 replaced with C, A or G;
With respect to each of the above described probes and primers, they have fewer nucleotides than the sequence of nucleotides 138 to 2126 of SEQ. ID. NO: 1 or fewer nucleotides than the sequence of nucleotides 83,580 to 156,577 of SEQ ID N0: 17.
1 ~ Antisense compounds can be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied 8iosystems (Foster City, Calif.). Any other means for such synthesis known in the art can additionally or alternatively be employed.
It is well known to use similar techniques to prepare oligonucleotides sash as the phosphorothioates and alkylated derivatives.
Antisense c~mpounds are typically 8 to 30 nucleotides in length complementary to a targeted to a nucleic acid molecule and modulates its expression. The targeted nucleic acid molecule represents the coding 2~ strand. For example, for the AiCAP10-5 alleleic variant an antisense compound is an antisense oligonucleotide which comprises the complement of at least an 8 nucleotide segment of SEQ ID N0: 3 including the nucleotide at position 2073 of SEQ ID N0: 3.
An antisense compound can contain at least one modified nucleotide which can confer nuclease resistance or increase the binding of the antisense compound with the target nucleotide. The antisense compound can containing at least one internucleoside linkage wherein the modified internucleoside linkage of the antisense oligonucleotide can be a phosphorothioate linkage, a morpholino linkage or a peptide-nucleic acid linkage.
Typical modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones;
sulfamate backbones; methyleneimino and methylenehydra~ino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and GHQ component parts.
Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos.:
5,034,505; 5,156,315; 5,185,444; 5,214,134; 5,215,141; 5,235,~33;
5,264,562; 5,264,564; 5,4~5,938; 5,434,257; 5,466,677; 5,47~,967;
5,489,677; 5,541,3~7; 5,561,225; 5,596,~86; 5,602,240; 5,61~,289;
5, 6Q2, 24~; 5, 6~8,~46; 5, 61 ~, 289; 5, 618, 704; 5, 623,~70; 5, 663, 312;
5,633,36~; 5,677,437; and 5,677,439, each of which is herein incorporated by reference.
An antisense compound can contain at least one least one modified sugar moiety wherein the modified sugar moiety of the antisense oligonucleotide is a 2'-O-methoxyethyl sugar moiety or a 2'-dimethylaminooxyethoxy sugar moiety.
Modified oligonucleotides can also contain one or more substituted sugar moieties. Typical oligonucleotides comprise one of the following at the 2' position: OH; F; O--, S--, or N-alkyl; O--, S--, or N-alkenyl; O--, S--_7$-or N-alkynyl; or 0-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C~ to Coo alkyl or C2 to Coo alkenyl and alkynyl. Exemplary oligonucleotides contain are O[(CH2)n O]m CH3, O(CHa)" OCH3, O(CH2)" NHS, O(CHz)~ CH3, O(CH2)~ NHS, and O(CH2) ON[(CH2)~ CH3)]~, where n and m are from 1 to about 10. Other oligonucleotides comprise one of the following at the 2' position: C, to C~~ lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, CI, 8r, CN, CF3, OCF3, SOCH3, SO~ CH3, ONO, N02, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for impr~ving the pharmacodynamic properties of an oligonucleotide, and ~ther substituents having similar properties. A typical modification includes an alkoxyalkoxy group, 2'-methoxyethoxy (2'-O-CH2 CHI OCH3, also known as 2'-0-(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 488-504). Another exemplary modificati~n includes 2'-dimethylaminooxyethoxy, i.e., a O(CH~)~ ON(CH3)2 group, also known as 2'-DMAOE.
Other modifications include 2'-methoxy (2'-0-CH3), 2°-aminopropoxy (2'-OCH~ CH2 CHI NHz) and 2'-fluoro (2°-F). Similar modifications can also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked oligonucleotides and the 5' position of 5' terminal nucleotide.
Oligonucleotides can also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the reparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957;
5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786;

_79_ 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909;
5,610,300; 5,627,0531 5,639,873; 5,646,265; 5,658,873; 5,670,633;
and 5,700,920, each of which is herein incorporated by reference.
An antisense compound can contain at least one modified nucleobase. Oligonucleotides can also include nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (lJ). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl deri~atieres of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.
Further nucleobases include those disclosed in U.S. Pat. No.
3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y. S., Crooke, S. T., and Lebleu, B. eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 289-302. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyl-adenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooks, S. T. and Lebleu, B., ads., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are typical base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications.
The antisense compound can be a chimeric oligonucleotide.
Chimeric antiasnsa compounds can be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers.
Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos.:
5,013,830; 5,149,79'x; 5,220,~~~'; 5,255,%75; 5,305,878; 5,403,711;
5,491,133; 5,555,350; 5,623,055; 5,552,355; 5,552,356; and 5,700,922, sash of which is herein incorporated by reference.
E. nBleasuring and Electr~cardi~gram Devices that can be used to measure an electrocardiogram are referred to as electrocardiographs. A variety of electrocardiographs are well known in the art and include, for example, those disclosed is U.S.
Pat. Nos. 4,377,813, 4,483,346, 4,98,479, 4,840,183, 4,974599. Any known electrocardiograph can be used in the methods provided herein.
Methods of using electrocardiographs to determine P-R interval and Q-T
interval also are well known in the art, and any such method can be used in the methods provided herein.

F. Association of AKAP10 Allelic Variants with Morbidity or Increased Mortality Polymorphisms of the genome can lead to altered gene function, protein function or mRNA instability. To identify those polymorphisms that have clinical relevance is the goal of a world-wide scientific effort.
Discovery of such polymorphisms will have a fundamental impact on the identification and development of diagnostics and drug discovery. The strategy to identify valuable polymorphisms is cumbersome and dependent upon the availability of many large patient and control cohorts to show disease association. Furthermore, genes, and their associated polymorphisms, that cause a general risk of the population to suffer from any disease will escape these case/control studies entirely.
A morbidity susceptibility gene could be a gene that is expressed in many different cell types or tissues (housekeeping gene) and its altered function can facilitate the expression of a clinical phenotype caused by a disease-specific susceptibility gene that is involved in a pathway specific for this disorder. In other words, morbidity susceptibility genes might predispose people to develop a distinct disease according to their genetic make-up for this disease. Candidates for these genes can involve basic cellular processes such as: transcription, translation, heat-shook proteins, protein trafficking, DNA repair, assembly systems for subcellular struc-tures (e.g., mitochondria, peroxysomes and other cellular microbodies), receptor signaling cascades, immunology, etc. Those pathways control the quality of life at the cellular level as well as for the entire organism.
Mutations/polymorphisms located in genes encoding proteins for those pathways can reduce the fitness of cells and make the organism more susceptible to express the clinical phenotype caused by the action of a disease-specific susceptibility gene. Therefore, these morbidity susceptibility genes can be potentially involved in a whole variety of different complex diseases if not in all.
An example of possible candidate morbidity susceptibility genes are mutants of the A kinase anchoring protein (AKAP) genes. Protein phosphorylation is an important mechanism for enzyme regulation and signal transduction in eukaryotic cells. cAMP dependent protein kinase (PKA) mediates a variety of hormonal and neurotransmitter responses by phosphorylating a wide variety of substrates including enzymes, membrane receptors, ion channels and transcription factors. AKAPs 1~ direct the subcellular localization of CAMP-dependent protein kinase by binding to its regulatory subunits and therefore plays a role in G-protein mediated receptor-signaling pathways. (Huang et al. Proc. Natl. Acad.
Sci., USA 94:111 S4, 1997). AKAPs have a PI<A binding region located in their C~~H-terminal portion.
Polymorphic AKAP genes, such as those provided herein, serve as markers for detecting predisposition to disease and various conditions.
~,Is~, the AI~c~P alleles and gene products, especially the AKAP10-5 gene product should be suitable pharmaceutical targets and gene therapy targets.
2~ In a further allele, designated AKAP10-7 contains a single nucleotide polymorphism (SNP), a G-to-A transition, at nucleotide position 129,600 of the human chromosome 17 sequence (also referred to herein as SNP "1n10"). This SNP is located four bases 3' to the exon 10lintron 10 boundary of AKAP10 gene. Another identified SNP, AKAP10-1 is an allelic variant with a T to C transversion at nucleotide position 156,277 of the AKAP10 genomic clone which is located in the 3' untranslated region of the gene (also referred to herein as SNP "3' UTR").

Utilizing a healthy patient database, the frequency of occurrence of two allelic variants of the AKAP10 gene, AKAP10-5 and AKAP10-1, in such a population were found to decrease with age. The AKAP10-5 and AKAP10-1 alleles are useful markers for predicting susceptibility to morbidity and/or increased or early mortality. The methods provided herein can be used for predicting susceptibility to morbidity, increased or early mortality, or morbidity and increased mortality, by detecting the presence of the various AKAP10 allelic variants known in the art or dislcosed herein, individually, or in combination with other AKAP10 allelic variants, in an organism, particularly an animal and particularly a human.
AKAP10-5 and other allelic variants of the AKAP10 gene known in the art or dislcosed herein are potential functional variants of a morbidity susceptibility gene and/or of a gene involved in increased mortality and/or a gene related to an alteration in signal transduction and associated disorders and thus is useful for screening for potential therapeutics.
G. Effect ~f Allelic !lariants The effect of an allelic variant on a AKAP10 gene etr~pression (amount of mRNA, mRNA stability) and AKAP protein (amount, stability, intracellular localization, activity) can be determined according to methods known in the art. Allelic variants of AKAP genes can be assayed individually or in combination.
In general, any method known to those skilled in the art of determining the presence or absence of a specific messenger RNA
transcript or a specific translated protein can be used to presence of absence of a polymorphic protein or a polymorphism in the genetic sequence.

1. RNA Analysis a. Northern Blot Detection of RNA
The northern blot technique is used to identify a RNA fragment of a specific size from a complex population of RNA using gel electrophoresis and nucleic acid hybridization. Northern blotting is a well-known technique in the art. Northern blot analysis is commonly used to detect specific RNA transcripts expressed in a variety of biological samples and have been described in Sambrook, J. et al. (Molecular Cloning, Brd Edition, Cold Spring Harbor Press).
Briefly, total RNA is isolated from any biological sample by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159). Poly-adenylated mRNA is purified from total RNA using mini-oligo (dT) cellulose spin column kit with methods as outlined by the suppliers (Invitrogen, Carlsbad CA.). ~enatured RNA is electrophoresed through a denaturing 1.5% agarose gel and transferred onto a nitrocellulose or nylon based matrix. The mRNAs are detected by hybridization of a radiolabeled or biotinylated oligonucleotide probe specific to the polymorphic regions as disclosed herein.
b. Dot Blot/Slot Blot Specific RNA transcripts can be detected using dot and slot blot assays to evaluate the presence of a specific nucleic acid sequence in a c~mplex mix of nucleic acids. Specific RNA transcripts can be detected by adding the RNA mixture to a prepared nitrocellulose or nylon membrane. RNA is detected by the hybridization of a radiolabeled or biotinylated oligonucleotide probe complementary to the AKAP
sequences as disclosed herein.
c. RT-PCR
The RT-PCR reaction can be performed, as described by K.-Q. Hu et al., Virology 181:721-726 ( 1991 ), as follows: the extracted mRNA is transcribed in a reaction mixture 1 micromolar antisense primer, and 25 U AMV (avian myeloblastosis virus) or MMLV (Moloney murine leukemia virus) reverse transcriptase. Reverse transcription is performed and the cDNA is amplified in a PCR reaction volume with Tap polymerase.
Optimal conditions for cDNA synthesis and thermal cycling can be readily determined by those skilled in the art.
2. Protein and Polypeptide Detection a. Expression of Protein in a Cell Line Using the disclosed nucleic acids AICAP10 proteins can be 1Q expressed in a recombinantly engineered cell such as bacteria, yeast, insect, mammalian, or plant cells. Those of skill in the art are knowledgeable in the numerous expression systems available for expression of a nucleic acid encoding proteins such as polymorphic human AI<AP10 proteins.
b. Expression of AKAP Protein The isolated nucleic acid encoding a full-length polymorphic human AI~AP10 protein, or a portion thereof, such as a fragment containing the site of the polymorphism, can be introduced into a vector for transfer into host cells. Fragments of the polymorphic human AICAP10 proteins can be produced by those skilled in the art, without undue experimentation, by eliminating portions of the coding sequence from the isolated nucleic acids encoding the full-length proteins.
Expression vectors are used expression of the protein in the host cell is desired. An expression vector includes vectors capable of expressing nucleic acids that are operatively linked with regulatory sequences, such as promoter regions, that are capable of effecting expression of such nucleic acids. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, a phage, recombinant virus or other vector that, upon introduction into an appropriate host cell, results in expression of the cloned DNA.
Appropriate expression vectors are well known to those of skill in the art and include those that are replicable in eukaryotic cells and/or prokaryotic cells and those that remain episomal or those which integrate into the host cell genome. Such plasmids for expression of polymorphic human AICAP10-encoding nucleic acids in eukaryotic host cells, particularly mammalian cells, include cytomegalovirus (CMV) promoter-containing vectors, such as pCMV5, the pSV2dhfr expression vectors, which contain the SV40 early promoter, mouse dhfr gene, SV40 polyadenylation and splice sites and sequences necessary for maintaining the vector in bacteria, and MMTV promoter-based vectors.
The nucleic acids encoding polymorphic human AKAP10 proteins, and vectors and cells containing the nucleic acids as provided herein permit production of the polymorphic proteins, as well as antibodies to the proteins. This provides a means to prepare synthetic or recombinant polymorphic human AKAP10 proteins and fragments thereof that are substantially free of contamination from other AKR~Ps and proteins in general, the presence of which can interfere with analysis of the polymorphic proteins. In addition, the polymorphic proteins can be expressed in combination with selected other proteins that AKAP10 can associate with in cells. The ability to selectively express the polymorphic AICAP10 proteins alone or in combination with other selected proteins makes it possible to observe the functioning of the recombinant polymorphic proteins within the environment of a cell. The expression of isolated nucleic acids encoding an AICAP protein will typically be achieved by operably linking, for example, the DNA or cDNA to a promoter (which is either constitutive or regulatable), followed by incorporation into an expression vector. The vectors can be suitable for replication and integration in either prokaryotes or eukaryotes. Typical _g7_ expression vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the DNA encoding a protein. To obtain high level expression of a cloned gene, it is desirable to construct expression vectors which contain, a strong promoter to direct transcription, a ribosome binding site for translational initiation, and a transcription/translation terminator. One of skill in the art would recognize that modifications can be made to an AKAP10 protein without diminishing its biological activity. Some modifications can be made to 1~ facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications are well known to those of skill in the art and include, for example, a methionine added at the amino terminus to provide an initiation site, or additional amino acids (e.g., poly His) placed on either terminus to create conveniently located purification sequences. Restriction sites or termination codons can also be introduced. There are expression vectors that specifically allow the expression ~f fu~,ctional proteins. One such vector, Plasmid 5~~, described in IJ.S. Pat. No. 6,0~0,12~ and incorporated herein by reference, has been constructed for the expression of secreted antigens 2~ in a permanent cell line. This plasmid contains the following DNA
segments: (a) a fragment of pBR322 containing bacterial beta-lactamase and origin of DNA replication; (b) a cassette directing expression of a neomycin resistance gene under control of HSV-1 thymidine kinase promoter and poly-A addition signals; (c) a cassette directing expression of a dihydrofolate reductase gene under the control of a SV-40 promoter and poly-A addition signals; (d) cassette directing expression of a rabbit immunoglobulin heavy chain signal sequence fused to a modified hepatitis C virus (HCV) E2 protein under the control of the Simian Virus 40 T-Ag promoter and transcription enhancer, the hepatitis B virus _gg_ surface antigen (HBsAg) enhancer I followed by a fragment of Herpes Simplex Virus-1 (HSV-1 ) genome providing poly-A addition signals; and (e) a fragment of Simian Virus 40 genome late region of no function in this plasmid. All of the segments of the vector were assembled by standard methods known to those skilled in the art of molecular biology.
Plasmids for the expression of secreted AKAP proteins can be constructed by replacing the hepatitis C virus E2 protein coding sequence in plasmid 577 with a AKAP sequence of SEQ ID N0: 3 or a fragment thereof. The resulting plasmid is transfected into CHO/dhfr-cells (D?CB-1 1 1 ) (Uriacio, et al., PNAS 77, 4451-4460; 1980); these cells are available from the A.T.C.C., 12301 Parklawn Drive, Rockville, Md.
20852, under Accession No. CRL 9096), using the cationic liposome-mediated procedure (P. L. Felgner et al., PNAS 84:7413-7417 (1987).
Proteins are secreted into the cell culture media.
Incorporation of cloned DNA into a suitable expression vector, transfection of cells with a plasmid vector or a combination of plasmid vectors, each encoding one or more distinct proteins or with linear DNA, and selection of transfected cells are well known in the art (see, e.g., Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press). Heterologous nucleic acid can be introduced into host cells by any method known to those of skill in the art, such as transfection with a vector encoding the heterologous nucleic acid by CaP04 precipitation (see, e.g., Wigler et al. (1979) Pr~e.
Nat/. Acad. Sci. USA 76:1373-1376) or lipofectamine (GIBCO BRL
#18324-012). Recombinant cells can then be cultured under conditions whereby the polymorphic human AKAP10 protein encoded by the nucleic acid is expressed. Suitable host cells include mammalian cells (e.g., HEK293, including but are not limited to, those described in U.S. Patent No. 5,024,939 to Gorman (see, also, Stillman et al. (1985) Mol. Cell.

_89_ Biol. 5:2051-2060); also, HEK293 cells available from ATCC under accession #CRL 1573), CHO, COS, BHKBI and Ltk- cells, mouse monocyte macrophage P388D1 and J774A-1 cells (available from ATCC, Rockville, MD) and others known to those of skill in this art), yeast cells, including, but are not limited to, Pichia pastoris, Saccharomyces cerevisiae, Candida tropicalis, Hansenula polymorpha, human cells and bacterial cells, including, but are not limited to, Escherichia coli.
~Cenopus oocytes can also be used for expression of in ~ritro RNA
transcripts of the DNA.
Heterologous nucleic acid can be stably incorporated into cells or can be transiently expressed using methods known in the art. Stably transfected mammalian cells can be prepared by transfecting cells with an expression vector having a selectable marker gene (such as, for example, the gene for thymidine kinase, dihydrofolate reductase, neomycin resistance, and the like), and growing the transfected cells under conditions selective for cells expressing the marker gene. To prepare transient transfectants, mammalian cells are transfected with a reporter gene (such as the E. coli f3-galactosidase gene) to monitor transfection efficiency. Selectable marker genes are not included in the transient transfections because the transfectants are typically not grown under selective conditions, and are usually analyzed within a few days after transfection.
Heterologous nucleic acid can be maintained in the cell as an episomal element or can be integrated into chromosomal DNA of the cell.
The resulting recombinant cells can then be cultured or subcultured (or passaged, in the case of mammalian cells) from such a culture or a subculture thereof. Methods for transfection, injection and culturing recombinant cells are known to the skilled artisan. Similarly, the polymorphic human AKAP10 proteins or fragments thereof can be _g0_ purified using protein purification methods known to those of skill in the art. For example, antibodies or other ligands that specifically bind to the proteins can be used for affinity purification and immunoprecipitation of the proteins.
b. Protein Purification The AKAP10 proteins can be purified by standard techniques well known to those of skill in the art. Recombinantly produced proteins can be directly expressed or expressed as a fusion protein. The recombinant protein is purified by a combination of cell lysis (e.g., sonication, French press) and affinity chromatography. The proteins, recombinant or synthetic, can be purified to substantial purity by standard techniques well known in the art, including detergent solubili~ation, selective precipitation with such substances as ammonium sulfate, column chromatography, immunopurification methods, and others. (See, for example, R. Scopes, Protein Purification: Principles and Practice, Springer-Verlag: New York (1952); Deutscher, Guide to Protein Purification, Academic Press (199~)). For ea;ample, antibodies can be raised to the proteins as described herein. Purification from E. coli can be achieved following procedures described in U.S. Pat. No. 4,511,5~3. The protein can then be isolated from cells expressing the protein and further purified by standard protein chemistry techniques as described herein.
Detection of the expressed protein is achieved by methods known in the art and include, for example, radioimmunoassays, Western blotting techniques or immunoprecipitation.
3. Immunodetection of the AKAP10 protein.
Generally, the AICAP proteins, when presented as an immunogen, should elicit production of a specifically reactive antibody.
Immunoassays for determining binding are well known to those of skill in the art, as are methods of making and assaying for antibody binding specificity/affinity. Exemplary immunoassay formats include ELISA, competitive immunoassays, radioimmunoassays, Western blots, indirect immunofluorescent assays, in vivo expression or immunization protocols with purified protein preparations. In general, the detection of immunocomplex formation is well known in the art and can be achieved by methods generally based upon the detection of a label or marker, such as any of the radioactive, fluorescent, biological or enzymatic tags.
Labels are well known to those skilled in the art (see U.S. Pat. Nos.
3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149 and 4,366,241, each incorporated herein by reference). 0f course, one can find additional advantages through the use of a secondary binding ligand such as a second antibody or a biotin/avidin ligand binding arrangement, as is known in the art.
Production of P~lyclonal Antisera Against AKAP
Antibodies can be raised to AKAP proteins, including individual, allelic, strain, or species variants, and fragments thereof, both in their naturally occurring (full-length) forms and ir, recombinant forms.
Additionally, antibodies are raised to these proteins in either their native configurations or in non-native configurations. Anti-idiotypic antibodies can also be generated. A variety of analytic methods are available to generate a hydrophilicity profile of proteins. Such methods can be used to guide the artisan in the selection of peptides for use in the generation or selection of antibodies which are specifically reactive, under immunogenic conditions. See, e.g., J. Janin, Nature, 277 (1979) 491-492; Wolfenden, et al., Biochemistry 20(1981 ) 849-855; Kyte and Doolite, J. Mol. Biol. 157 (1982) 105-132; Rose, et al., Science 229 ( 1985) 834-838.
A number of immunogens can be used to produce antibodies specifically reactive with AKAP proteins. Isolated recombinant, synthetic, or native polypeptides are typical immunogens (antigen) for the production of monoclonal or polyclonal antibodies. Polypeptides are typically denatured, and optionally reduced, prior to formation of antibodies for screening expression libraries or other assays in which a putative AKAP protein is expressed or denatured in a non-native secondary, tertiary, or quartenary structure.
The AKAP protein (SEQ ID NO: 4, or a portion thereof) is injected into an animal capable of producing antibodies. Either monoclonal or polyclonal antibodies can be generated for subsequent use in immunoassays to measure the presence and quantity of the protein.
Methods of producing polyclonal antibodies are known to those of skill in the art. In brief, an immunogen (antigen), typically a purified protein, a protein coupled to an appropriate carrier (e.g., GST, keyhole limpet hemanocyanin, etc.), or a protein incorporated into an immunization vector such as a recombinant vaccinia virus (see, U.S. Pat. No.
4,722.,848) is mixed with an adjuvant and animals are immunized with the mixture. The animates immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to the proteiri of interest. When appropriately high titers of antibody to the immunogen are obtained, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the protein is performed where desired (See, e.g., Coligan, Current Protocols in Immunology, Wiley/Greene, NY
(1991); and Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press, NY (1989)).
b. Western Blotting of Tissue Samples for the AKAP protein Biological samples are homogenized in SDS-PAGE sample buffer (50 mM Tris-HCI, pH 6.8, 100 mM dithiothreitol, 2% SDS, 0.1 bromophenol blue, 10% glycerol), heated at 100 degrees Celsius for 10 min and run on a 14% SDS-PAGE with a 25 mM Tris-HCI, pH 8.3, 250 mM Glycine, 0.1 % SDS running buffer. The proteins are electrophoretically transferred to nitrocellulose in a transfer buffer containing 39 mM glycine, 48 mM Tris-HCI, pH 8.3, 0.037% SDS, 20%
methanol. The nitrocellulose is dried at room temperature for 60 min and then blocked with a PBS solution containing either bovine serum albumin or 5% nonfat dried milk for 2 hours at 4 degrees Celsius.
The filter is placed in a heat-sealable plastic bag containing a solution of 5% nonfat dried milk in PBS with a 1:100 to 1:2000 dilution 1~ of affinity purified anti-AKAP peptide antibodies, incubated at 4 degrees Celsius for 2 hours, followed by three 10 min washes in PBS. An alkaline phosphatase conjugated secondary antibody (i.e., anti-mouse/rabbit IgG), is added at a 1:200 to 1:2000 dilution to the filter in a 150 mM iVaCl, 50 mM Tris-HCI, pH 7.5 buffer and incubated for 1 h at room temperature.
The bands are visualized upon the addition and development of a chromogenic substrate such as 5-bromo-4-chloro-3-indolyl phosphal:e/nitro blue tetrazoliun, (BCIP/i~BT). The filter is incubated in the solution at room temperature until the bands develop to the desired intensity. Molecular mass determination is made based upon the mobility 2~ ~f pre-stained molecular weight standards (Rainbow markers, Amersham, Arlington Heights, III.).
c. Microparticle Enzyme Immun~assay (MEIA) AKAP10 proteins and peptides are detected using a standard commercialized antigen competition EIA assay or polyclonal antibody sandwich EIA assay on the IMx.RTM Analyzer (Abbott Laboratories, Abbott Park, III.). Samples containing the AKAP10 protein are incubated in the presence of anti-AKAP10 coated microparticles . The microparticles are washed and secondary polyclonal anti-AKAP10 antibodies conjugated with detectable entities (i.e., alkaline phosphatase) are added and incubated with the microparticles. The microparticles are washed and the bound antibody/antigen/antibody complexes are detected by adding a substrate (i.e. 4-methyl umbelliferyl phosphate) (MUP) that will react with the secondary conjugated antibody to generate a detectable signal.
d. Immunocytochemistry Intracellular localization of the AICAP10 protein can be determined by a variety of in situ hybridization techniques. In one method cells are fixed with fixed in 4% paraformaldehyde in 0.1 M phosphate buffered 1~ saline (PBS; pH7.4) for 5 min., rinsed in PBS for 2 min., dilapidated and dehydrated in an ethanol series (50, 70 and 95°/~) (5 min, each and stored in 95°/~ ethanol at 4 degrees Celsius).
The cells are stained with the primary anti-AICAP10 antibody and a mixture of secondary antibodies used for detection. Laser-scanning confocal microscopy is performed to localize the AICAP10 protein.
4. Binding Assays Assays to measure the interaction between AICAP10 a~,d the regulatory subunits RI and/or RII of the Protein ICinase A holoenzyme include immobilized binding assays, solution binding assays and the like.
2~ In some instances, it can be desirable to monitor binding between AICAP10 and PICA. In other instances, it can be desirable to specifically monitor the binding between AICAP10 and a cellular component (other than PICA) to which it binds. Assays can be performed in a variety of formats, including cell-based assays, such as di-hybrid screening or complementation assays as described in U.S. Pat. No. 5,283,173 and Patent Cooperation Treaty (PCT) Publication No. W0 91 /16457, respectively. Assays of this type are particularly useful for assessing intracellular efficacy of test compounds. Non-cell-based assays include scintillation proximity assays, CAMP competition assays, ELISA assays, radioimmunoassays, chemiluminescent assays, and the like. Such assay procedures are well known in the art and generally described, e.g., in Boudet et al., J. Immunol. Meth., 142:73-82 (1991 ); Ngai et al., J.
Immunol. Meth., 158:267-276 (1993); Pruslin et al., J. Immunol. Meth., 137:27-35 (1991 ); Udenfriend et al., Proc. Natl. Acad. Sci. USA, 82:8672-8676 (1985); Udenfriend et al., Anal. Biochem., 161:494-500 (1987); Bosworth and Towers, Nature, 341:167-168 (1989); Gilman, Proc. Natl. Acad. Sci. USA, 67:305-312 (1970); and U.S. Pat. No.
4, 568, 649.
a. In vitr~ binding assay Huang et al. Proc. Natl. Acad. Sci. USA, 272:8057-8064 ( 1997);
Protein preparations containing AI~AP10 are incubated with glutathione resin in PBS for 2 hours at 4 degrees Celsius with 0.1 ~f~ Triton ?~-100, 1 mM phenylmethylsulfonyl fluoride, 1 mM E~TA, 5mM benzamidine, and 5mM B-mercapthoethanol and washed extensively with the same buffer.
200 micrograms of PICA regulatory subunit RII and/or RI were added to the resin and incubated at 4 degrees Celsius. Proteins associated with the AI~AP10 are eluted and analyzed by Laemmli electrophoresis. The proteins were visualized by Coomassie Staining. PICA proteins can be radiolabeled or labeled with a flurophore to allow detection.
b. PICA phosphorylation of protein substrate Cyclic AMP-dependent protein kinase (PICA) catalyzes the transfer of gamma phosphate from adenosine triphosphate (ATP) to a serine or threonine residue in a protein substrate. A short synthetic peptide (Leucine-Arg-Arg-Alanine-Serine-Leucine-Glycine or LRRASLG) is used as a substrate to assay the specific type of PICA activity as described in Pearson et. al., Methods of Enzymology 200, 62-81 (1991 ).
The PICA assay is typically carried out in a reaction of the enzyme with a peptide substrate and gamma 32P-ATP followed by separation of the 32P-peptide product from the unreacted gamma 32P-ATP on a phosphocellulose membrane. This method requires at least one basic amino acid residue in the peptide substrate. The peptide substrate can be tagged with a biotin group so that the biotinylated 32P-peptide product consistently binds to a streptavidin membrane in a manner independent of the peptide sequence as described in Goueli et al Analytical Biochemistry 225, 10-17, (1995). The separation of the 32P-peptide product from the free gamma 32P-ATP using affinity binding and ultrafiltration separation to analyze a mixture sample as described in U.S.
Patent No. 5,869,275.
If the mutation is located in an intron, the effect of the mutation can be determined, e.g., by producing transgenic animals in which the allelic variant has been introduced and in which the wild-type gene or predominant allele can have been knocked out. Comparison of the level of expression of the protein in the mice transgenic for the allelic variant with mice transgenic for the predominant allele will reveal whether the mutation results in inci°eased or decreased synthesis of the associated protein and/or aberrant tissue distribution or intracellular localization of the associated protein. Such analysis could also be performed in cultured cells, in which the human variant allele gene is introduced and, e.g., replaces the endogenous gene in the cell. For mutant AI~AP
proteins binding to signaling enzymes such as PICA is also examined.
Thus, depending on the effect of the alteration a specific treatment can be administered to a subject having such a mutation. Accordingly, if the mutation results in decreased production of AICAP protein, the subject can be treated by administration of a compound which increases synthesis, such as by increasing AKAP gene expression, and wherein the compound acts at a regulatory element different from the one which is mutated. Alternatively, if the mutation results in increased AICAP

_97_ protein, the subject can be treated by administration of a compound which reduces protein production, e.g., by reducing AKAP gene expression or a compound which inhibits or reduces the activity of AKAP
protein.
H. Diagnostic and Prognostic Assays Typically, an individual allelic variant that associates with morbidity and/or mortality and/or an alteration in signal transduction will not be used in isolation as a prognosticator. An allelic variant typically will be one of a plurality of indicators that are used. The other indicators can be the manifestation of other risk factors for morbidity and/or mortality and other evidence of altered signal transduction.
Useful combinations of allelic variants of the AKAP10 gene can be determined. Variants can be assayed individually or assayed simultaneously using multiplexing methods as described above or any other labelling method that allows different variants to be identified. In particular, variants of the AKAP10 gene can be assayed using kits (see below) or any of a variety microarrays known to those in the art. For example, oligonucleotide probes comprising the polymorphic regions surrounding any polymorphism in the AKAP10 gene can be designed and 2~ fabricated using methods such as those described in U.S. Patent Nos.
5,492,806; 5,525,464; 5,695,940; 6,018,041; 6,025,136; WO
98/30883; WO 98/56954; W099/09218; WO 00/58516;

9, or references cited therein.
I. Databases Use of databases containing sets of parameters associated with subjects in populations selected on the basis of apparent good health, not manifesting detectable disease (i.e., an unbiased population not selected for any disease state), allows for identification of such morbidity susceptibility genes tsee, U.S. Provisional Application Serial No.

_98_ 60/159,176 filed October 13, 1999, U.S. Provisional Application Serial No. 60/217,658 filed on July 10, 2000 and U.S. Application Serial No.
09/687,483 filed October 13, 2000).
For example, in a method for determining susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality in a human being, provided herein, exemplary steps include detecting the presence or absence of an allele of the human AKAP10 containing other than an A at position 2073 of the coding sequence of the AKAP10 gene; wherein the presence of an allele containing other than an A at position 2073 is indicative of increased susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality as compared to the susceptibility of a human being who does not comprise an allele containing other than an A at position 2073 of the AKAP10 gene coding sequence.
As noted above, using a healthy patient database (see, U.S.
Provisional Application Serial No. 60/159,176, U.S. Provisional ~4pplication Serial fro. 50/217,558 and U.S. Application Serial l~o.
09/587,483 filed October 13, 2000), the frequency of occurrence of the AKAP10-5 SNP in such a population was found to decrease with age, thus making the allele a potential morbidity susceptibility gene, a gene associated with increased mortality or both. Using the healthy database, it was found that the homozygote GG genotype drops in the elderly population (over > 60 years), by a statistically significant amount, p = 0.02.
J. Isolation of Polymorphic AKAP10 Gene Sequences Exemplary nucleic acid sequences encoding polymorphic human AKAP10 proteins are represented by nucleotides which encode the amino acid sequence as set forth in SEQ. ID. NO: 3. Such polymorphic nucleotide sequences can encode variant amino acid sequences, such as _99_ the sequence set forth in SEQ. ID. NO: 4 in which amino acid 646 has been replaced with a valine; other amino acid sequence variants at amino acid 646 include leucine or phenylalanine.
Other exemplary nucleic acid sequences represent allelic variants of the AKAP10 gene which are not located in protein coding regions.
Such as set forth in nucleotide position 83,580 to position 156,577 of SEQ ID N0: 13, 14 and 18.
Nucleic acid encoding polymorphic human AKAP10 proteins and genes provided herein can be isolated by screening suitable human cDNA
or human genomic libraries under suitable hybridization conditions with nucleic acids such as those provided in SEQ. ID. NOS: 1, 3, 13, 14, 17 and 18. Suitable libraries can be prepared from human tissue and cell samples. In order to isolate cDNA encoding a polymorphic human AKAP10 libraries prepared from different tissues can be screend since the allele can not be expressed in all tissues or at similar levels in different tissues. The library can be screened with a portion of DNA
including substantially the entire human AKAP10 or polymorphic AKAP10 protein-encoding sequence as set forth in SECO. ID. NOS. 1, 3, 13, 14, 17 and 18, or the library can be screened with a suitable probe.
After screening the library, positive clones are identified by detecting a hybridization signal; the identified clones are characterized by restriction enzyme mapping and/or DNA sequence analysis, and then examined, by comparison with the sequences set forth herein to ascertain whether they include DNA encoding a complete polymorphic human AKAP10 protein (i.e., if they include translation initiation and termination codons). If the selected clones are incomplete, they can be used to rescreen the same or a different library to obtain overlapping clones. If the library is genomic, then the overlapping clones can include exons and introns. If the library is a cDNA library, then the overlapping clones will include an open reading frame. In both instances, clones can be identified by comparison with the DNA and encoded proteins provided herein.
In an alternative method, oligonucleotides based on the human AKAP10 or polymorphic AKAP10 protein-encoding sequence as set forth in SEQ. ID. NOS. 1, 3, 13, 14, 17 and 18, can be used to amplify fragments of the protein coding region of the AKAP10 gene from human cDNA or genomic sequence.
The isolated nucleic acid sequences can be incorporated into vectors for further manipulation. As used herein, vector (or plasmid) refers to discrete elements that are used to introduce heterologous DNA
into cells for either eacpression or replication thereof. Selection and use of such vehicles are well within the skill of the artisan, K. Transgenic Animals Methods for making transgenic animals using a variety of transgenes have been described in Wagner et al., Proc. Nat. Acad. Sc.
Cd.S.A., Vol. 78, p. 50158 1981; Stewart e~ ~/., Science, Vol. 217, p, 1045, 1982; Constantini a~ al., Nature, Vol. 294, p. 92, 1981; Lacy et a/., Cell, Vol, 34, p. 343, 1983; McKnight et al., Cell, Vol. 34., p. 335, 1983; 8rinstar et al., Nature, Vol. 306, p. 332, 1983; Palmiter e~ al., Nature, Vol. 300, p. 611, 1982; Palmiter eta/.,Cell, Vol. 29, p. 701, 1982 and Palmiter et al., Science, Vol. 222, p. 809, 1983. Such methods are described in U.S. Patent Nos. 5,175,057; 6,180,849 and 6,133,502.
The term "firansgene" is used herein to describe genetic material that has been or is about to be artificially inserted into the genome of a mammalian cell, particularly a mammalian cell of a living animal. The transgene is used to transform a cell, meaning that a permanent or transient genetic change, typically a permanent genetic change, is induced in a cell following incorporation of exogenous DNA. A
permanent genetic change is generally achieved by introduction of the DNA into the genome of the cell. Vectors for stable integration include, but are not limited to, plasmids, retroviruses and other animal viruses and YACS. Of interest are transgenic mammals, including, but are not limited to, cows, pigs, goats, horses and others, and particularly rodents, including rats and mice. Typically, the transgenic-animals are mice.
Transgenic animals contain an exogenous nucleic acid sequence present as an extrachromosomal element or stably integrated in all or a portion of its cells, especially germ cells. Unless otherwise indicated, it will be assumed that a transgenic animal comprises stable changes to the germline sequence. During the initial construction of the animal, "chimeras" or "chimeric animals" are generated, in which only a subset of cells have the altered genome. Chimeras are primarily used for breeding purposes in order to generate the desired transgenic animal.
Animals having a heterozygous alteration are generated by breeding of chimeras. f~iale and female hetero~ygotes are typically bred to generate homozygous animals.
The exogenous gene is usually either from a different species than the animal host, or is otherwise altered in its coding or non-coding sequence. The introduced gene can be a wild-type gene, naturally occurring polymorphism or a genetically manipulated sequence, for example having deletions, substitutions or insertions in the coding or non-coding regions. When the introduced gene is a coding sequence, it is usually operably linleed to a promoter, which can be constitutive or inducible, and other regulatory sequences required for expression in the host animal.
Transgenic animals can comprise other genetic alterations in addition to the presence of alleles of AKAP genes. For example, the genome can be altered to affect the function of the endogenous genes, contain marker genes, or contain other genetic alterations (e.g., alleles of other genes associated with cardiovascular disease).
A "knock-out" of a gene means an alteration in the sequence of the gene that results in a decrease of function of the target gene, typically such that target gene expression is undetectable or insignificant.
A knock-out of an endogenous AKAP gene means that function of the gene has been substantially decreased so that expression is not detectable or only present at insignificant levels. "Knock-out"
transgenics can be transgenic animals having a heterozygous knock-out of an AKAP gene or a homozygous knock-out. "Knock-outs" also include conditional knock-outs, where alteration of the target gene can occur upon, for example, exposure of the animal to a substance that promotes target gene alteration, introduction of an enzyme that promotes recombination at the target gene site (e.g., Cre in the Cre-lox system), or other method for directing the target gene alteration postnatally.
A "knock-in" of a target gene means an alteration in a host cell genome that results in altered expression (e.g., increased (including ectopic)) of the target gene, e.g., by introduction of an additional copy of the target gene, or by operatively inserting a regulatory sequence that provides for enhanced expression of an endogenous copy of the target gene. "Knock-in" transgenics of interest can be transgenic animals having a knock-in of an AKAP gene. Such transgenics can be heterozygous or homozygous for the knock-in gene. "Knock-ins" also encompass conditional knock-ins.
A construct is suitable for use in the generation of transgenic animals if it allows the desired level of expression of an AKAP encoding sequence or the encoding sequence of another gene associated with cardiovascular disease. Methods of isolating and cloning a desired sequence, as well as suitable constructs for expression of a selected sequence in a host animal, are well known in the art and are described below.
For the introduction of a gene into the subject animal, it is generally advantageous to use the gene as a gene construct wherein the gene is ligated downstream of a promoter capable of and operably linked to expressing the gene in the subject animal cells. Specifically, a transgenic non-human mammal showing high expression of the desired gene can be created by microinjecting a vector ligated with the gene into a fertilized egg of the subject non-human mammal (e.g., rat fertilized egg) downstream of various promoters capable of expressing the protein and/or the corresponding protein derived from various mammals (rabbits, dogs, cats, guinea pigs, hamsters, rats, mice etc., typicall rats ete.) Useful vectors include Escherichia coli-derived plasmids, Sacillus subtilis-derived plasmids, yeast-derived plasmids, bacteriophages such as lambda, phage, retroviruses such as I~lloloney leukemia virus, and animal viruses s~acll as vaccinia virus or baculovirus.
Useful promoters for such gene expression regulation include, for example, promoters for genes derived from viruses (cytomegalovirus, Moloney leukemia virus, JC virus, breast cancer virus etc.), and promoters for genes derived from various mammals (humans, rabbits, dogs, cats, guinea pigs, hamsters, rats, mice ete.) and birds (chickens etc.) (e. g., genes for albumin, insulin II, erythropoietin, endothelin, osteocalcin, muscular creatine kinase, platelet-derived growth factor beta, keratins K1, K10 and K14, collagen types I and II, atrial natriuretic factor, dopamine beta-hydroxylase, endothelial receptor tyrosine kinase (generally abbreviated Tie2), sodium-potassium adenosine triphosphorylase (generally abbreviated Na,K-ATPase), neurofilament light chain, metallothioneins I and IIA, metalloproteinase I tissue inhibitor, MHC class I antigen (generally abbreviated H-2L), smooth muscle alpha actin, polypeptide chain elongation factor 1 alpha (EF-1 alpha), beta actin, alpha and beta myosin heavy chains, myosin light chains 1 and 2, myelin base protein, serum amyloid component, myoglobin, renin etc.).
In one embodiment, the above-mentioned vectors have a sequence for terminating the transcription of the desired messenger RNA in the transgenic animal (generally referred to as terminator); for example, gene expression can be manipulated using a sequence with such function contained in various genes derived from viruses, mammals and birds. In one example, the simian virus SV40 terminator etc. are commonly used.
Additionally, for the purpose of increasing the expression of the desired gene, the splicing signal and enhancer region of each gene, a portion of the intron of a eukaryotic organism gene can be ligated 5' upstream of the promoter region, or between the promoter region and the translational region, or 3' downstream of the translational region as desired.
A translational region for a protein of interest can be obtained using the entire or portion of genomic DNA of blood, kidney or fibroblast origin from various mammals (humans, rabbits, dogs, cats, guinea pigs, hamsters, rats, mice etc.) or of various commercially available genomic DNA libraries, as a starting material, or using complementary DNA
prepared by a known method from RNA of blood, kidney or fibroblast origin as a starting material. Also, an exogenous gene can be obtained using complementary DNA prepared by a known method from RNA of human fibroblast origin as a starting material. All these translational regions can be used in transgenic animals.
To obtain the translational region, it is possible to prepare DNA
incorporating an exogenous gene encoding the protein of interest in which the gene is ligated downstream of the above-mentioned promoter (typically upstream of the translation termination site) as a gene construct capable of being expressed in the transgenic animal.
DNA constructs for random integration need not include regions of homology to mediate recombination. Where homologous recombination is desired, the DNA constructs will comprise at least a portion of the target gene with the desired genetic modification, and will include regions of homology to the target locus. Conveniently, markers for positive and negative selection are included. Methods for generating cells having targeted gene modifications through homologous recombination are known in the art. For various techniques for transfecting mammalian cells, see ICeown et al. (1 J90) Methods in Enzymology 155:57-537.
The transgenic animal can be created by introducing an AI~AP
gene construct into, for example, an unfertilized egg, a fertilized egg, a spermatozoon or a germinal cell containing a primordial germinal cell thereof, typically in the embryogenic stage in the development of a non-human mammal (more typically in the single-cell or fertilized cell stage and generally before the S-cell phase), by standard means, such as the calcium phosphate method, the electric pulse method, the lipofection method, the agglutination method, the microinjection method, the particle gun method, the DEAE-dextran method and other such method. Also, it is possible to introduce a desired AICAP gene into a somatic cell, a living organ, a tissue cell or other cell, by gene transformation methods, and use it for cell culture, tissue culture and any other method of propagation. Furthermore, these cells can be fused with the above-described germinal cell by a commonly known cell fusion method to create a transgenic animal.
For embryonic stem (ES) cells, an ES cell line can be employed, or embryonic cells can be obtained freshly from a host, e.g. mouse, rat, guinea pig, etc. Such cells are grown on an appropriate fibroblast-feeder layer or grown in the presence of appropriate growth factors, such as leukemia inhibiting factor (LIF). When ES cells have been transformed, they can be used to produce transgenic animals. After transformation, the cells are plated onto a feeder layer in an appropriate medium. Cells containing the construct can be detected by employing a selective medium. After sufficient time for colonies to grow, they are picked and analyzed for the occurrence of homologous recombination or integration of the construct. Those colonies that are positive can then be used for embryo manipulation and blastocyst injection. Blastocysts are obtained from 4 to 6 week old superovulated females. The ES cells are trypsinized, and the modified cells are injected into the blastocoel of the blastocyst. After injection, the blastocysts are returned to each uterine horn of pseudopregnant females. Females are then allowed to go t~ term and the resulting litters screened for mutant cells having the construct.
Sy providing for a different phenotype of the blastocyst and the ES cells, chimeric pr~geny can be readily detracted. The chimeric animals are screened f~r the presence of the m~dified gene and males and females having the modification are mated to produce homozygous progeny. If the gene alterations cause lethality at some point in development, tissues or organs can be maintained as allogeneic or congenic grafts or transplants, or in in ~ritr~ culture.
Animals containing more than one transgene, such as allelic variants of AICAP genes and/or other genes associated with morbidity and/or mortality can be made by sepuentially introducing individual alleles into an animal in order to produce the desired phenotype (manifestation of morbidity and/or predisposition to early mortality).

L. Screening assays for modulators Modulators of AKAP10 biological activities can be identified by using any of the disclosed methods related to AKAP10 binding to PKA, AKAP10 localization in the mitochondria, binding to other signaling enzymes and phosphorylation by PKA.
In particular, once a variant protein such as AKAP10-5 is contacted with a potential modulating molecule the effect of the molecule on the binding between AKAP protein and PKA can be determined by using the assays disclosed in the section entitled " Effect of Allelic Variants". For example mitochondria can be isolated from cells exposed to the potential modulating molecule. PKA protein can then be isolated and quantitated or phosphor,<lation can be determined using the disclosed PKA assay. An increase in the amount of PICA protein in the mitochondria or the quantity of test peptide phosphorylated by mitochondrial isolated PKA would indicate a positive effect of the test molecule. Binding of AKAP10 protein and PKA could be directly assessed using an in vitro binding assay, or rather disclosed binding assays, or by immunoassays such as immunoprecipitati~n.
For allelic variants that d~ not alter the AKAP10 protein the effect of a potential modulating molecule can be assayed by examining PKA
RNA using the various methods disclosed for RNA analysis.
M. Ribozymes A ribozyme targets the RNA genome and RNA transcripts and copies thereof. Each ribozyme molecule contains a catalytically active segment capable of cleaving the plus or minus strand of RNA, and further comprises flanking sequences having a nucleotide sequence complementary to portions of the target RNA. The flanking sequences serve to anneal the ribozyme to the RNA in a site-specific manner.
Absolute complementarity of the flanking sequences to the target sequence is not necessary, however, as only an amount of complementarity sufficient to form a duplex with the target RNA and to allow the catalytically active segment of the ribozyme to cleave at the target sites is necessary. Thus, only sufficient complementarity to permit the ribozyme to be hybridizable with the target RNA is required.
In some embodiments of the present invention the enzymatic RNA
molecule is formed in a hammerhead motif but the ribozyme can also be formed in the motif of a hairpin, hepatitis delta virus, group I intron or RNAse P RNA (in association with an RNA guide sequence). Examples of hammerhead motifs are described by Rossi et al., AIDS Res. Hum.
Retrovir. 8:183 ( 1992), hairpin motifs are described by Hampel et al., f3iochem. 28:4929 (1989) and Hampel et al., Nucl. Acids Res. 18:299 (1990), the hepatitis delta virus motif is exemplified in Perrotta and Been, l3iochem. 31:16 (1992), an RNAseP motif is described in Cueerier-Takada et al., Cell 35:849 (1983), and examples of the group I intron motif are described in Cech et al., U.S. Pat. No. 4,987,071, each of the foreg~ing disclosures being incorporated herein by reference.
Ribozymes can be prepared by chemical synthesis or produced by recombinant vectors according to methods established for the synthesis of RNA molecules. See, e.g., Sambrook et al., Molecular Cloning, A
Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989), incorporated herein by reference. The ribozyme sequence can be synthesized, for example, using RNA
polymerases such as T7 or SP6. The ribozymes can be prepared from a corresponding DNA sequence (DNA which on transcription yields a ribozyme) operably linked to an RNA polymerase promoter such as the promoter for T7 RNA polymerase or SP6 RNA polymerase. A DNA
sequence corresponding to a ribozyme can be ligated in to a DNA vector, such as a plasmid, bacteriophage or other virus. Where the transfer vector contains an RNA polymerase promoter operably linked to DNA
corresponding to a ribozyme, the ribozyme can be conveniently produced upon incubation with an RNA polymerase. Ribozymes can therefore be produced in vitro by incubation of RNA polymerase with an RNA
polymerase promoter operably linked to DNA corresponding to a ribozyme, in the presence of ribonucleotides. In vivo, procaryotic or eucaryotic cells (including mammalian cells) can be transfected with an appropriate vector containing genetic material corresponding to a ribozyme, operably linked to an RNA polymerase promoter such that the ribozyme is transcribed in the host cell. Ribozymes can be directly transcribed in vivo from a transfer vector, or alternatively, can be transcribed as part of a larger RNA molecule. For example, DNA
corresponding to ribozyme sequence can be ligated into the 3' end of a carrier gene, for example, after a translation stop signal. Larger RNA
molecules can help to stabilize the ribozyme molecules against nuclease digestion within the cells. On translation the carrier gene can give rise to a protein, e~hose presence can be directly assayed if desired, for example, by enzymatic reaction when the carrier gene encodes an enzyme.
Those of skill in the art based on the above description and the sequences disclosed herein can design ribozymes to target RNA
representing the allelic variants of the AffAP1 ~ gene. For example, the sequence of anti-AICAP10-5 hammerhead ribozyme is 5-UCCA CUGANGAGCCUGGACGAAACU-3'(SEQID
NO: 25). The sequence UGCA is complementary to target RNA with C
hybridizing to the G nucleotide at position 2073 of SEQ ID NO: 3 of the AICAP1O-5 allelic variant. The simplest hammerhead ribozyme must have UG at the 5' end of the substrate binding site.

N. Kits Kits can be used to indicate whether a subject is at risk of increased susceptibility to morbidity and/or predisposition for premature or increased or early mortality. The kits can also be used to determine if a subject has a genetic predisposition to a disorder related to signal transduction. This information could be used, e.g., to optimize treatment of such individuals as a particular genotype can be associated with drug response.
The kits comprise a probe or primer which is capable of hybridizing adjacent to or at a polymorphic region of AKAP1 O and thereby identifying whether the AKAP1 ~ gene contains an allelic variant which is associated with increased susceptibility to morbidity and/or predisposition for premature or increased or early mortality or a genetic predisposition to a disorder related to signal transduction and/or protein phosphorylation.
The kits further comprise instructions for use in carrying out assays, interpreting results and diagnosing a subject as having increased susceptibility to morbidity an~9/or predisposition for premature or increased or early mortality or a genetic predisposition to a disorder related to signal transduction and/or protein phosphorylation.
Kits for amplifying a region of AKAP1 ~ gene or other genes associated with morbidity and/or mortality and/or signal transduction comprise two primers which flank a polymorphic region of the gene of interest. For example primers can comprise the sequences of SEQ ID
NOs.:S, 6, 7, 10, 12 and 16. For other assays, primers or probes hybridize to a polymorphic region or 5' or 3' to a polymorphic region depending on which strand of the target nucleic acid is used. For example, specific probes and primers comprise sequences designated as SEQ ID NOs: 8, 15, 19 and 20. Those of skill in the art can synthesize primers and probes which hybridize adjacent to or at the polymorphic regions described herein and other SNPs in genes associated with morbidity and/or mortality and/or signal transduction Yet other kits comprise at least one reagent necessary to perform an assay. For example, the kit can comprise an enzyme, such as a nucleic acid polymerise. Alternatively the kit can comprise a buffer or any other necessary reagent.
Yet other kits comprise microarrays of probes to detect allelic variants of the AKAP10 gene. The kits further comprise instructions for their use and interpreting the results.
The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. The practice of methods and development of the products provided herein employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, for example, i~iolecular Cloning A Laboratory f~lanual, end Ed., ed. by Sambrook, Fritsch and lifiianiatis (Cold Spring Harbor Laboratory Press: 1989); DNA
Cloning, Volumes I and II (D.N. Glover ed., 1985); ~ligonucleotide 2~ Synthesis (M.J. Gait ed., 1984); Mullis era/, IJ.S. Patent No. 4,683,195;
Nucleic Acid Hybridizatiion (B.D. Names 8~ S.J. Higgins eds. 1984);
Transcription and Translation (B.D. Hames ~c S.J. Higgins eds. 1984);
Culture of Animal Cells (R.1. Freshney, Alan R. Liss, Inc., 19871;
Immobilized Cells and Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., New York); Gene Transfer Vectors For Mammalian Cells (J.H. Miller and M.P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al, eds., Immunochemical Methods In Cell and Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook of Experimental Immunology, Volumes I-IV (D.M. Weir and C.C. Blackwell, eds., 1986);
Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).
The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.
EXAMPLES

Isolation of DNA from blood samples of a healthy donor population 1 ~ The results are provided of a screen comparing allele frequencies of 6,5~~ SNPs located in approximately 5,0~~ genes between a sample of young and elderly healthy individuals. This resulted in the identification of a gene encoding a functional variant with an impact on morbidity that can be inv~Ived in the etiology of cardiac dysfunction.
All subjects involved in the studies signed a written informed consent and the institutional ethics committees of participating institutions appr~ved the e~zperimental protocols. Subjects for the disease susceptibility genome screen were part of a sample thafi was recruited during a routine blood donation from private blood collection 2~ centers in San Bernardino and Rancho Mirage, California, IJSA. The staff of the blood collection agencies invited all healthy blood donors to participate, and helped the subjects fill out a consent form and a simple personal data collection form prior t~ sample collection. The data collection form included information about age, sex, body size, personal and family disease history, and ethnic background of both parents.
Information about the identity of the study participants was not recorded.
Subjects would be excluded if they failed to meet the blood donation eligibility guidelines established by the American Red Cross. Ethnicity was defined for each subject if they identified both parents as having the same ethnic/geographic bacleground, otherwise they are indicated as "Other". For the purpose of identifying disease susceptibility associated SNPs, derived from this collection was a discovery cohort consisting of male and female Caucasian-Americans divided into young (18-39 years) and old ( > 60 years) groups. These groups and others used in this study are shown in Table 4.

Group Gender N Age Range Mean Age (S.D.) CA-YF Female 276 18-39 27.0 (6.68) 1 ~ CA-YM Male 276 18-39 27.1 (6.65) CA-OF Female 184 60-69 64.1 (2.84) CA-OM Male 367 60-79 66.7 (4.78) HI-YF Female 359 18-39 29.0 (6.42) HI-YM Male 173 18-39 28.9 (6.67) HI-OF Female 61 50-78 55.6 (5.66) HI-OM Male 64 50-89 57.9 (7.49) ~RF Female/il~lale 97/97 18-76 37.4 (11.49) AS Female/Male 62/64 18-65 34.4 ( 12.18) Table 4.. Composition of age-, gender-, and ethnicity-stratified groups.
Abbreviations:
2~ CA, Caucasian-American; HI, Hispanic-American; AF, African-American; AS, Asian-American; YF, Young Female; YM, Young Male; ~F, Old Female; OM, Old Male;
S.D., Standard Deviation.
A follow-up study of the SNPs significantly associated with age in the genome scan was carried out in a sample of 417 Caucasian twin pairs from the adult twin registry at St Thomas Hospital, London, United Kingdom. Participants in this collection were enrolled without regard to health status as previously described (Andrew et al., 2001, Twin Res., 4:464-477). For this study, 97 traits were selected to explore possible disease associations. The selected traits have connections to many disease areas, including cardiovascular diseases, diabetes, hypertension, obesity, and osteoporosis.

Practically a healthy subject, when human, is defined as human donor who passes blood bank criteria to donate blood for eventual use in the general population. These criteria are as follows: free of detectable viral, bacterial, mycoplasma, and parasitic infections; not anemic; and then further selected based upon a questionnaire regarding history.
Thus, a healthy population represents an unbiased population of sufficient health to donate blood according to blood bank criteria, and not further selected for any disease state. Typically such individuals are not taking any medications.
Blood was obtained from a donor by venous puncture and preserved with 1 mM EDTA pH 8Ø Ten milliliters of whole blood from each donor was centrifuged at 2000x g. One milliliter of the buffy coat was added to 9 milliliters of 155mM NH4,C1, 1 OmM I<HC03, and 0.1 mM
Na2EDTA, incubated 10 minutes at room temperature and centrifuged for 10 minutes at 2000x g. The supernatant was removed and the white cell pellet was washed in 155mM NH4C1, 1 OmM I~HC03, and 0.1 mM
f~la~EDTRa and resuspended in 4.5 milliliters of 50m1~i Tris, 5mf~i EDTA, and 1 % 3DS. Proteins were precipitated from the cell lysate by 5M
ammonium acetate pH 7.3 and separated from the nucleic acid by centrifugation at 3000x g. The nucleic acid was recovered from the supernatant by the addition of an equal volume of 100% isopropanol and centrifugation at 2000x g. The dried nucleic acid pellet was hydrated in IOmM Tris pH 7.6 and 1 mM Na~EDTA and stored at 4°C.
Statistical Analysis Estimates of allele frequencies derived from pooled DNA were based on independent mass spectrometry measurements of four analyte aliquots derived from a single PCR reaction. The median standard deviation for these values was approximately 0.01. For comparing allele frequencies between the young and old pools, females and males were analyzed separately. The statistic used to test the difference in allele frequencies between pools was of the form:
py ' po __________________________________________________ (py(~-py)/2ny+(po)/2o+ey+Eo)~iz which follows a standard normal distribution. Here py and p0 are the allele frequency estimates and Ey and Eo are estimates of measurement variability calculated from measurement replicates in the young and old pools, respectively. In this study, no correction was made for additional 1~ sources of variation or for multiple testing. Rather, SNPs were identified that had p-values less than 0.05 among all measured SNPs, followed by a second, independent measurement of all significant SNPs based on three separate PGRs of each DNA pool. The results of the second round of measurement were analyzed in a manner similar to the first round, and were compared for consistency. SNPs that showed statistically significant differences between young and old groups from pooled DNA
analyses were individually genotyped for final validation.
Estimates of allele frequencies using individual genotype data were found using the gene counting method. Comparisons of allele 2~ frequencies as well as genotype frequencies between groups were carried out using a chi-squared test of independence.
The SNPs found to be associated with age were further analyzed for association with disease-related quantitative traits in the twin collection. The analysis was conducted using a quantitative transmission-disequilibrium test (QTDT) as described by Abecasis et al., 2000, Am J Hum Genet., 66:279-292 to take advantage of the twin-based sample and to control for admixture and other non-genetic sources of variation. The form of the test was implemented that does not require the estimation of variance components. Formal statistical procedures to account for multiple testing were not use, but the distribution of the resulting p-values is reported.
Results of Genome-wide SNP Analysis for Morbidity Gene Discovery A strategy was pursued that utilizes estimates of allele frequencies in DNA pools to screen large numbers of SNPs. To apply this to disease susceptibility gene discovery, the Caucasian-American individuals were divided by age (under 40 and over 60 years) and by sex (Table 4). The fraction of included subjects reporting any health problem was only 1.8%
and 2.9% in young females and males, and 3.8% and 3.5~/o in old females and males, respectively. In this study, a collection was used of 6,500 exonic SNPs located in approximately 5,000 genes or expressed sequence tag (EST) clusters. The majority of assays for these SNPs, originally identified in an in silico discovery project, were developed in collaboration with the National Cancer Institute (NCI).
Identification of D-AKAP2 as a Candidate Gene More than 50 markers were identified out of the 6,500 tested markers that show a reproducibly significant allele frequency change between the two age groups in at least one gender (P G 0.05). The SNP
that demonstrated the strongest association with age in both genders is located within the D-AKAP2 gene.
D-AI<AP2 codes for dual-specific A-kinase anchor protein 2, which is part of a family of scaffold proteins known as A-kinase anchoring proteins (AKAPs). AKAPs bind the regulatory subunit of cAMP-dependent Protein Kinase (PKA), and target the kinase to various intracellular locations, localizing CAMP-mediated activation of the kinase.
PKA is a broad specificity kinase and phosphorylates numerous proteins that function in many essential cellular processes such as metabolism, gene transcription, cell division, and neuronal transmission. In the inactive state, PKA is a tetramer consisting of two catalytic (C) and two regulatory (R) subunits. The dual specificity of D-AKAP2 is defined by its ability to bind both the RI and RII isoforms of PKA.
An A>G polymorphism in the 3' untranslated region (3'UTR) of D-AKAP2 showed a significant decrease of about 8% (P < 0.01 ) of the G
allele in the older sample of both genders (Table 5). The marker was individually genotyped and the frequency differences between young and old individuals calculated from the genotypes were very similar to the pool results. There was a slight skewing of frequencies in the pools likely resulting from uneven PCR amplification of the two alleles. This led to an underestimation of the G allele frequency in all pools but did not impact the significance of the differences between young and old (Table 5).

Allelle Frequency Young Old Difference P-Value P~~I Date 3' UTR
Caucasian Female 0.322 0.240 0.082 0.007 Caucasian Male 0.362 0.232 0.076 0.002 Genotype ~ata 3' UTR
Caucasian Female 0.274 0.212 0.062 0.034 Caucasian Male 0.304 0.232 0.072 0.004 Caucasian Female0.402 0.318 0.084 0.009 Causian Male 0.429 0.369 0.060 0.030 Hispanic Female 0.445 0.316 0.129 0.008 Hispanic Male 0.436 0.375 0.061 0.229 In10 Caucasian Female 0.877 0.871 0.006 0.147 Caucasian Male 0.880 0.865 0.015 0.360 Table 5. Comparison of allele frequencies between young and old groups.
Sample sizes are the same as those of the corresponding groups in Table 2. Allele frequencies for each SNP are given for the G allele.
To identify common polymorphisms in the D-AICAP2 gene, the 15 axons and 100-200 by of the flanking sequence were sequences. The analysis of 36 chromosomes revealed only two additional polymorphisms: An A > G SNP in intron 10, six nucleotides downstream from axon 10 (1n10), and an A>G SNP in axon 14 (corresponding to AI<AP10-5 at nucleotide 2073 of SE(~ ID N0:1 ), leading to an amino acid substitution Ile to Val at p~sition 646 (1646V). Individual genotyping of the Caucasian-American samples showed that the intron 10 SNP exhibits no morbidity-association. The 1646V polymorphism, however, was found to be significantly different between y~~ane~ and ~1d in both males (P =
0.03) and females (P = 0.009) (Table 5). There was n~ significant difference between young males and females and between old males and females. The Bayesian, coalescent theory-based method (Stephens et al., 2001, e4m ,l Hum Genet. 68:978-989) was applied to construct haplotypes at these three tightly linked sites for each subject. The estimates of the disequilibrium (D') between the 3'UTR and the 1646V
and In10 SNPs were 0.991 and 0.255 (r2 = 0.55 and 0.03), respectively. The distance between the markers in strong disequilibrium, 3'UTR and 1646V which both showed association, is about 4 kb, while the intron 10 SNP is located approximately 23 kb upstream of 1646V.
As expected, the changes in genotype frequencies between age groups for the three sites showed a similar level of statistical significance as the changes in allele frequencies. At the 3'UTR and the 1646V
variable sites, GG homozygotes were reduced and AA homozygotes increased in the older sample population of both genders. This further supports the hypothesis that the G allele, which determines the Val allele at 1646V, is associated with a negative health impact.
Hispanic-American samples were also genotyped for the 1646V
variation. Since there were only a small number of Hispanic-American individuals over 60 years, the older sample population was extended to all individuals older than 50 years of age (Table 4). While females showed a statistically significant allele frequency difference between old and young (P = 0.008), the males did not, which can be due to the relatively small number of male individuals (Table 5). The allele frequency differences in both genders were comparable to those observed in Caucasian-Americans. The frequency of the G allele decreased by 0.129 in females and 0.061 in males, the GG homozygote by 0.087 in females and 0.072 in males. These results further support the association of the Val allele with morbidity and/or mortality, and therefore the involvement of this gene in one or several disease processes. Another non-synonymous ~-AKAP2 variation retrieved from dbSNP has been verified. The G-A transversion in exon 4 results in an Arg to His substitution at position 249 (R249H; corresponding to a G to A transversion at nucleotide 883 of SEQ I~ N0:1 encoding human ~-AKAP2). The Arg was found to be in complete linkage disequilibrium with the Ile at position 646, occurring together in every case, and therefore shows the same age effect.
Association of D-AKAP2 Genotypes with a Cardiac Trait In an effort to identify traits correlated with the observed age association of the 1646V SNP, we utilized a cohort of 417 fasting Caucasian twin pairs with extensive coverage for a variety of disease-related traits. Of the 97 traits analyzed, only the PR interval was statistically significant at a nominal level of 0.05. The estimate from the QTDT model of the average effect of the G allele (Val) was to decrease the PR interval 6.3 units (P = 0.007). The genotype means in the subset of 207 informative twin pairs were 157 ~ 23.4, 152 ~ 26.9, and 146 ~ 25.4 (mean ~ standard deviation) for genotypes AA, GA, and GG, respectively at a position corresponding to nucleotide 2073 of SEQ ID N0:1.

Detection of AI(AP10-1 by MassEXTENDT"~ Assay ~etection Methods AKAP10-1 is an allele of the AI~AP10 gene with a single nucleotide polymorphism at nucleotide number 156277 (based on the sequence of a genomic clone of the Af~AP10 gene, GenSank Accession No. AC005730). The single nucleotide polymorphism is a T to C
transversion located in the 3'non-translated region of the gene encoding AICAP10. PCR primers were synthesized by OPERON (Alameda, CA) using phosphoramidite chemistry. Amplification of the s41GAP10 target sequence was carried out in single 50~u1 PCR reaction with 25ng of human genomic DNA obtained from samples as described in Eacample 1.
Each reaction containing IX PCR buffer (Qiagen, Valencia, CA), 200~M
dNTPs, 1 U Hotstar Taq polymerase (Qiagen, Valencia, CA), 4mM MgCl2, and 25 pmols of the forward primer containing the universal primer sequence and the target specific sequence 5'-TCTCAATCATGTGCATTGAGG-3' (SEQ ID NO: 5) 2 pmoles of the reverse primer 5'-AGCGGATAACAATTTCACACAGGGATCACACAGCCATCAGCAG-3' (SEQ ID NO: 6) and IOpmoles of a biotinylated universal primer complementary to the 5' end of the PCR amplicon 5'-AGCGGATAACAATTTCACACAGG-3' (SEQ ID NO: 7). Alternatively, the biotinylated universal primer could be 5'-GGCGCACGCCTCCACG-3' (SEQ ID NO: 16). After an initial round of amplification of the target with the specific forward and reverse primer, the 5' biotinylated universal primer was hybridized and acted as a reverse primer thereby introducing a 3' biotin capture moiety into the molecule. The amplification protocol resulted in a 5'-biotinylated double stranded DNA amplicon, which dramatically reduces the cost of high throughput genotyping by eliminating the need to 5' biotin label each forward primer used in a genotyping. Thermal cycling was performed in 0.2mL tubes or 96 well plate using an MJ Research Thermal Cycler (Waltham, MA) (calculated temperature) with the following cycling parameters: 94°C for 5 min; 45 cycles: 94°C for 20 sec, 56°C for 30 sec, 72°C for 60 sec; 72°C 3 min.
Immobilization of ~i~A
The 50~u1 PCR reaction was added to 25,1 of streptavidin coated magnetic bead (Dynal) prewashed three times and resuspended in 1 M
i~H4,Cl, O.OGi~I i~Hq,OH. The PCR amplicons were allowed to bind to the beads for 15 minutes at room temperature. The beads were then collected with a magnet and the supernatant containing unbound DNA
was removed. The unbound strand was release from the double stranded amplicons by incubation in 100mM NaOH and washing of the beads three times with 10mM Tris pH B.O.
Genotyping Genotyping was carried out using the MassEXTENDTM assay and MALDI-TOF. The SNP identified at position 156277 of AICAP10 in the GenBank sequence is represented as a T to C transversion. The MassEXTENDTM assay detected the sequence of the complementary strand at the polymorphic position, thus the primer extension product incorporated either a T or a C. The DNA coated magnetic beads were resuspended in 26 mM Tris-HCL pH 9.5, 6.5 mM MgCl2 and 50 mM
each of dTTPs and 50 mM each of ddCTP, ddATP, ddGTP, 2.5U of a thermostable DNA polymerase (Amersham Pharmacia Biotech, Piscataway, NJ) and 20 pmoles of a template specific oligonucleotide primer 5'-CTGGCGCCCACGTGGTCAA-3' (SEQ ID NO: 8) (Operon, Alameda, CA). Primer extension occurs with three cycles of oligonucleotide primer was hybridization and extension. The extension products were analyzed after denaturation from the template with 50 mM
NH~CI and transfer of 150 n1 each sample to a silicon chip preloaded with 150 n1 of H3PA (3-hydroxy picolinic acid) (Sigma Aldrich, St. Louis, MO) matrix material. The sample material was allowed to crystallize and analyzed by MALDI-TOF (Broker Daltonics, Billerica, MA, PerSeptive, Foster City, CA). The mass of the primer used in the MassE~TENDT""
reaction was 5500.6 daltons. The allelic variant results in the addition of ddC to the primer to produce an extension product having a mass of 5773.8 daltons. The predominant allele is extended by the addition of dT and ddG to tile primer to produce an ea~tension product having a mass of 5101 daltons.
The SNP that is present in AI~AP10-1 is a T to C transversion at nucleotide number 156277 of the sequence of a genomic clone of the AICAP10 gene (GenBank Accession No. AC005730) (SEQ ID N0: 17).
SEO. ID N0:17 represents the nucleotide sequence of human chromosome 17, which contains the genomic nucleotide sequence of the human AICAP10 gene at approximately nucleotide 83,580 to nucleotide 156,577. SEQ ID NO: 18 represents the nucleotide sequence of human chromosome 17, which contains the genomic nucleotide sequence of the human AICAP10-1 allele.
The frequency of the AI~AP10-1 allelic variant was measured in a population of age selected healthy individuals. Five hundred fifty-two (552) individuals between the ages of 18-39 years (276 females, 276 males) and 552 individuals between the ages of 60-79 ( 184 females between the ages of 60-69, 368 males between the age of 60-79) were tested for the presence of the allelic variant localized in the non-translated 3' region of AICAP 10. Differences in the frequency of this variant with increasing age groups were observed among healthy individuals. Statistical analysis showed that the significance level for differences in the allelic frequency for alleles between the "younger" and the "older" populations was p = 0.0009 and for genotypes was 1~ p=0.003. Differences between age groups are significant. For the total population allele significance is p = 0.0009, and genotype significance is p = 0.003.
The young and old populations were in Hardy-l~Veinberg equilibrium. A
preferential change of one particular genotype was not seen.
The polymorphism is localized in the non-translated 3'-region of the gene encoding the human protein kinase A anchoring protein (AI<AP10). The gene is located on chromosome 17. Its structure includes 15 exzons and 14 intervening sequences (introns). The encoded protein is responsible for the sub-cellular localization of the cAMP-dependent protein kinase and, therefore, plays a key role in the G-protein mediated receptor-signaling pathway (Huang et al. PNAS (1007) 94:1 1 184-1 1 189). Since its localization is outside the coding region, this polymorphism is most likely in linkage disequilibrium (LD) with other non-synonymous polymorphisms that could cause amino acid substitutions and subsequently alter the function of the protein.

Discovery of AKAP10-5 Allele G.enomic DNA was isolated from blood (see Example 1 ) of seventeen (17) individuals with a genotype CC at the AKAP10-1 gene locus and a single heterozygous individual (CT) (as described in Example 2). A target sequence in the AKAP10-1 gene which encodes the C-terminal PKA binding domain was amplified using the polymerase chain reaction. PCR primers were synthesized by OPERON (Alameda, CA) using phosphoramidite chemistry. Amplification of the AKAP10-1 target sequence was carried out in individual 50,u1 PCR reaction with 25ng of human genomic DNA templates. Each reaction containing I X PCR buffer (O.iagen, !lalencia, CA), 200~1~ dNTPs, IU Hotstar Taq polymerase (C~iagen, l~alencia, CA), 4. mfVl l~lgCl~, and 25 pmols of the forward primer containing the universal primer sequence and the target specific sequence 5'-TCC CAA AGT GCT GGA ATT AC-3' (SEQ ID N0: 9), 2pmoles of the reverse primer 5'-GTC CAA TAT ATG CAA ACA GTT
G-S'(SEQ ID i~0:10). Thermal cycling was performed in 0.2 mL tubes or 96 well plate using an fi~IJ Research Thermal Cycler (ii~iJ Research, Waltham, MA) (calculated temperature) with the following cycling parameters: 94°C fior 5 min; 45 cycles; 94°C for 20 sec, 56°C for 30 sec, 72°C for 60 sec; 72°C 3min. After amplification the amplicons were purified by chromatography (Mo Bio Laboratories (Solana Beach, CA) .
The sequence of the 1 B amplicons, representing the target region, was determined using a standard Sanger cycle sequencing method with 25 nmoles of the PCR amplicon, 3.2 ,uM DNA sequencing primer 5'-CCC
ACA GCA GTT AAT CCT TC-3' (SEQ ID N0:1 1 ) and chain terminating dRhodamine labeled 2', 3' dideoxynucleotides (PE Biosystems, Foster City, CA) using the following cycling parameters: 96°C for 15 sec, cycles: 55°C for 15 sec, 60°C for 4 min. The sequencing products were precipitated by 0.3M NaOAc and ethanol, the precipitate was centrifuged and dried. The pellets were resuspended in deionized formamide and separated on a on a 5% polyacrylamide gel. The sequence was determined using the "Sequencher" software (Gene Codes, Ann Arbor, MI).
The sequence of all 17 of the amplicons which are homozygous for the AKAP10-1 SNP revealed a polymorphism at nucleotide position 152171 (numbering for GenBank Accession No. AC005730 for AICAP10 genomic clone) with A replaced by G. This SNP can also be designated as located at nucleotide 2073 of a cDNA clone of the wildtype AICAP10 (SEQ ID N0:1 ) (GenBank Accession No. AF037439). This single nucleotide polymorphism was designated as AI~AP10-5 (SEQ ID N0:3) and results in a substitution of a valine for an isoleucine residue at amino acid position 646 (SEQ ID N0:4).
E~Ce4IVIPLE 4.
~~6~ ~r~pllflcatl~n and I~a~~E~'~Eb~~rM ~~~ay d~t~c$i~n ~f ~1~~9~'i ~-5 in a healthy d~n~r p~pulati~n A healthy population stratified by age is a very efficient and a universal screening tool for morbidity associated genes by allowing for the detection of changes of allelic frequencies in the young compared to the old population. Individual samples of this healthy population base can be pooled to further increase the throughput.
Healthy samples were obtained through the blood bank of San Bernardino, CA. Both parents of the blood donors were of Caucasian origin. Practically a healthy subject, when human, is defined as human donor who passes blood bank criteria to donate blood for eventual use in the general population. These criteria are as follows: free of detectable viral, bacterial, mycoplasma, and parasitic infections; not anemic; and then further selected based upon a questionnaire regarding history.
Thus, a healthy population represents an unbiased population of sufficient health to donate blood according to blood bank criteria, and not further selected for any disease state. Typically such individuals are not taking any medications.
PCR primers were synthesized by OPERON (Alameda, CA) using phosphoramidite chemistry. Amplification of the AICAP10 target sequence was carried out in single 50~u1 PCR reaction with 1 OOng- 1 ug of pooled human genomic DNAs in a 50,u1 PCR reaction. Individual DNA
1 ~ concentrations within the pooled samples were present in equal concentration with the final concentration ranging from 1-25ng. Each reaction contained 1 ~ PCR buffer (Oiagen, !lalencia, CA), 200,ciM dNTPs, 1lJ Hotstar Taq polyrtierase (~iagen, ~/alencia, CA), 4 mM MgCl2, and 25 pmols of the forward primer containing the universal primer sequence and the target specific sequence 5'-AGCGGATAACAATTTCACACAGGGAGCTAGCTTGGAAGATTGC-3' (SEf~ ID i~0:12), 2pmoles of the reverse primer 5'-GTCCAATATATGCAAACAGTTG-~' (SEQ ID NO: 10) and 10 pmoles of a biotinylated universal primer complementary to the 5' end of the 2~ PCR amplicon 510:5'-AGCGGATAACAATTTCACACAGG-3' (SEO. ID NO:
7). After an initial round of amplification with the target with the specific forward and reverse primer, the 5' biotinylated universal primer can then hybridized and acted as a forward primer thereby introducing a 5' biotin capture moiety into the molecule. The amplification protocol resulted in a 5'-biotinylated double stranded DNA amplicon and dramatically reduces the cost of high throughput genotyping by eliminating the need to 5' biotin label every forward primer used in a genotyping.
Thermal cycling was performed in 0.2 mL tubes or 96 well plate using an MJ Research Thermal Cycler (Waltham, MA) (calculated temperature) with the following cycling parameters: 94°C for 5 min; 45 cycles: 94°C for 20 sec, 56°C for 30 sec; 72°C for 60 sec; 72°C 3 min.
Immobilization of DNA
The 50,u1 PCR reaction was added to 25~u1 of streptavidin coated magnetic beads (Dynal, Oslo, Norway) (Lake Success, NY), which were prewashed three times and resuspended in 1 M NH~.CI, 0.06M NH40H.
The 5' end of one strand of the double stranded PCR amplicons were allowed to bind to the beads for 15 minutes at room temperature. The 1~ beads were then collected with a magnet and the supernatant containing unbound DNA was removed. The hybridized but unbound strand was released from the double stranded amplicons by incubation in 100mM
NaOH and washing of the beads three times with 10mM Tris pH ~Ø
Gr~notyping The identity of the nucleotide present at the polymorphic site of AICAP 10-5 was determined by using the MassE?CTENDTM assay and f~iALDI-TOF (see, U.S. Patent f~lo. 5,043,031 ). The I~iassE~TENDT""
assay is a primer extension assay that utilizes a primer that hybridizes adjacent to the polymorphic region and which is extended in the presence of one or more ddNTPs. Extension is stopped by the incorporation of a dideoxy nucleotide. At a polymorphic site the different alleles produce different length extension products, which are distinguishable by mass spectrometry.
The MassE?CTENDTM assay detected the sepuence of the sense strand and resulted in the incorporation of either T or C into the extension product. The DNA coated magnetic beads were suspended in 26mM Tris-HCL pH 9.5; 6.5 mM, MgCl2 and 50mM each of dTTPs and 50mM each of ddCTP, ddATP, ddGTP, 2.5U of a thermostable DNA
polymerase (Amersham Pharmacia Biotech, Piscataway NJ) and 20 pmoles of a template specific oligonucleotide primer 5'-ACTGAGCCTGCTGCATAA-3' (SEQ ID N0:15) (Operon) (Alameda, CA). Primer extension occurs with three cycles of oligonucleotide primer hybridization and extension. The extension products were analyzed after denaturation from the template with 50 mM NH4C1 and transfer of 150 n1 each sample to a silicon chip preloaded with 150 n1 of H3PA (3-hydroxy picolinic acid) (Sigma Aldrich, St. Louis, MO) matrix material. The sample material was allowed to crystallize and analyzed by MALDI-TOF
(Bruker Daltonics, Billerica, MA, PerSeptive, Foster City, CA). The primer had a mass of 5483.6 daltons. The allelic variant resulted in the addition of a ddC to the primer to produce an extension product having a mass of 5756.8 daltons. The predominant allele resulted in the addition a T and ddG to the primer giving an extension product with a mass of 6101 daltons.

Discovery of AKAP10-7 Genomic DNA isolation, amplification of the target regions and sequencing of amplicons was carried out as in Example 3. lJsing the sequence of the cDNA for AKAP10, chromosome 17 was BLAST
searched to identify the number of axons. Sanger sequencing of the regions around and containing the axons was performed and resulted in the discovery of AKAP10-7 polymorphic region. For AfCAP10-7 the forward sequencing primer was CACTGCACCCAGCCTTATG (SEO. ID
N0: 23) and the reverse sequencing primer was CTGGGATGTGAAGGAAAGGA (SEQ ID NO: 24).

MassEXTENDT"~ assay detection of AKAP10-7 Samples are obtained and amplified as in Example 4.

The identity of the nucleotide present at the polymorphic site of AKAP 10-7 is determined by using the MassEXTENDTM assay and MALDI-TOF (see, U.S. Patent No. 6,043,031 ). The MassEXTENDTM assay detects the sequence of the complementary strand and resulted in the incorporation of either G or A into the extension product. Reactions are carried out as in Example 4. The template specific oligonucleotide primer 5'-CTCTGCGTCTCAGGTATT-3' (SEQ ID NO: 20). (Operon, Alameda, CA). The primer has a mass of 5456.6 daltons. The allelic variant results in the addition of a ddA to the primers to produce an extension product having a mass of 5753.6 daltons. The predominant allele results in the addition a G and ddA to the primer giving an extension product v~rith a mass of 6033.0 daltons.
Since modifications veil) be apparent to those of skill in this art, it is intended that this invention be limited only by the scope of the appended claims.

SEQUENCE LISTING
<110> SEQUENOM, INC.
Braun, Andreas ICammerer, Stefan <120> ASSOCIATION OF POLYMORPHIC ICINASE ANCHOR PROTEINS WITH CARDIAC
PHENOTYPES AND RELATED METHODS
<130> 24736-2074PC
<140> Not Yet Assigned <141> Herewith <150> US 60/453,215 <151> 2003-03-07 <150> US 60/453,208 <151> 2003-03-07 <150> US 60/453,350 <151> 2003-03-07 <160> 25 <170> FastSEQ for Windows Versi~n 4.0 <210> 1 <211> 2363 <212> DNA
<213> Homo Sapiens <220>
<221> CDS
<222> (138)...(2126) <223> Wild Type ATCAP-10 <300>
<308> GenBank AF037439 <309> 1997-12-21 <400>

gcggcttgtt gataatatgg tgcctgggca tcccgaggag gcggtggggc60 cggctggagc ccactcccgg aagaagggtc ggcccctctg gacccggaag120 ccttttcgcg ctagtgcagc tccgggccgg ttgctga ccc ccg cag tcc 170 atg tcc cgc agg gga gcc ggg Met Arg Gly Pro Pro Gln Ser Ala Gly Ser Arg CCC aCCCtC Cgt CCC gac ggc gccatgtCC ttC cgg 218 CgC ccg ccc ttC

Pro ThrLeu Arg Pro Asp Gly AlaMetSer Phe Arg Arg Pro Pro Phe cgg gtgaaa ggc aaa gaa gag acctcagat aag tcc 266 aaa caa aag gtg Arg ValLys Gly Lys Glu Glu ThrSerAsp Lys Ser Lys Gln Lys Val att gettca ata tcc gta tcc caaaaaagc aaa aat 314 aaa cat cca act Ile AlaSer Ile Ser Val Ser GlnLysSer Lys Asn Lys His Pro Thr cat ttgctg gag get gca cca catgttgca aat gcc 362 gcc gga agt atc His LeuLeu Glu Ala Ala Pro HisValAla Asn Ala Ala Gly Ser Ile _2_ atttctgcc aacatggac tccttttca agtagcagg acagccaca ctt 410 IleSerAla AsnMetAsp SerPheSer SerSerArg ThrAlaThr Leu aagaagcag ccaagccac atggagget getcatttt ggtgacctg ggc 458 LysLysGln ProSerHis MetGluAla AlaHisPhe GlyAspLeu Gly agatcttgt ctggactac cagactcaa gagaccaaa tcaagcctt tct 506 ArgSerCys LeuAspTyr GlnThrGln GluThrLys SerSerLeu Ser aagaccctt gaacaagtc ttgcacgac actattgtc ctcccttac ttc 554 LysThrLeu GluGlnVal LeuHisAsp ThrIleVal LeuProTyr Phe attcaattc atggaactt cggcgaatg gagcatttg gtgaaattt tgg 602 IleGlnPhe MetGluLeu ArgArgMet GluHisLeu ValLysPhe Trp ttagagget gaaagtttt cattcaaca acttggtcg cgaataaga gca 650 LeuGluAla GluSerPhe HisSerThr ThrTrpSer ArgIleArg Ala cacagtcta aacacaatg aagcagagc teactgget gagcctgtc tct 698 HisSerLeu AsnThrMet LysGlnSer SerLeuAla GluProVal Ser ccatctaaa aagcatgaa actacagcg tctttttta actgattct ctt 746 ProSerLys LysHisGlu ThrThrAla SerPheLeu ThrAspSer Leu gataagaga ttggaggat tctggctca gcacagttg tttatgact cat 794 AspLysArg LeuGluAsp SerGlySer AlaGlnLeu PheMetThr His tcagaagga attgacctg aataataga actaacagc actcagaat cac 842 SerGluGly IleAspLeu AsnAsnArg ThrAsnSer ThrGlnAsn His ttgctgctt teecaggaa tgtgacagt gcccattct ctccgtctt gaa 890 LeuLeuLeu SerGlnGlu CysAspSer AlaHisSer LeuArgLeu Glu atggccaga gcaggaact caccaagtt tccatggaa acccaagaa tct 938 MetAlaArg AlaGlyThr HisGlnVal SerMetGlu ThrGlnGlu Ser tcctctaca cttacagta gccagtaga aatagtccc gettctcca cta 986 SerSerThr LeuThrVal AlaSerArg AsnSerPro AlaSerPro Leu aaagaattg tcaggaaaa ctaatgaaa agtatagaa caagatgca gtg 1034 LysGluLeu SerGlyLys LeuMetLys SerIleGlu GlnAspAla Val aatactttt accaaatat atatctcca gatgetget aaaccaata cca 1082 AsnThrPhe ThrLysTyr IleSerPro AspAlaAla LysProIle Pro attacagaa gcaatgaga aatgacatc atagcaagg atttgtgga gaa 1130 IleThrGlu AlaMetArg AsnAspIle IleAlaArg IleCysGly Glu gatggacaggtg gatcoc aactgtttcgtt ttggcacag tccatagtc 1178 AspGlyGlnVal AspPro AsnCysPheVal LeuAlaGln SerIleVal tttagtgcaatg gagoaa gagoactttagt gagtttctg cgaagtcac 1226 PheSerAlaMet GluGln GluHisPheSer GluPheLeu ArgSerHis catttctgtaaa taccag attgaagtgctg accagtgga actgtttac 1274 HisPheCysLys TyrGln IleGluValLeu ThrSerGly ThrValTyr ctggetgacatt ctottc tgtgagtcagcc ctcttttat ttctctgag 1322 LeuAlaAspIle LeuPhe CysGluSerAla LeuPheTyr PheSerGlu tacatggaaaaa gaggat gcagtgaatatc ttacaattc tggttggca 1370 TyrMetGluLys GluAsp AlaValAsnIle LeuGlnPhe TrpLeuAla gcagataactto cagtct oagcttgetgcc aaaaagggg caatatgat 1418 AlaAspAsnPhe GlnSer GlnLeuAlaAla LysLysGly GlnTyrAsp ggacaggaggca cagaat gatgocatgatt ttatatgac aagtactto 1466 GlyGlnGluAla GlnAsn AspAlaMetIle LeuTyrAsp LysTyrPhe tccctocaagoc acacat octottggattt gatgatgtt gtaogatta 1514 SerLeuGlnAla ThrHis ProLeuGlyPhe AspAspVal ValArgLeu gaaattgaatco aatatc tgcagggaaggt gggccactc cccaactgt 1562 GluIleGluSer AsnIle CysArgGluGly GlyProLeu ProAsnCys ttcaoaactcoa ttaCgt oaggcotggaoa aooatggag aaggtcttt 1610 PheThrThrPro LeuArg GlnAlaTrpThr ThrMetGlu LysValPhe ttgCCtggCttt ctgtcc agcaatctttat tataaatat ttgaatgat 1658 LeuProGlyPhe LeuSer SerAsnLeuTyr TyrLysTyr LeuAsnAsp ctcatccattcg gttcga ggagatgaattt ctgggcggg aaogtgtcg 1706 LeuIleHisSer ValArg GlyAspGluPhe LeuGlyGly AsnValSer CCgaCtgetCCt ggCtot gttggccctCCt gatgagtCt CaCCCaggg 1754 ProThrAlaPro GlySer ValGlyProPro AspGluSer HisProGly agttotgaoagc tctgog totoagtcoagt gtgaaaaaa gooagtatt 1802 SerSerAspSer SerAla SerGlnSerSer ValLysLys AlaSerIle aaaatactgaaa aatttt gatgaagcgata attgtggat goggoaagt 1850 LysIleLeuLys AsnPhe AspGluAlaIle IleValAsp AlaAlaSer ctggatccagaa tottta tatoaacggaca tatgooggg aagatgaca 1898 LeuAspProGlu SerLeu TyrGlnArgThr TyrAlaGly LysMetThr ttt gga aga gtg agt gac ttg ggg caa tto atc cgg gaa tct gag cct 1946 Phe Gly Val Asp GlyGln PheIleArg Glu Ser Pro Arg Ser Leu Glu gaa cct gta aaa aaagga tccatgttc tca caa atg 1994 gat agg tca get Glu Pro Val Lys LysGly SerMetPhe Ser Gln Met Asp Arg Ser Ala aag aaa gtg gga actgat gaggcccag gaa gag get 2042 tgg caa aat cta Lys Lys Val Gly ThrAsp GluAlaGln Glu Glu Ala Trp Gln Asn Leu tgg aag get atg gtcagt gacattatg cag cag cag 2090 att aaa ata get Trp Lys Ala Met ValSer AspIleMet Gln Gln Gln Ile Lys Ile Ala tat gat ccg gag tctaca aagttatga ctcaaaactt 2136 caa tta aaa Tyr Asp Pro Glu SerThr LysLeu Gln Leu Lys gagataaaggaaatctgctt tttcccttgg 2196 gtgaaaaata ttggattctt agagaacttt caacacagccaatgaaaaca cactgttgtt 2256 gcactatatt tccagggaga tctgatctgt gaatggggagacaatcctag tacctgtagg 2316 gacttccacc gcataattgg ctaatgcagt atggcacatgatgtttcaca ttaccaa 2363 cagtgaggag tctttaaagg <210>

<211>

<212>
PRT

<213> Sapiens Homo <400> 2 Met Arg Gly Ala Gly Pro Ser Pro Arg Gln Ser Pro Arg Thr Leu Arg Pro Asp Pro Gly Pro Ala Met Ser Phe Phe Arg Arg Lys Val Lys Gly Lys Glu Gln Glu Lys Thr Ser Asp Val Lys Ser Ile Lys Ala Ser Ile Ser Val His Ser Pro Gln Lys Ser Thr Lys Asn His Ala Leu Leu Glu Ala Ala Gly Pro Ser His Val Ala Ile Asn Ala Ile Ser Ala Asn Met Asp Ser Phe Ser Ser Ser Arg Thr Ala Thr Leu Lys Lys Gln Pro Ser His Met Glu Ala Ala His Phe Gly Asp Leu Gly Arg Ser Cys Leu Asp Tyr Gln Thr Gln Glu Thr Lys Ser Ser Leu Ser Lys Thr Leu Glu Gln Val Leu His Asp Thr Ile Val Leu Pro Tyr Phe Ile Gln Phe Met Glu Leu Arg Arg Met Glu His Leu Val Lys Phe Trp Leu Glu Ala Glu Ser l45 150 155 160 Phe His Ser Thr Thr Trp Ser Arg Ile Arg Ala His Ser Leu Asn Thr Met Lys Gln Ser Ser Leu Ala Glu Pro Val Ser Pro Ser Lys Lys His Glu Thr Thr Ala Ser Phe Leu Thr Asp Ser Leu Asp Lys Arg Leu Glu Asp Ser Gly Ser Ala Gln Leu Phe Met Thr His Ser Glu Gly Ile Asp Leu Asn Asn Arg Thr Asn Ser Thr Gln Asn His Leu Leu Leu Ser Gln Glu Cys Asp Ser Ala His Ser Leu Arg Leu Glu Met Ala Arg Ala Gly Thr His Gln Val Ser Met Glu Thr Gln Glu Ser Ser Ser Thr Leu Thr Val Ala Ser Arg Asn Ser Pro Ala Ser Pro Leu Lys Glu Leu Ser Gly Lys Leu Met Lys Ser Ile Glu Gln Asp Ala Val Asn Thr Phe Thr Lys Tyr Ile Ser Pro Asp Ala Ala Lys Pro Ile Pro Ile Thr Glu Ala Met Arg Asn Asp Ile Ile Ala Arg Ile Cys Gly Glu Asp Gly Gln Val Asp Pro Asn Cys Phe Val Leu Ala Gln Ser Ile Val Phe Ser Ala Met Glu Gln Glu His Phe Ser Glu Phe Leu Arg Ser His His Phe Cys Lys Tyr Gln Ile Glu Val Leu Thr Ser Gly Thr Val Tyr Leu Ala Asp Ile Leu Phe Cys Glu Ser Ala Leu Phe Tyr Phe Ser Glu Tyr Met Glu Lys Glu Asp Ala Val Asn Ile Leu Gln Phe Trp Leu Ala Ala Asp Asn Phe Gln Ser Gln Leu Ala Ala Lys Lys Gly Gln Tyr Asp Gly Gln Glu Ala Gln Asn Asp Ala Met Ile Leu Tyr Asp Lys Tyr Phe Ser Leu Gln Ala Thr His Pro Leu Gly Phe Asp Asp Val Val Arg Leu Glu Ile Glu Ser Asn Ile Cys Arg Glu Gly Gly Pro Leu Pro Asn Cys Phe Thr Thr Pro Leu Arg Gln Ala Trp Thr Thr Met Glu Lys Val Phe Leu Pro Gly Phe Leu Ser Ser Asn Leu Tyr Tyr Lys Tyr Leu Asn Asp Leu Ile His Ser Val Arg Gly Asp Glu Phe Leu Gly Gly Asn Val Ser Pro Thr Ala Pro Gly Ser Val Gly Pro Pro Asp Glu Ser His Pro Gly Ser Ser Asp Ser Ser Ala Ser Gln Ser Ser Val Lys Lys Ala Ser Ile Lys Ile Leu Lys Asn Phe Asp Glu Ala Ile Ile Va_1 Asp Ala Ala Ser Leu Asp Pro Glu Ser Leu Tyr Gln Arg Thr Tyr Ala Gly Lys Met Thr Phe Gly Arg Val Ser Asp Leu Gly Gln Phe Ile Arg Glu Ser Glu Pro Glu Pro Asp Val Arg Lys Ser Lys Gly Ser Met Phe Ser Gln Ala Met Lys Lys Trp Val Gln Gly Asn Thr Asp Glu Ala Gln Glu Glu Leu Ala Trp Lys Ile Ala Lys Met Ile Val Ser Asp Ile Met Gln Gln Ala Gln Tyr Asp Gln Pro Leu Glu Lys Ser Thr Lys Leu <210> 3 <211> 2363 <212> DNA
<213> Homo Sapiens <220>
<221> CDS
<222> (138) . . . (2126) <223> AICAP-10-5 <221> allele <222> 2073 <223> Single Nucleotide Polymorphism: A to G
<400> 3 gcggcttgtt tgcctgggca tcccgaggag 60 gataatatgg gcggtggggc cggctggagc ccactcccgg ggcccctctg 120 aagaagggtc gacccggaag ccttttcgcg ctagtgcagc tccgggccgg 170 ttgctga atg agg gga gcc ggg ccc tcc ccg cgc cag tcc Met Arg Gly Ala Gly Pro Ser Pro Arg Gln Ser ccccgcacc ctccgtccc gacccg ggccccgccatg tccttcttc cgg 218 ProArgThr LeuArgPro AspPro GlyProAlaMet SerPhePhe Arg cggaaagtg aaaggcaaa gaacaa gagaagacctca gatgtgaag tcc 266 ArgLysVal LysGlyLys GluGln GluLysThrSer AspValLys Ser attaaaget tcaatatcc gtacat tccccacaaaaa agcactaaa aat 314 IleLysAla SerIleSer ValHis SerProGlnLys SerThrLys Asn catgccttg ctggagget gcagga ccaagtcatgtt gcaatcaat gcc 362 HisAlaLeu LeuGluAla AlaGly ProSerHisVal AlaIleAsn Ala atttctgcc aacatggac tccttt tcaagtagcagg acagccaca ctt 410 IleSerAla AsnMetAsp SerPhe SerSerSerArg ThrAlaThr Leu aagaagcag ccaagccac atggag getgetcatttt ggtgacctg ggc 458 LysLysGln ProSerHis MetGlu AlaAlaHisPhe GlyAspLeu Gly agatcttgt ctggactac cagact caagagaccaaa tcaagcCtt tct 506 ArgSerCys LeuAspTyr GlnThr GlnGluThrLys SerSerLeu Ser aagaccctt gaacaagtc ttgcac gacactattgtc ctcccttac ttc 554 LysThrLeu GluGlnVal LeuHis AspThrIleVal LeuProTyr Phe attcaattc atggaactt cggcga atggagcatttg gtgaaattt tgg 602 IleGlnPhe MetGluLeu ArgArg MetGluHisLeu ValLysPhe Trp ttagagget gaaagtttt cattca acaacttggtog cgaataaga gca 650 LeuGluAla GluSerPhe HisSer ThrThrTrpSer ArgIleArg Ala cacagtcta aacacaatg aagcag agctcactgget gagCCtgtC tct 698 HisSerLeu AsnThrMet LysGln SerSerLeuAla GluProVal Ser ccatctaaa aagcatgaa actaca gcgtctttttta actgattct ctt 746 ProSerLys LysHisGlu ThrThr AlaSerPheLeu ThrAspSer Leu gataagaga ttggaggat tctggc tcagcacagttg tttatgact cat 794 AspLysArg LeuGluAsp SerGly SerAlaGlnLeu PheMetThr His tcagaagga attgacctg aataat agaactaacagc actcagaat cac 842 SerGluGly IleAspLeu AsnAsn ArgThrAsnSer ThrGlnAsn His ttgctgctt tcccaggaa tgtgac agtgcccattct ctccgtctt gaa 890 LeuLeuLeu SerGlnGlu CysAsp SerAlaHisSer LeuArgLeu Glu _7_ atggccaga gcaggaact caccaagtt tccatggaa acccaagaa tct 938 MetAlaArg AlaGlyThr HisGlnVal SerMetGlu ThrGlnGlu Ser tcctctaca cttacagta gccagtaga aatagtccc gettctcca cta 986 SerSerThr LeuThrVal AlaSerArg AsnSerPro AlaSerPro Leu aaagaattg tcaggaaaa ctaatgaaa agtatagaa caagatgca gtg 1034 LysGluLeu SerGlyLys LeuMetLys SerIleGlu GlnAspAla Val aatactttt accaaatat atatctcca gatgetget aaaccaata cca 1082 AsnThrPhe ThrLysTyr IleSerPro AspAlaAla LysProIle Pro attacagaa gcaatgaga aatgacatc atagcaagg atttgtgga gaa 1130 IleThrGlu AlaMetArg AsnAspIle IleAlaArg IleCysGly Glu gatggacag gtggatccc aactgtttc gttttggca cagtccata gtc 1178 AspGlyGln ValAspPro AsnCysPhe ValLeuAla GlnSerIle Val tttagtgca atggagcaa gagcacttt agtgagttt ctgcgaagt cac 1226 PheSerAla MetGluGln GluHisPhe SerGluPhe LeuArgSer His oatttctgt aaataccag attgaagtg ctgaccagt ggaactgtt tac 1274 HisPheCys LysTyrGln IleGluVal LeuThrSer GlyThrVal Tyr ctggetgac attctcttc tgtgagtca gccctcttt tatttctct gag 1322 LeuAlaAsp IleLeuPhe CysGluSer AlaLeuPhe TyrPheSer Glu tacatggaa aaagaggat gcagtgaat atcttacaa ttctggttg gca 1370 TyrMetGlu LysGluAsp AlaValAsn IleLeuGln PheTrpLeu Ala gcagataac ttccagtct cagcttget gccaaaaag gggcaatat gat 1418 AlaAspAsn PheGlnSer GlnLeuAla AlaLysLys GlyGlnTyr Asp ggacaggag gcacagaat gatgccatg attttatat gacaagtac ttc 1466 GlyGlnGlu AlaGlnAsn AspAlaMet IleLeuTyr AspLysTyr Phe tccctccaa gccacacat cctcttgga tttgatgat gttgtacga tta 1514 SerLeuGln AlaThrHis ProLeuGly PheAspAsp ValValArg Leu gaaattgaa tccaatatc tgcagggaa ggtgggcca ctccccaac tgt 1562 GluIleGlu SerAsnIle CysArgGlu GlyGlyPro LeuProAsn Cys ttcacaact ccattacgt caggcctgg acaaccatg gagaaggtc ttt 1610 PheThrThr ProLeuArg GlnAlaTrp ThrThrMet GluLysVal Phe ttgCCtggC tttctgtcc agcaatctt tattataaa tatttgaat gat 1658 LeuProGly PheLeuSer SerAsnLeu TyrTyrLys TyrLeuAsn Asp _g_ ctcatccat tcggttcga ggagatgaa tttctgggc gggaacgtg tcg 1706 LeuIleHis SerValArg GlyAspGlu PheLeuGly GlyAsnVal Ser ccgactget CCtggCtct gttggccct cctgatgag tctcaccca ggg 1754 ProThrAla ProGlySer ValGlyPro ProAspGlu SerHisPro Gly agttctgac agctctgcg tctcagtcc agtgtgaaa aaagccagt att 1802 SerSerAsp SerSerAla SerGlnSer SerValLys LysAlaSer Ile aaaatactg aaaaatttt gatgaagcg ataattgtg gatgcggca agt 1850 LysIleLeu LysAsnPhe AspGluAla IleIleVal AspAlaAla Ser ctggatcca gaatcttta tatcaacgg acatatgcc gggaagatg aca 1898 LeuAspPro GluSerLeu TyrGlnArg ThrTyrAla GlyLysMet Thr tttggaaga gtgagtgac ttggggcaa ttcatccgg gaatctgag cct 1946 PheGlyArg ValSerAsp LeuGlyGln PheIleArg GluSerGlu Pro gaacctgat gtaaggaaa tcaaaagga tccatgttc tcacaaget atg 1994 GluProAsp ValArgLys SerLysGly SerMetPhe SerGlnAla Met aagaaatgg gtgcaagga aatactgat gaggcccag gaagagcta get 2042 LysLysTrp ValGlnGly AsnThrAsp GluAlaGln GluGluLeu Ala tggaagatt getaaaatg atagtcagt gacgttatg cagcagget cag 2090 TrpLysIle AlaLysMet IleValSer AspValMet GlnGlnAla Gln tatgatcaa ocgttagag aaatctaca aagttatga ctcaaaactt 2136 TyrAspGln ProLeuGlu LysSerThr LysLeu gagataaagg tttcccttgg 2196 aaatctgctt ttggattctt gtgaaaaata agagaacttt caacacagcc cactgttgtt 2256 aatgaaaaca tccagggaga gcactatatt tctgatctgt gaatggggag tacctgtagg 2316 acaatcctag gcataattgg gacttccacc ctaatgcagt atggcacatg ttaccaa 2363 atgtttcaca cagtgaggag tctttaaagg <210>

<211>

<212>
PRT

<213>
Homo Sapiens <400>

MetArgGly AlaGlyPro SerProArg GlnSerPro ArgThrLeu Arg ProAspPro GlyProAla MetSerPhe PheArgArg LysValLys Gly LysGluGln GluLysThr SerAspVal LysSerIle LysAlaSer Ile SerValHis SerProGln LysSerThr LysAsnHis AlaLeuLeu Glu AlaAlaGly ProSerHis ValAlaIle AsnAlaIle SerAlaAsn Met AspSerPhe SerSerSer ArgThrAla ThrLeuLys LysGlnPro Ser HisMetGlu AlaAlaHis PheGlyAsp LeuGlyArg SerCysLeu Asp _g_ Tyr Gln Thr Gln Glu Thr Lys Ser Ser Leu Ser Lys Thr Leu Glu Gln Val Leu His Asp Thr Ile Val Leu Pro Tyr Phe Ile Gln Phe Met Glu Leu Arg Arg Met Glu His Leu Val Lys Phe Trp Leu Glu Ala Glu Ser Phe His Ser Thr Thr Trp Ser Arg Ile Arg Ala His Ser Leu Asn Thr 165 170 ' 175 Met Lys Gln Ser Ser Leu Ala Glu Pro Val Ser Pro Ser Lys Lys His Glu Thr Thr Ala Ser Phe Leu Thr Asp Ser Leu Asp Lys Arg Leu Glu Asp Ser Gly Ser Ala Gln Leu Phe Met Thr His Ser Glu Gly Ile Asp Leu Asn Asn Arg Thr Asn Ser Thr Gln Asn His Leu Leu Leu Ser Gln Glu Cys Asp Ser Ala His Ser Leu Arg Leu Glu Met Ala Arg Ala Gly Thr His Gln Val Ser Met Glu Thr Gln Glu Ser Ser Ser Thr Leu Thr Val Ala Ser Arg Asn Ser Pro Ala Ser Pro Leu Lys Glu Leu Ser Gly Lys Leu Met Lys Ser Ile Glu Gln Asp Ala Val Asn Thr Phe Thr Lys Tyr Ile Ser Pro Asp Ala'Ala Lys Pro Ile Pro Ile Thr Glu Ala Met Arg Asn Asp Ile Ile Ala Arg Ile Cys Gly Glu Asp Gly Gln Val Asp Pro Asn Cys Phe Val Leu Ala Gln Ser Ile Val Phe Ser Ala Met Glu Gln Glu His Phe Ser Glu Phe Leu Arg Ser His His Phe Cys Lys Tyr Gln Ile Glu Val Leu Thr Ser Gly Thr Val Tyr Leu Ala Asp Ile Leu Phe Cys Glu Ser Ala Leu Phe Tyr Phe Ser Glu Tyr Met Glu Lys Glu Asp Ala Val Asn Ile Leu Gln Phe Trp Leu Ala Ala Asp Asn Phe Gln a_.05 410 415 Ser Gln Leu Ala Ala Lys Lys Gly Gln Tyr Asp Gly Gln Glu Ala Gln Asn Asp Ala Met Ile Leu Tyr Asp Lys Tyr Phe Ser Leu Gln Ala Thr His Pro Leu Gly Phe Asp Asp Val Val Arg Leu Glu Ile Glu Ser Asn Ile Cys Arg Glu Gly Gly Pro Leu Pro Asn Cys Phe Thr Thr Pro Leu Arg Gln Ala Trp Thr Thr Met Glu Lys Val Phe Leu Pro Gly Phe Leu Ser Ser Asn Leu Tyr Tyr Lys Tyr Leu Asn Asp Leu Ile His Ser Val Arg Gly Asp Glu Phe Leu Gly Gly Asn Val Ser Pro Thr Ala Pro Gly Ser Val Gly Pro Pro Asp Glu Ser His Pro Gly Ser Ser Asp Ser Ser Ala Ser Gln Ser Ser Val Lys Lys Ala Ser Ile Lys Ile Leu Lys Asn Phe Asp Glu Ala Ile Ile Val Asp Ala Ala Ser Leu Asp Pro Glu Ser Leu Tyr Gln Arg Thr Tyr Ala Gly Lys Met Thr Phe Gly Arg Val Ser Asp Leu Gly Gln Phe Ile Arg Glu Ser Glu Pro Glu Pro Asp Val Arg Lys Ser Lys Gly Ser Met Phe Ser Gln Ala Met Lys Lys Trp Val Gln Gly Asn Thr Asp Glu Ala Gln Glu Glu Leu Ala Trp Lys Ile Ala Lys Met Ile Val Ser Asp Val Met Gln Gln Ala Gln Tyr Asp Gln Pro Leu Glu Lys Ser Thr Lys Leu <210> 5 <211> 21 <212> DNA

<213> Artificial Sequence <220>

<223> 0ligonucleotide Primer <400> 5 tctcaatcat gtgcattgag g 21 <210> 6 <211> 43 <212> DNA

<213> Artificial Sequence <220>

<223> Oligonucleotide Primer <400> 6 agcggataac aatttcacac agggatcaca cagccatcag cag 43 <210> 7 <211> 23 <212> DNA

<213> Artificial Sequence <220>

<223> Oligonucleotide Primer <400> 7 agcggataac aatttcacac agg 23 <210> 8 <211> 19 <212> DNA

<213> Artificial Sequence <220>

<223> 0ligonucleotide Primer <400> 8 ctggcgccca cgtggtcaa 19 <210> 9 <211> 20 <212> DNA

<213> Artificial Sequence <220>

<223> 0ligonucleotide Primer <400> 9 tcccaaagtg ctggaattac 20 <210> 10 <211> 21 <212> DNA

<213> Artificial Sequence <220>
<223> Oligonucleotide Primer <400> 10 gtccaatata tgcaaacagt t 21 <210> 11 <211> 20 <212> DNA
<213> Artificial Sequence <220>
<223> Oligonucleotide Primer <400> 11 cccacagcag ttaatccttc 20 <210> 12 <211> 43 <212> DNA
<213> Artificial Sequence <220>
<223> 0ligonucleotide Primer <400> 12 agcggataac aatttcacac agggagctag cttggaagat tgc 43 <210> 13 <211> 162025 <212> DNA
<213> Homo Sapien <220>
<221> allele <222> 83587 <223> Nucleotide sequence of Chromosome 17 with genomic sequence of the allelic variant AICAP10-6 <400> 13 gaattcctat ttcaaaagaa acaaatgggc caagtatggt ggctcatacc tgtaatccca 60 gcactttggg aggccgaggt gagtgggtca cttgaggtca ggagttccag gccagtctgg 120 ccaacatggt gaaacactgt ctctactaaa aatacaaaaa ttagccgggc gtggtggcgg 180 gcacctgtaa tcccagctac tcaggaggct gaggcaggag aattgcttga acctgggaga 240 tggaggttgc agtgagccga gatcgcgcca ctgctctcca gcctgggtgg cagagtgaga 300 ctctgtctca aaaagaaaca aagaaataaa tgaaacaatt ttgttcacat atatttcaca 360 aatttgaaat gttaaaggta ttatggtcac tgatatcctg tttcattctt tatataatca 420 ttaagtttga aatgtatact tgcactacta acacagtagt taatcttagt cctacaagtt 480 actgctttta cacaatatat tttcgtaata tgtatgcact ggtgtttatg tacgtgttta 540 tgtttatatc tgttaaaatt agcagtttcc atctttttct attttgtacc atcacatcag 600 ttcagaagga ttgacagagc aaaatgattt gatgaagtat aaaagtcaca tggtgagtgg 660 cataaataca actctgaaca attaggaggc tcactattga ctggaactaa actgcaagcc 720 agaaagacac atatcctata tgtcaagaga tgtaccaccc aggcagttaa agaagggaag 780 tacacataga aagcacaatg gtgaataatt aaaaaattgg aatttatcag acactggatt 840 catttgctcc taaagtcaga gtcctctatt gtttttttgt ttttgtgggt ttctttttaa 900 atttttttat tttttgtaga gtcggagtct cactgtgtta cccgggctgg tctagaactc 960 ctggcctcaa acaaacctcc tgcctcagct tcccaaagca ttgggattac agacatgagc 1020 cactgagccc agcccagacg ctttagcatt tatgaagctt ctgaaatagt tgtagaaacc 1080 gcataagctt tccatgtcac tttcaaagtt tgatggtctc tttagtaaac caaccaagtt 1140 attcctcaag ggcaaaataa catttctcag tgcaaaactg atgcacttca ttaccaaaag 1200 gaaaagacca caactataga ggcgtcattg aaagctgcac tcttcagagg ccaaaaaaaa 1260 aggtacaaac acatactaat ggaacattct ttagaagagc cccaaagtta atgataaaca 1320 ttttcatcaa agagaaaaga gaacaaggtg ttagcaaatt cctctatcaa ataacactaa 1380 acatcaagga acatcaatgg catgccatgt ggaagaggaa gtgctagctc atgtacaaac 1440 cagtagataa tttcaacttg ctgccgaatg aaacctcttt gcaaggtatg aatcagcact 1500 _12_ tctcatgtttgttttgctttgttttgttttgtttttagagacaggcccttgctctgtcac 1560 acaggctggagtgcagtggcacgatcagagctcactgcaacctgaaactcctgggctcaa 1620 gggatCCtCCtgccttagcctcccaagtagCtgggaCtaCaggCCCaCCatgcccagcta 1680 attttttaaattttctatagagatgggatctcactagcacctttcatgtttgatgttcat 1740 atacaacgaccaaggtacaatgtggaaaagggtctcagggatctaaagtgaaggaggacc 1800 agaaagaaaaggggttgctacatagagtagaagaagttgcacttcatgccagtctacaac 1860 actgctgttttcctcagagcagagttgatgatctaaatcaggggtccccaacccccagtt 1920 catagcctgttaggaaccgggccacacagcaggaggtgagcaataggcaagcgagcatta 1980 ccacctgggcttcacctcccgtcagatcagtgatgtcattagattctcataggaccatga 2040 accctattgtgaactgagcatgcaagggatgtaggttttccgctctttatgagactctaa 2100 tgccggaagatctgtcactgtcttccatcaccctgagatgggaacatctagttgcaggaa 2160 aacaacctcagggctcccattgattctatattacagtgagttgtatcattatttcattct 2220 atattacaat gtaataataatagaaataaaggcacaataggccaggcgtggtggctcaca 2280 cctgtaatcccagcacttcgggaggccaaggcaggcggatcacgaggtcaggagatcgag 2340 accatcctggctaaaacggtgaaaccccgtctactaaaaattcaaaaaaaaattagccgg 2400 gtgtggtggtgggcacctgtagtcccagctactcgagaggctgaggcaggagaatggtgt 2460 gaacctgggaggcagagcttgaggtaagccgagatcacgccactgcactccagcctgggc 2520 gacagagcgatactctgtctcaaaaaaaaaaaaaaaaaaaaaagaaataaagtgaacaat 2580 aaatgtaatgtggctgaatcattccaaaacaatccccccaccccagttcacggaaaaatt 2640 ctcccacaaaaccagtccctggtgccaaaaaggttggggaccgctaatctaaataatcta 2700 atcttcattcaatgctaaaaaatgaataaacttttttttaaatacacggtctcactttgt 2760 tgcccaggctggagtacggtggcatgatcacagctcactgtagcctcaatcacccaggcc 2820 ccagcgatcctcccacctaaacttcctgagtagctgggactacaggcacgcacc'accatg2880 cccagctaatttttaaattttttatagagatgggggtctcaccatgttgcccagactggt 2940 CtCaaaCCCtgggCtCaagtgatCCtCCCtcaaactcctggactcaagtgatcctccttc 3000 cttggcctcccaaagtgctgggattacaagcatgagccactgtacccagctggataaaca 3060 ttttaagtcgCa.CtaCagtCatggaCaatCaggCttttCaaCatgCagtatggacagtga 3120 gtcccagggtctgcttttccatactgaaatacatgtgatactaaggagaaaggtgctcgc 3180 aaggatatttaaaatgaagaatatttaaaatgaggaaaaaactgtttcttcatgactttg 3240 ataaggctgataaagaccatttctgtgatctcaggtgattcactcaagtagtatatttca 3300 gtaatcattatctggaacagCCtgaatCttaaccaaaataccatgattttttaatgctgt 3360 tatgataccttgatgatatgaccaaactgcaatgtaggcagctaaatctccacgagtttg 3420 acttccccgagagttgacagttttcttcacaaattaaagaaatatattttttgatacatg 3480 attggcatatttaaaaactacactgaaatgctgcaaaatgatataaagaaacattttcca 3540 gaatcaaatgcaatcaaagagtggattaggaatctactcaccattatcaactaaatagaa 3600 acacttggactgggtgtggtggctcacatctgtaatctcagcactttgggaggccaaggc 3660 aggtggattgcttgaggccaggagctcaagaccagcctgagcaacatagcaaaactctgt 3720 ctctacaaaaaaaaaaaaaaattaaccaggcatggtggcagatgcttgtaatcccagcta 3780 CtCtggaagCtgaagtaggaggaCtgCttgagCCCaggagatCaagaCtgCagtgagCCg 3840 tggtCatgCtgCgCCaCagCCtgagtgaCagagagagaCCCtgtCtCaaaaaCaaaaaCa 3900 aacaaaaaacacttaaccttcctgttttttgctgttgttgttgttgtttgtttgttttga 3960 gatggagtctCaCtCtgttgcccaggctggagtgcagtggcgtgatcttggctcactgca 4020 agCtCtgCCtCCCgggttCaCgCCattCtCCtgCCtCagCCtCCCgagtagCtgggaCta 4080 taggcgcccgCCaCCaCgCCCggCtaCttttttgCatttttagtagagatggggtttCaC 4140 cgtgttagccaggatggtcttgatCtCCtgaCCtCgtgatCCaCCtgCCtCggCCtCCCa 4200 aagtgctgggattacaggcatgagccaccgcacccggccaacctttctgttttttagttt 4260 gatatgcttgttaactcagcagctgaaagaatgctgaaagtggccttcagtaaaaaaatt 4320 tcactagaatctctacatccatatttaatctgaatgcatatccagattgatcagttagag 4380 caaaaacactcatcatcattcctgatgacctctaattctggtttcggctttctatttcaa 4440 tggaaacagaataaggaaagaaatggaagggctctggaaatttgtcctgggctatagata 4500 ctatcaaagatcaccaacaataagatctctcctataaatataaaacaagtataattaatt 4560 ttttaattatttttttctcttcagaggattttatttcaagataaaacataacttctaccc 4620 atactattgattccaaaggttagaaaaagtgtttttcctcatcttatccttcaaagaggt 4680 cacagcaatgcaaacatctataaaatgcctctgcataattgtcagaagctatagtccaga 4740 aatcattgaaaatgcttttccattttaagcttaggtgaggtgtcttaggaaacctctatg 4800 acaacttactctatttattgggaggtaaactcccagactctcccagggtctcctgtattg 4860 atctcattttttaggcttcctaatcccttgaagcacaatcgaaaaagccctggatctctt 4920 ttctgcacatatcatcgcggaattcattcggcttccagcaagctgacactccatgataca 4980 agcggcctcgcccttctccggacgccagtccttgctgcggttagctaggatgaggggttt 5040 gctgggcttcagtgcaggcttctgcgggttcccaagccgcaccaggtggcctcacaggct 5100 ggatgtcaccattgcacactgagctcctggcaggctgtaccaattttttaattatttaat 5160 atttatttttaaaattatggtgaatattttggtattctgctctaaaataggcccataaat 5220 gcacagcagatatctcttggaacccacagctttccactggaagaactaagtatttttctt 5280 ttaaagatgctactaagtctctgaaaagtccagatcctctacctctttccatcccaaact 5340 aagacttggaatttatgagagatctagctaacagaaatcccagacacatcattggttctt 5400 cccagagtgcagtcctcctaaagaggctcagccctaagcaggcccctgcaccaggagggt 5460 gggtctgagacccacatagcacttcccaaggtgcatgctccagagaggcactgaaacagc 5520 tgagcacaagcctgcaagcctggagaactctcacagtcagaacggagggggcccagtggg 5580 actaacataaagagaaaagggaacacagagaaatggatggcaccaacaaccagcaaagcc 5640 ttcatggccaatgaaagcatcagtgacggggccagaaccctcatccccaaagactcttca 5700 ctgcctttagtgaaaaacaatggctagagagtgaagttatgatcatgtatagagaggtaa 5760 agttacatttttatattctgactctgctaatgtgaaattccctatctgctagactaaaag 5820 tttcagacaccctgttcaaatatcccattagttgctagagacttaaaatgaacagaacgc 5880 acattgtcaggatgactattaccaaaaaatcaaaagacagcaagtattggtgaggatgta 5940 gagaaactggaacttttgtgcactgtttatgagaatgtaaaatggagcagctgctgtgga 6000 aaagagtatgcaggttcctcaaagagtaaaaccaagatgtggaaacaactaaatgcccat 6060 cagtggatgaaggggtagacaatatgtggtatatacataccatggagtactattcagcct 6120 ctaaaaaaaaaaaaggaaattctataacatgcaacagcatggatgaatcttgaggacatt 6180 ttgctaatgaaataaggcagtcatagaaagacaaatactgcacgactccacttatatgag 6240 ataccaaaaatagacaaattcatagaatcaaagagtacaatggaggttacctggagctgc 6300 agggcgggaaacgaggagttactaatcaacgaacataacgttgcagttaagtaagatgaa 6360 taagctctcaagatcagctgtacaacactgtacctagagtcaacaataatgtattgtaca 6420 cttaaaaatttgttaagggtagattaacaaatgtagtagatccacaaatgtggttaagtg 6480 ttcttaccacagtaaaataaaaaaagaatatcaagcccaggagttcgagactagcctggg 6540 taacatggtgaaaccctgtctctacagaaaatacaaaaattagccagctgtggaggtgca 6600 ctcctagggaggctgaggtgggaggcttgcttgagcccaggaggtcaaggctgcagtgag 6660 ccatgattgcaccactgtactccagcccagatgacagagcaagacaccaccccccccaaa 6720 aaaagaaaaagaatatcaaacattttaaaagatcagatacgcaagaacaacaacaaaaaa 6780 gagatgaacagagcatcgaccctcatctagtgggattcttggtctaactgaaaaacagac 6840 attgagagacaaacaatgacagtgatgtgatcacagcaattacacaggtatcccctgggg 6900 actgcagaagaaaggaggaatgcctaactttcagaaaatagagaaagcgtcaaacagttg 6960 gtgaaagccttccaaaactagagagaactgcacacaccaaatcacagaaagaagaaaagc 7020 cgtgggagattctgggacccaccggctatttttgatggctgaacaccctgctgcaggaga 7080 gacaggagctggaaagcatggtgggatgaaacctcaaacagctttgcctgcattgcttaa 7140 gatgactgggcttgattaactctagtcaatggggacaattcaatcaaagaagaaagatgc 7200 tcaaattcacattttagaatgattttttatggcagtatggggaatagattaaaagagagt 7260 gaagctggaggcaagaaacttgttaagaggCaaCtgaaaCagtCtagatgataaataata 7320 aactgacagagtgactagaaaaatcagaacaggctgaatcaacagatacctagatgaaaa 7380 taacaggacttgatcaccagttgtatcttggagaggaagg,agttgtttccttgctttccc 7440 tacgactgggaatacggaaggtttgccgtgtgtattggttatatactggtgtgtagccaa 7500 tcactgacaaecatttagcagcttaaaacacaaaggcttatctcccagtttctgtgggcc 7560 aggaatctaagataggcttagctggctggttctggctcagagtttctcaagaggttgcaa 7620 tcaagatgtcagctggggttgcatcatctgaaggctcaactggggccggagggtccactt 7680 ccaaggagttcactcacctgcctgacaaggcagtgctggttgttggcaggagatctcaat 7740 tcattgccaagtgagcctctctatagcattgctggaacatcctccccatctggcagttgg 7800 cttctctcagcatgagtgatctgagagagagagcaaggaggaagccacagtgttcttcct 7860 aCtCCtaCtCCtaaCaCtatggacctactcCtaaCaCtCtCa.CttCtgCCttattCCatt 7920 agttagaaagggaactaagctccacctcttgaaataagaagtgtcaaagaatttgtggat 7980 atatttaaaaatcatcacactgtggaagtggatagggggttcaattaatgctgaacttga 8040 aatgcctgagacattcaaatgtccaacaggcaatgaacatacccatagatggtcatgact 8100 ttagcaagaatagaggaagatcacagaattaaggaggaattgaaaggtaaaagaagtgga 8160 gtcagattccccctgaaaagtgagccatgaaaggaactttaactattgagttagaggtca 8220 gagtaggaaatttcggtggaattcttttttaaagaaaggaaccatataagcatgttttga 8280 ggtagagggagaataaatcagtagacagggagaggtaaaaaacataaatgataggggata 8340 gttgacaaaggtcttggcagaatcccttacccattgacttggggccaagagagggacact 8400 tctttgtttgagggataaggaaaataagaaagaatgggtgctatttagtgtggtcctgtc 8460 tctagggcaaacgcataggtaacaaactgtgtgtgttaggaatatagatgtgacctcaca 8520 ttgagattctcacctcaaatccattttgttgttacctgtaccttcctaccttctcttttt 8580 gctacatgcagactgctgttttgtcttcctggcctgttccaggtttcagcattctggcat 8640 atctgctaccctgttcccaaacctctctagagtccatgctccttccttggatagtgtttg 8700 attgggccacgtatctaagaagtgatgccttcagttaggcctgagaacctcctctatgga 8760 aatctccatcagtgaccctgacagacttggtatcttggagatgtcactgctcccagcctg 8820 tggtctaggagaatctcagcctgggcctctagtagtatggataaggcgttaaggtatctt 8880 tgaaccagagtctgtcatattcctcaatgtgggacagataaaacagtggtagtgctggtg 8940 tttctgagctagaactctggtttttggtctagattctttgatgtatgacctttcagaggt 9000 attaaaatttgttctaatacaatgttcaatacaaatgtagttccttttctgttaggacct 9060 caacaaaacatgaccaactgtagatgaacattaaactatgacaattcatggaaatgaata 9120 cagtaatacctgcggttcccccattttagcagtcactatggtgacatttggcacaaatgg 9180 ctatttaagggtgcttttgttaaaacctaccatcttactaggcacatgatattgaaacta 9240 atgaaataatggagaaacttcttaaaaacttttaatgaataaagtgatgaagtgataata 9300 ttttagctgc tatttataaa gtgactatta caggtcaaac attcttctag ggtttttttg 9360 ttgaagttgt cacatttaat ccttaataac ccactatgag tcaggtattc ttctctcccc 9420 tttggacagt tggggaaatg ggggtcagag aggttaggta atttgctcag ggccacacaa 9480 cctgcatgta gaaaatctga gatttgtaca ggaacgtatc aaactctgaa gtccatgctt 9540 ctattttccc atgctgcctt tctaataaaa ggtaactaat gctactggat gctgccccca 9600 aagtgagtca ctttcacccc accctacttg attttctcca taaaactaat cacatcctga 9660 caacttattt attgctgatc tcccccaCta gattataaac tcaataaaag caagatcctt 9720 gtctgctgaa tatcagtacc taaaacgctg tctagcacag agcaagtaat taatatttgt 9780 tgaatgaaca aataaaggaa aaaaattcaa aggaagaaaa agccctaaaa cagatgttta 9840 cctaaacata cattttaaaa gaaagcatat aacaaattca ggacagaatt taaatttgat 9900 tttttaaaga aataaccaag tgctagctgg gcacagtggc tcacacctgt aatcctagca 9960 ctctgggagg ccgaggcagg cagatcactt gaggtcaaga gttcaagacc agcctggcca 10020 acatggtgaa acctgtctct actaaaaata cagaaattat ccaggcatgg tggcaggtcc 10080 ctgtaacccc agctactcag gaggctgagt caggagaatt gcttgaaccc aggaggcaga 10140 ggttgcagtg ggccaagatt gcaccactgc actccagcct gagtaacaaa gcaagactct 10200 gtctgaagga gaaggaaaga aagaaggaaa gaaggaaaga aggaaagaag gaaagaagga 10260 aagaaagaaa gaaagaaaga aagaaagaaa gaaagaaaga aagaaagaaa gaaagaaaga 10320 aagaaagaaa aagaaagaaa gaaagaaaga accaagtgct tatttgggac ctactatgct 10380 atgtttttcc atgcacgcta ttttcagtaa agcagttagc aaacttgcaa gatcataaca 10440 acaaatatat gcttctataa ctctaaaatt gtgctttaag aagttcctct ttaccagctc 10500 atgtatgcat tagttttcta agagttacta gtaacttttt ccctggagaa tatccacagc 10560 cagtttattt aaccaaagga ggatgcttac taacatgaag ttatcaaatg tgagcctaag 10620 ttgggccagt tcatgttaat atactccaga acaaaaacca tcctactgtc ctctgacaat 10680 tttacctgaa aattcatttt ccacattacc aaggagccag ggtaggagaa tatagaaaga 10740 CCaCCCaaga atCCttaCtt ctttcagcaa aatcaattca aagtaggtaa ctaaacacat 10800 gccctaacaa tgaatagcag attgtgctca gaagaatgat ctacaacatc ttactgtgaa 10860 ggaactactg aaatattcca ataagacttc tctccaaaat gattttattg aatttgcatt 10920 ttaaaaaata ttttaagcct aaattttaaa aggtttgata ttggtacatg aatagaCaaa 10980 cagacatgga ctagaccaag aattaggttc aaacatatac aggaatttaa tatacgataa 11040 atctagtatt ccaaaggaac caacaaatgg tgttcagaca gcaggatagg catcaggaaa 11100 aacacagttg ggcaccctac cttactccta acaccaggag taactgaagg agcaccaaat 11160 atttatttat tttaattata gttttaagtt ctagggtacg tgtgcacaac atgcaggttt 11220 attacatagg tatacatgtg ccatgttggt gaggagcacc aaatatttaa aagaaaaaaa 11280 ttggccaggg gcggtggctc acacctgtaa tcccagcact ttgggaggcc aaggtgggca 11340 gatcacctga ggtcgggagt tcgagaccag cctgagcaac atggagaaac cccatctcta 11400 ctaaaaatac aaaattagcc aggcatggtg gcacatgcct gtaatcccag ctacttggga 11460 ggctgaggca ggagaatagc tttaatctgg gaggcacagg ttgcggtgag ctgagatatt 11520 gcactcCagc ctgggcaaca agagcaaaac ttcaactcaa aaaaattaat aaataaataa 11580 aaataaagaa agaaaagaaa aaaatgaaaa tagtataatt agcagaagaa aacaccgtag 11640 aatcctcgga ctcttaggat ggggaatgcc tata_atataa aaaccctgaa gttataaaag 11700 agaaaatcac ctacatacaa accaaatctt tctacatgcc taaaacatag cacaaacaca 11760 gctaaataat catagctgaa tgaactggga aaacaaaact tgactcatat ccagacagag 11820 ttaattttcc tacacataaa gagtacctat ataaacccaa caaaaaaacc accactaacc 11880 caaaataaaa atgtgacagg taatgaacag gtagttcaca gagaatacaa atggctcttc 11940 ggcacataag atgctcagac tgacttttac ttatttattt tttgagagac agggtctcac 12000 gatgttgccc aggttaggct caaactcctg ggctcaaatg atagtaccag gactacaggt 12060 gtgccccacc gcacctggct cctcaaccac ctgtattaac aggaaatgca aaataaaact 12120 ttcaaatcta ttttacctat tagaatggca aaaatttgaa aaacttcaaa catcatcatg 12180 ttggtgagaa tgtgaggaga ctggcactct cattttttgc tgatagcata tatatactga 12240 tggcttctat ggaaagcaat ctggcagcgt ctatcaaatg tacaagtgca tatatccttt 12300 gacaaagcaa ttccactcta ggaatgtgtt ctatatggtt gtgcttcctg gggctgggaa 12360 ctgggagcta agggacaggg gcagaagata atcttctttt ccctccttcc ccgttaaaca 12420 tgttgaattt tatatactgt aatatattat ttttcacaaa agataatttt taagcgatat 12480 gtctgggaat tttttttttt cttttctgag acagggtctc actctgtcat ccaggctgga 12540 atgccatggt atgatctcag ctgactgcag cctcgacctc ctgggttcaa gcaatcctcc 12600 cacctcagcc tcctgagtag ctgggactac aggcacgtgc catcatgcta atttttgtat 12660 atacagggtc tcactatgtt gcccaggcta atgtcaaact cctaggctca agcaatccac 12720 ccacctcagg ctccaaagtg ctgggattac aggcgtgagc caccgcgcct ggccctggga 12780 attcttacaa aagaaaaaat atctactctc cccttctatt aaagtcaaaa cagagaagga 12840 aattcaacct ataatgaaag tagagaaggg cctcaaccct gagcaacaaa cacaaaggct 12900 atttctgaga caggaatttg ctgaacaaaa tcgagggaag atgacaagaa tcaagactca 12960 cttctcggct gggcgcagtg gctcacacct gtaatcccag cactttggga ggccgaggcg 13020 gacagatcac gaggtcagga gattgagacc atactggcta acacagtgaa acccagtctc 13080 tactaaaaat acaaaaaatt agccgggcgt ggtggcaggt gcctgtagtc ccagctactt 13140 gggaagctga ggcaggagaa tggcgtgaac ccaggaagcg gagcttgcag tgagccgaga 13200 tcacgccactgcactccagcctgggtgacagagcaagactctgtctcaaaaaaaaaaaaa13260 aagactcatttctctagatcttgagccgtattcaaatttatctcagcttagtgagaggtt13320 aaagcaaggaatatccttccctgtgggccctgctccttactgaaggaaggtaacggatga13380 gtcaaggacaccaatggagaaaagcactaacaccattatctgatgaacattacgtgaaga13440 agggtaagaagtgaagtggaattgctgaagaagtcagtgaaagcggacattcatttgggg13500 aaatggaatataggaaatccataaaagtgattaaaaagatgttagaggctgaggcggggg13560 gaccacagggtcaggagatcgagaccatcctggctaacacggtgaaaccccatctctact13620 aaaaatacaaaaaattagccaggcgtggtggcaggcacctgtagtcccaactactcggga13680 gactgaggcaggagaatggcatgaacctgggagacggagcttgcagtgagccgagatcac13740 gccactgcactccagcctgggtgacagagtgagactccatctcaaaaaaaaaagttagat13800 acgagagataaagatccaacagacacacaactgctaattctgaacagaacaaaacaaatg13860 gcacaggaaaagaaaatttaagatataacaccggaaaactttcctgaaattgagtaactg13920 aatctatagcttgaaagggtttagcatatgccaagaaaaatcagtagagtccaaccagca13980 caagacacatctagcaaggctggtgattctaccaacacagagaaagaagtgggtgaccca14040 taatgcggaaaaaggcagaccatctgcagtcttctccagaacactggagtctgaagacaa14100 aagaatgctgcctactgagccagaagggagagaaagtgacccaacacatctttaccaagt14160 tagaatgtcacgcattatttaaaggctgcaaaagccatgaaagacatgaaagaacacaag14220 catttacaacatgaaagaacacaagcattctcatactcaagaatccttaagaaaaatgta14280 gtcctaatccagcccactgaaagttaaatgtacttaatgtgctcattaatgggaacttca14340 tagcttcaaatcagtctggtcccatctaccaacatctctcgcccggctttcctgcaatag14400 tCagCaCCtttCCCtCCtCCCagtCttgtCCCCtggagtCtgctctcagcatagcagagt14460 gaccacatcaacacccaagtcagagccctccagtgcgcactggtctacaaagcccttccc14520 aCCCCCCa.CCCCaCgtgCCCtccggatccttgtgacgtgtCtCCtgCataCCCtagcagC14580 CCtggCCtCCtCaCtgCCCCtCCtgtaCatcaggaaggcgactccttgagtcttggctct14640 ggccgcctcctccacctgcagtgagttaactcccttacctactctaggtcattgctcaaa14700 tgtCagCatCtCaatggggCCCtCCCtgaCtaCCCtatttaaattCtaCataCtCCCCtt14760 gaCCCCatggaCCtCa.CtCaCCCtattCCaCttttattCttaCaatttagCaCttgttCt1482~

CttCtaaCgtattCtaagaCttaCrCatttattaCattgtttgCCaCCCCCtCtagtaCa14880 taaactccagaggggcagggatttctgtctatttattcatttctttatccctaggacata14940 gaacagggcatagttcagagtattcaatgttatcaatgaatgaactagcagtagtaccag15000 ttccagttaggcacagaattaaatctaaatagaattaaatctcatggtctgggttaacta15060 tggatagaaaattagatataattttaagaagcctagaaagaaaaaattaataatgtaaaa15120 ataatattaatttgataataataacaaaaactctgccaggcactgtggctcaaatctgca15180 atcccagctactcaggaggctgaggtggaaggatcacttgagaccagagttcaagactca15240 gcctaggcaacacggcaagaaactgtctctaaaaaaattaaaacttaaatttttaaaaaa15300 gaattctcaaagcgtcacaaaaactggagattaaggtacaggaagtgtgaagtaatatta15360 ctatgctaatggttttttttttttttagaaaggtataaccaa_aagatttctttctcaagt15420 cgataaactgagaaagataagcatatcttccaattaacagagggggaggaaaagccagat15480 acaacaaaataagatataaattagtttccagttgaaaacaagagtaggagttattttgca15540 tcacctcacctgtgacctcccccagcccaaaaaacactactgataaacagggtagaaaag15600 catcatctcagataaagcaggaaaaactgccacagtctcaaaccacaaactataagcaca15660 cacctggccaaccctgccaagtctgggctcagtaggaggaacgtgctgagagctaggatg15720 taccaacttagacattctgtgggatacagatgtccctggaagggtcacaccatctcaaag15780 gcacctgtaatgCCCaCtgattacagccaccatatgtgagagagaaactcagggcactta15840 gagagtataacaagaaccttatgtcatctgagatgaggaatcctcagccctgcaaattaa15900 ccaactctttagaacaactggcaaaacataaatatccacaacttttgtttcagtaattcc15960 actcttagatatcaatccaaagtacatgagacagcagatacacacacaaaatggtattta16020 ctgcagcattgtttataatagcaaaaaacaagaaataatccatatgtctcaataggatac16080 tgggtacatgagggtatgtacccatcattcaaccatcaaaaagagtgatatggatgtcca16140 cagatggacataaaaagctgtgtgttacgtgaaaacaaactcaagcagcagcaggatggg16200 cttatgatagtcagtatgagctaatttctggaaaaaaaaatctagtgtgtgcacagaaaa16260 catctgaaagaacagaaacaaaactatcagcagaatattgagatgttttactaagttgta16320 tatctatactgcttgtaatttttaccccaagcaagaattactttttggaaaaagaaaatt16380 caggaaataaagcatttctttaaacttcatgtttaaacaaatggtgatggaataaaagag16440 ttcttattcatcataaacacacacagcacacatgcacgcatgtgcgtgagcacacccttt16500 acttgataaataccatgttgaatattttagtctttccttttaggttctatcccttcactc16560 aaaatgcggttataaataaatgtacttttcatgtgccttctgcctaaacccactttaata16620 taactttacagtcccattatcattatagtctcaaagctagactcagcctgaaactaccct16680 ttcatttggaacccttattaaaatgccacatacagctccttcaaataaaaacaaacccta16740 ggacctgacactaggcttcctttgttgctactcataatggccaagttctgtgcttataat16800 acatcttctttcattttattgctacatatccaagggttttatatgtttttcttattatat16860 cttaattcaaaacaccatcacgctcttttccagatgaaaataaggaaaagaaattgagca16920 actgactgacttaaaggtcataaaactatatagtagcagagtcagcaaaagaagaaacac16980 acatctcccaagtagaggctgaaaaccagtaccattcacctccagggtgagctatataca17040 gattacaaagtcaccttctctaaatgttcaaactgaatcccatacccatactttaccact17100 acctcgtaagaacagcctcagatcttgttatagccttttttttagcatgctgaagccaat17160 aaaatgcttcccattcagcaagagaaacaagttctgaaacactgaataatctgcccaggg17220 cctatgaacatttccactgtgagaaatgttctccactgtgtggagaagatccttactctt17280 ctccacacaggcagaacattagaaaaattcttggattctatgatgcacagcttaggagtc17340 tgtttagcacaatttaagtccaaatagttattaaatcctcctctgttccagaaacagtgc17400 taaatactgtgaatataaaaattgaaaagatactctcctggctcccaagaaagtcagcca17460 gatagaggagacacaggcacacaaatcactgtcacatgaagctctacctccctaacttca17520 aacgagggcctaagtcaccaagaatacagtagcagtt'gtgactacgagtaactactataa17580 ttcaatactttatcttcccttagaaaactcttctcccttggaaatttatttgcatttcta17640 aataccattccttactaaaaggaagcagggctccttggggaaatagctgattctaggtgt17700 ggactatgaaatgaaaatggtgagtctgggacatcccatgttgcccagaaatcaaggaac17760 tgcccaaagattaacagagtcatgttaaatggacctaagagtgaaccagaaggagctcac17820 tttgccccgcgtggaacaatttcaagaaaaacatgacagtaatgaattataaaacatgaa17880 ttaaaatacatattggtactaaaaagagaacaaaaggatgtggctttggataaagctctt17940 cttcatggaagaataccagctaataaatgtaaaggaaatgagagaattagaaaaattatc18000 attttgtaaaccttaatatattcacctagacatgctaaaaccactgagtaaaaggctgct18060 tgggaagaggatgctcacatgatctcagagtttcacaccacagataatttattagataca18120 ggaaggaagatgtgatcaagCttCCtgtgaCCCCCagCCaggccccacaacactatgtgc18180 ctccttgtgatgtgggagctacacagcatcgcccacacagcttctcgccaaaactgtttg18240 aagctaatcacaagggaagaactggacagcttctgaccatgagacgctccaccagacaac18300 ttgcttggcctctccaaagaaacttgcttggcctctccaaagaaaactcagtttcattta18360 aaaacaaaactaattatttaaaaacaaacgaaaagcaagttgtggacttgagctccaggg18420 acagagcagacatacttttccctgttcttcccagtaagtggtaataaaaaccctcaacac18480 tagatataaaacaaatataagaaggttctggaaggggaagaggaggcagactatccaggt18540 gccttgaggcccacagaacaacccagtgatgggttcactgggtcttctttttgcttcatt18600 atctcagacttggagctgaagcagcaggcaacttcaaaacaccaaggggcacagattgaa18660 aagccccaagaaaagCCtgCCCtCtCtagCCaaaggaCCaggaaggagacagtctaatga18720 gatggaacacatttagacagtaactgcccatttaccagcaataactgagcagggagccta18780 gacttccagtcttgtgaggacgtaccaaggtacccaacacccccaccaaggctgagtaag18840 gactgcgacttttatccctgcatggcagtagtaaggagcccatccctcacccgccagcag18900 tgtcaggggaacctggacttccactcccacccaggagtgatgaggccctccctgctgggg18960 tcatgtcagaggaggcctagtggagattcagtgacttaaccttttcccagagataatgag19020 gCCa.CCtttCCtCCCtCttCCCCCatggtgacagtgaaagcactgtggcaagcagtaggc19080 aCtCCtaCCCCtCCtagCCagggaggtatcagggaggccaagtagggaaccagaataccc19140 acaaccacccagcagcaacaggggtCCCCCaCCCCattgggtgtCaatggaagcagagcg19200 gaaagcctggatatttacccccatctagaagtaacaagctgatgtcccccttcttctact19260 acaatggtgttcaaaacaggtttaaataaggtctagagtctgataacgtaatacccaaat19320 cgttgaagttttcattgaggatcatttataccaagagtcaggaagatcccaaactgaaag19380 agagaaaagacaattgacagacactagcactaagagagcacagatattagaactacctga19440 aaggatgttaaagcacatatcataagcctcaacaggctgggcgcggtggctcacgcctgt19500 aaccccagcactttgggaggccgaggcaggtggatcacaagatcaggagatcgagaccat19560 cctggctaacacggtgaaaccccgtctctactaaaaatacaaaaaaaaatagcaaggcat19620 ggtggtgggCaCCtgtagtCCCagCtaCtCgggagcctgaggcaggagaatggcatgaac19680 ctgggaagaggagcagtgagCCgagatCgCaCCaCCgCaCtCCagCCtgggCaaCagagC19740 aagacttcgtcccaaaaaaaaaaaaaaaaaaaaaaaaagcctcaacaaacaactacaaac19800 gtgcttgaaacaaatgaaaaaaaaatcttggcaaagaaataaaagatatatattttggcc19860 aggtgcagtggctcacagcctgtaatCCCtgCa.Ctttgggaggctgaggcaggcggatca19920 CCtgaggtCaggagtttgagaCCagCCtgaCCaaCatggagaaaCCCCgtCtCtaCtaaa19980 aatacaaaattagccagtcatggtggcacatgcctgtaatcctagctactcaggaggccg20040 aggcaggagaatcgcttgaactcaggaggtggaggttgcggtgagccgagatcccgccat20100 tgcacattgcactccagcctgggcaacaagagcaaaactccatctcaaaaaaatagatac20160 atattttaatggaaattttagaattgaaaaatacagtaaccaaattgaatggaaagacaa20220 catagaatggagggggcagacaaaataatcagtgaacttcaacagaaaataatagaaatt20280 acccaatatgaagaacagaaagaaaatagactggccaaaaaataaagaagaaaaaagagg20340 agcagcaggaggaatgatggaaaaagagaaaggaaggaaggaagggaaggagggagggaa20400 ggagtgagggagaaagtctcaaagacctctgagactaaaataaaagatctaacacttgtc20460 atcagggtccaggaaagagacaaagatggcacagctggaaacgtattcaaaaaataatag20520 ctgaaaacttcccaaatttggcaagagacataaacctatagattcgaaatgctgaacccc20580 aaataaaaagcccaataaaatccacaccaaaatacatcatagtcaaacttctgaaaagac20640 gaaaagagaaaacgtcttgaaagcagtgagtgaaacaacacttcatgtataagggaaaaa20700 caattcaagtaacagatttcttacagaaattaaggaagccagaaggaaatgacacaatgg20760 ttttcaagtgctgaaagaaaagaagtgtcaacacaaaattctagattcagtaaaaatatc20820 cttcaagaatcaatgggaaatcaagacagtctcagataaagcaaaataagagaatatgtt20880 gccagcagatctcccctaaaggaatggcaaaaggaagatcatgcaacagaccaaaaaatg20940 atgaaagaaggaatccagaaacatcaagaagaaagaaataacatagtaagcaaaaataca21000 tgtaattacaataaaatttctatctcctcttaagacttctaaattatattgatggttgaa21060 gcaaaaattataaccctgtctgaagtgcttctactaaatgtatgcagagaattataaatg21120 gggaaagtataggtttctatacctcattgaagtggtaaaatgacaacactgtgaaaagtt21180 acatacacacacacacgtaagtatatataaatatatgtgtgtatatgtgtgtgtatatat21240 atatatacatataatgtaatacagcaaccactaacaacactatacaaagagataataacc21300 aaaaacaatttagataaattgaaatggaattctaaaaaatattcaaatactctacaggaa21360 gacaagacaaaaagagaaaaaaagaggaggacaaactaaattttttaaaaacataaataa21420 aatggtagacttaagccctaacttatcaataattacataaatgtaaatgatctaattata21480 tcaattaaaagacagagatagcagagttaatttaaaaacatagctataagaaacctgctt21540 tgggctgagtgcagtgactcacacttgtaatcccagcacttcgggaggccaaggcgggtg21600 gatcacctgaggtcaggagttccagaccagcctggacaacatggtaataccccatctcta21660 ctaaaaatacaaaaaaattagccaggcatggtggcacacgcctgtagtcccaactactca21720 ggaggctgcgacacaagaactgcttgaacccgggcagcagaggtagcagtgggccaagat21780 tgcgccactccagcctgaacgacagagtgagactccacctcagttgaaaaacaaaaaaga21840 aacctgctttaaatataccaacatatgttggttgaaattaaaagaataaaatatatcatg21900 aaaacattaatcaaaagaaaggagtggctatattaataacataaaatagacttcagagaa21960 aagaaaatttcaagagacaggaataaaaggatcaagaaaagatcctgaaagaaaagcagg22020 caaatcaatcattctgcttggagattcaacaccctctcttaacaactgatagaacaacta22080 gacaaaaaaatcagcatggagttgagaagaacttaacaccactgaacaacaggatctaat22140 agacatttacggaacactctacccaacaatagcaaaataaacattcttttcaagtattca22200 ctgaacatatccttagaccctaccctgggccataaaacaaagctcactagtgattgccga22260 aggcttggatggacagtggaagagctgcatggggagggagaaggtgacagttaaagagtg22320 taggatttctttttgggataatgaaaatgttccaaaattgattgtggtgatgttggcgca22380 actctacaaatataaaaaaggccattgaattgtacgttttaagtgggtgaaacatatggt22440 atgtggattatatctaacgctttttaaaaacttaacacatttcaaagaatagaagtcata22500 cagagtgtgctctactggaatcaaactagaaagaggtaactggaggataacgagaaaagc22560 ctccaaatacttgaaaactggacagcacatttctaaaatcatccgtgggtcaaagatatt22620 catttctgatattcatttttattgtttaatgtatttttaaaaatttcttaagggaaataa22680 aCtgaCtaaaaatgaatatggCtgggtgCggtggCtCaCgCCtgtgatCCCagCaCtttg22740 ggaggCCgaggCtggtggatcacaagatcaggagttcgagaccagcctggccaagatggt22800 gaaaCCCCgtCtCaaCtaaaaaactacaaaaagtagccaagCgCagtggCgggagCCtgt2286~

ggtcccagctacttgggaggctgaggtaggagaatcgcttgaacacaggcagcagaggtt22920 gcagtgagccaagattgtgccactgcacgccagcctgggcgacagagactgcctcaaaaa22980 aaaaaaaaaaaaaaagaatatcaaaatttgtgggacatagttaaagcaatgctgagaggg23040 aaatttataacactaaatgtttacattagaaaagagaaaaagtttcaaatcaatagtctc23100 cactcccatctcaagaacacagaagatgaagagcaaaataaacccaaagcaagcaaaaga23160 aagaaaatataaaaataaatcagtaaaattgaaaacagaaacacaataaagaaaatcagt23220 gaaacaaagtactgattcttcgaaagattaataaaattgacaaacctctagcaaggctaa23280 caaacaaaaaagaaagaagacacggattaccagttattagaatgaaagcataattagaaa23340 caactctacacattataaatttgacaatgtagatgaaatggaetaattactgaaaaaaca23400 caaattaccacaactcacccaatatgaaatagataattgggatagcctgataactactga23460 gaaaattgaatttgtaattttaacactcttaaaacagaaacattaaacttaatattttat23520 aaatattagataaggtaattatacccttccttaacaaataaaaacgacaaattattttgc23580 agctaaagagatgtatgtactgtgaaaaatatcttcagaaaaatagaactttgtttgaag23640 .

aataaggatttaaaaaatgtttttaactctcaagaagcaaatatctgggcccagatggtt23700 tcactgaagaattctaccaaatgtttaatgaagaattaccaccaactctacatagcatct23760 ttgagaaaactgaagagaagggaacatctcccagttcattttatgaagtgggtgttactc23820 tgatactagaactgtataaggacagctactcttgacacactgcctatgggtagctctgct23880 ctgcaggaacagtcagaaaaaaaaaaaaaagaagcactggacaagggcagtataaaaaaa23940 gaaaactgggccaggtgcagtggctcacacctgtaatctcagcactttgggaggctgacg24000 ctggtggatcacctgaggtcaggagtttgagaCtagCCtggccaacatggtaaaaccctg24060 tctctactaaaatacaaaaattagccaggcagggtggtggggaaaataaaaaggaaaaaa24120 aaacaaaaataaactgcagaccaatatccttcatgagtatagacacaaaactccttaaac24180 tccttaacaaaatattagcaagtagaagcaatatataaaaataattatacaccatgatca24240 agtgggacttattccagaaacgcaagtctggttcaacatttgaaaacaaggtaacccact24300 atatgaacgtactaaagaggaaaactacataatcacatcaatcaatgcagaaaaaagcat24360 ttgccaaaatccaatatccattcatgatactctaataagaaaaataagaataaaggggaa24420 attccttgacttgataaagcttacaaaagactacaaaagcttacagctaacctatactta24480 atggtgaaaaactaaatgctttcccctacgatcaggaacaaagcaaggatgttcactctc24540 attgctcttatttaacatagccctgaagttctaacttgtgcaaaacgataagaaagggaa24600 atgaaagacctgcagattggcaaagaagaaataaaactgttcctgtttgcagatgacatg24660 attgtctcatagaaaatgtaaagcaactaggggtaggggggcagtggagacacgctggtc24720 aaaggataccaaatttcagttaggaggagtaagttcaagatacctattgcacaacatggt24780 aactatacttaatatattgtattcttgaaaatactaaaagagtgggtgttaagcgttctc24840 accacaaaaatgataactatgtgaagtaatgcatacgttaattagcacaacgtatattac24900 tccaaaacat catgttgtac atgataaata cacacaattt tatctgtcag tttaaaaaca 24960 catgattttg gccaggcaca gtggctcata cctgtaatcc cagcatttta ggaggctgag 25020 gcgagcagaa aacttgaggt cgggagtttg agaccagaat ggtcaacata gtgaaatccc 25080 gtctccacta ataatacaaa aattagcagg atgtggtggc gtgcacctgt agacccagct 25140 acttgggagg ctgaggcacg agaattgctt gaacaaggga ggcagaggtt gcagtgagct 25200 gggtgccact gcattccagc ctggtgacag agtgagactc catctcaaaa aaaataaaat 25260 aaagcatgac ttttcttaaa tgcaaagcag ccaagcgcag tggctcatgc ctgtaatccc 25320 accactttgg gaggccgagg caggcagatc acaaggtcag gagtttgaga ccagcctgac 25380 caacatggtg aaaccccatc tctactaaaa aatatataaa ttagccaggc atgtgtagtc 25440 tcagctactc aggaggctga ggcaggagaa tcacttgaac ccggaggcag aggttgcagt 25500 gttgagccac cgcactccag cctgggtgag agaacgagac tccgtctcaa aaaaaaaaag 25560 caaaataacc taattttaaa aacactaaaa ctactaagtg aattcagtaa gtctttagga 25620 ttcaggatat atgatgaaca tacaaaaatc aattgagctg gacaaaggag gattgtttta 25680 ggtcagtagt ttgaggctgt aatgcacaat gattgtgcct gtgaatagct gctgtgctcc 25740 agcctgagca gcataatgag accacatctc tatttaaaaa aaaaaaaatt gtatctctat 25800 gtactagcaa taagcacatg ggtactaaaa ttaaaaacat aataaatac't gtttttaatt 25860 gcctgaaaaa aatgaaatac ttacatataa atctaacaaa atgtgcagga cttgtgtgct 25920 gaaaactaca aaacgctgat aaaagaaatc aaagaagact taaatagcgt gaaatatacc 25980 atgcttatag gttggaaaac ttaatatagt aaagatgcca attttatcca aattattaca 26040 caggataaca ttattactac caaaatccca gaaaaatttt acatagatat agacaagatc 26100 atacaaaaat gtatacggaa atatgcaaag gaactagagt agctaaaaca aatttgaaaa 26160 agaaaaataa agtgggaaga atcagtctat ccagtttcaa gacttacata gctacagtaa 26220 tcaagactgt gatattgaca gagggacagc tatagatcaa tgcaaccaaa tagagaacta 26280 agaaagaagc acacacaaat atgcccaaat gatttctgac aaaggtgtta aaacacttca 26340 acgggggaag atatgtctct cattaaaggg tgtagagtca ttgcacatct ataggcaaaa 26400 agatgaacct gaacctcaca ccctacagaa aaattaactc aaaatgactc aaggactaaa 26460 cataagatat acatctataa aacatttaga aaaaggccac gcacggtggc tcacgctcgt 26520 aatcccagca ctttgggagg ccaaggcagg tggatcacct aaggtcagga gtttgagacc 26580 agccggatca acatggagaa gccccatctc tactaaaaat acaaaattag ctggacgtgg 26640 tggcacatgc ctgtaatccc agctacttgg gaggctgagg catgagaatc gcttgaaccc 26700 ggggggcaga ggttgcggtg agccaagatc acaccattgc actccagcct gggcaacaag 26760 agcaaaactc caactcaaaa aaaaaaaaaa aaaggaaaaa tagaaaatct ttgggatgta 26820 aggcgaggta aagaattctt acacttgatg ccaaactaag atctataagg ccagtcgtgg 26880 tggctcatgc ctgtaattcc agcactttgg tcaactagat gaaaggtata tgggaattca 26940 ctgtattatt ctttcaactt ttctgtaggt ttgacatttt tttagtaaaa aattggggga 27000 aagacctgac gCagtggCtC aCaCCtgtaa tcccagcact ttgggaggcc ggggcaggtg 27060 gatcacacgg tcaggagttc gagaccagcc tggccaacat ggtgaaaccc cgtctctacc 27120 aaaaatataa aaaattagcc gggtgtcatg gtgcatgcct gtaatcccag ctactgagga 27180 ggctgaggca ggagaatcac ttgaacctgg gaggtggaag ttgcagtgag ccgagattgt 27240 gccactgcac tccagccttg ggtgacagag cgagactccg tctcaaaaga aaaaaaaaaa 27300 aaagaatatc aaacgcttac tttagaaact atttaaagga gccagaattt aattgtatta 27360 gtatttagag caatttttat gctccatggc attgttaaat agagcaacca gctaacaatt 27420 agtggagttc aacagctgtt aaatttgcta actgtttagg aagagagccc tatcaatatc 27480 actgtcattt gaggctgaca ataagcacac ccaaagctgt aectccttga ggagcaacat 27540 aaggggttta accctgttag ggtgttaatg gtttggatat ggtttgtttg gccccaccga 27600 gtctcatgtt gaaatttgtt ccccagtact ggaggtgggg ccttattgga aggtgtctga 27660 gtcatggggg tggcatatcc ctcctgaatg gtttggtgcc attcttgcag gaatgagtga 27720 gttcttactc ttagttCCCa CaaCaaCtgg ttattaaaaa CagCCtggCa CtttCCCCCa 27780 tCtCtCgCtt CCtCtCtcaC catgtgatct CaCtggttCC CCttCCCttt atgcaatgag 27840 tggaagcagc ctgaagccct cgccagaagc agatagtgat gccatgcttc ttgtacagcc 27900 tacaaaacca tgagcccaat aaaccttttt tctttataaa ttatccagcc tcaggtattc 27960 ctttatagca agacaaatga accaagacag ggggaaatca acttcattaa aataatctat 28020 gcagtcacta aacaaataag aacaagaggc tccagaagtg ggaagccaat acccagagtt 28080 cctacaatac agtatctgaa aagtccagtt tccaaccaaa aaatatatat atacaggccg 28140 gacatggtag cttatgtctg taatcccagc actttgggat gctgaggcgg gcagatcacc 28200 ctaggtcagg agttcgagac cagcctggcc aatatggcaa aaccccgtct ctactaaaaa 28260 tacaaaaatt agccaggcat ggtggtggat gcctgtaatc ccagctactc gggaggctga 28320 ggcagggaat cacttgaacc caggaggcag aggttgcagt gagccgagat cacgccactg 28380 aactccagcc tgggcaacaa agtgagactc cacctcaaaa aaaaaaaaaa tatacatata 28440 tatatgtgtg tgtgtgtgtg tgcgcgcgtg tgtgtatata cacatacaca tatatacata 28500 tatacagaca cacatatata tatgaagcat gaaaagaaac aaggaagtat gaaccatact 28560 ttctgtggtt atgataggat ggggtatcac gggggaagta gacaagggaa actgcaagtg 28620 agagcaaaca gttatcagat ttaacagaaa aagactttgg agtaaccatt ataaatatgt 28680 ccacagaatt aaagaaaagc gtgattaaaa aaggaaagga aagtatcata acaatattac 28740 tccaaataga gaatatcaat aaaggcatag aaattataaa atataataca atggaaattc 28800 cggagttgaa aggtagaata actaaaattt aaaattcact agagaaggtt caacactata 28860 tttgaactgg cagaagaaaa atttagtgag acaaatatac ttcaatagac attattcaaa 28920 tgaaaaataa aaagaaaaaa gaatgaagaa aaataaacag aatctcagca aaatgtggca 28980 caccattaat cacattaaca tatgcatact gagagtaccg gaagcagatg agaaagagga 29040 agaaaaaata ttcaaatgat ggccagtaac ttcctagatt tttgttttaa agcaataacc 29100 tatacaatca agaaactcaa tgaattccaa gtaggataaa tacaaaaaga accacaaaca 29160 gatacaccat ggtaaaaatg ctgtaagtca aaaacagaga aaatattgaa agcagctaga 29220 ggaaaactta taagagaacc tcacttacaa aagaacatca cttataaaag aaccacaata 29280 atagaaacag ttgacctctc atcagaaaca atgaatgata acatatttga agtgctcaaa 29340 gaaaaaaaat aaagattcct atatacgaca aagctgtctt tcaaaaatat acatccaaaa 29400 ggattgaaac cagggtcttg aagagttatt tgtacatcca tgttcatagc agcattattc 29460 acaatagcca aaaggtagaa gcaacccaag ggtccatcga caaataaata aaatgtggta 29520 tatgtataca caatggaatt tattcagtat taaaaaggaa tgaaattctg acacatgcta 29580 caacatggct aaaccttgag aacactatgc taagtgaaat aagccagcca caaaaggaca 29640 aataccatat tacttcactt gtatgaaata cctagggtag tcaaattcag agatagaaag 29700 taaaacagtg gttgccaagg gctgagggag ggagtaacgt ggagttattg ttgaatgggt 29760 acagaatttc agttttgcaa gataaaaaga gttctggaga cagatggtgg tgagggtggt 29820 acaacaatac aaatatactt tatactactg aacagtatac ttaaaaatga ttaacatggt 29880 gaaaccccgt ctctactaaa aatacaaaaa aattagctgg gtgtggtggc gggcacctgt 29940 aatcccagct acttgggagg ctgaggcagc agaattgctt gaaaccagaa ggcggaggtt 30000 gcagtgagct gagattgcgc caccgcactc tagcctgggc aataagagca aaactccgtc 30060 tcaaaaaata aaaaataaaa aaaatttaaa aatgattaag caggaggcca ggcacggtgg 30120 ctcacaccta taatgccagc actttgggag gccgaggcag gcgatcactt gagaccagga 30180 gtttgagacc agcctggcca acatggcaaa accctgtctc tgctaaaaat acaaaaatta 30240 gccaggcatg gtggcatata cttataatcc cagctactgg tgagactgag acacgagaat 30300 tgcttgaacc caggaggcag agattgcagt gagtcgagat cgcgccactg aattccagcc 30360 tgggcgacag agcaagattc tgtctcgaaa aaacaaaaac aaaaacaaaa agcaaaacca 30420 aaaaataatt aagcaggaaa cgagattgct gctgaggagg agaaagatgt gcaggaccaa 30480 ggctcatgag agcacaaaac ttttcaaaaa atgtttaatg attaaaatgg taaattttat 30540 atgtatctta ccacaaaaaa aagggctggg gggcaggaaa tgaaggtgaa ataaagacat 30600 cccagagaaa caaaagtaga gaatttgttg ccttagaaga aacaccacag gaagttcttc 30660 aggctgaaaa caagtgaccc cagagggtaa tctgaattct cacagaaaat tgaagcatag 30720 cagtaaaggt tattctgtaa ctatgacact aacaatgcat attttttcct ttcttctctg 30780 aaatgattta aaaagcaatt gcataaaata ttatatataa agcctattgt tgaacctata 30840 acatatatag aaatatactt gtaatatatt tgcaaataac tgcacaaaag agagttggaa 30900 caaagctgtt actaggctaa agaaattact acagatagta aagtaatata acagggaact 30960 taaaaataaa attttaaaaa atttaaaaat aataattaca acaataatat ggttgggttt 31020 gtaatattaa tagacataat acaaaa_atac cacaaaaagg gaagaagaca atagaactac 31080 ataggaataa cattttggta tctaactaga attaaattat aaatatgaag tatattctgg 31140 taagttaaga cacacatgtt aaaccctaga tactaaaaag taactcacat aaatacagta 31200 aaaaaataaa taaaataatt aaaatgtttg tattagtttc ctcagggtac agtaacaaac 31260 taccacaaat tgagtggctt aacacaactt aaatgtattt tctcccagtt ctggaggcta 31320 aacacctgca atcaaggtga gtacagggcc atgctccctg tgaaggctct aggaaagaat 31380 CCtCCCttgt CtCttCCagC ttCCagtggt tctcagtaac CCtaagtgCt CCttggCttg 31440 tagctatatc attcctagca accagaaaga agaaaataat aaagattatg gcaaaaaata 31500 atgaaatcaa aaggagaaaa atggaaaaaa ataaataaaa ccaaaagcta gttctttgaa 31560 aagatcaacc aagttaacaa accttttaac tagactgaca aaaaggaggt aagactcaaa 31620 ttactagaat cagaaataaa agaggggaca ttactaatga gggattagaa aagaatacta 31680 cgaacaaatg tgtgccaaca aattagaaaa cttagatgaa atggacaggt tcctaggaca 31740 acatcaacta ccaaaattta ctcaagaaga aagagacaat ttgaatgagc tataacaagg 31800 gaagagactg aattgacaac caagaaacta tccacaaaga aaatcccagg cccagaagat 31860 ttcactgtga aattctttca aacttataaa tataaattaa catcagttct tcacaaactc 31920 ctccaaaaaa aagaacagat ctctatttac aggcgatacg atctttagaa aatcctaagg 31980 gaactactaa gacactatga taactgataa acaagttcag caaggctgca ggatagaaaa 32040 ccaatataca aaaatctatt atatttctat acacttgcag tgaacaaccc aaaaatgaga 32100 ttaagaaaat aattcaattt acaataacat caaaaagaat aaaaacactc aaaaataaat 32160 ttattcaagt aagtgcaaaa cttatactct agaagctaca aaacactgtt aaaagaaatt 32220 aaaggtttac ataaatgaaa aactatccca tgttcatgga tcaaaagact tattactggc 32280 aatgctctcc aaattgatct ataaattcaa caaaatcctt atcaaaatcc cagatgaggc 32340 tgggggtggc ggttcatgcc tgtaatccca gcactttggg aggctgaggc acgcagatta 32400 cctgaggtcg ggagctcgag atcagcctga ccaacatgga gaaaccctat ctcttctaaa 32460 aatacaaaat tagtcaggcg tggtggcaca tgcctataat cccagctact cgggaagctg 32520 aggcaggaga atcgcttgaa cccaggaggc agaggttgca gtgagccaag atcgtgccat 32580 tgcactccag cctgggcaac aagagcaaaa ttccatctca aaaaaaaaaa aaaaaaaatc 32640 ccagatgact tcactgttga aattgaaaag attattctaa aattcacatg gaattgcaag 32700 accttgagaatagccaaaacaaacttgaaaaacacgaacaaaatataggatgactcactt32760 gccaattgcaaatgttacgacacagcaacagtaatcaagactgtgtggtactggcaaaag32820 acacatacatacatacatatcaatggaatataattgagagtacagaaacaagcctaaaca32880 tctatggtaagtgcttttctatttttttctttttttttttcttttttgtagagatagaat32940 ctcaccatgttgcccaggctggtcttcaacttctgggctcaagcaatcctcccactgtgg33000 cctcccaaagtgctgggataactggcatgagccaccacatccagcccagatgattttcaa33060 aaaagtcaacaagaccattcttttcaacaaataggtctgggatgatcagatagtcacatg33120 aaaaaaaaaatgaagttggaccctccatcacactaaagtgctgcgattataggcatcagc33180 caccacatccagcccaaatgattttcaaaaaggtcaacaagaccattcttttcaacaaat33240 aggtctgggataatcagatagtcacatgaaaaaaaaaatgaagttggaccctccatcaca33300 ccatatgcaaaaattaattcaaaaatgaattgatgacttaaacgtaagagttacgactgt33360 aaaactcttagaaggaaacatacgggtaaatcttaaagacgttaggtttgacaaagaatt33420 cttagacatgacaccaaaagcatgaccaactaaggtaaaatagggtaaattgtacctacc33480 aaaatgaaaaacctttgtgctggaaaggacaccatcaagaaatggaaagccaaaatagcc33540 aaggcaatattaagcaaaaagaacaaagctggaggcatcatactacctgacttcaaagca33600 acagtaaccaaaacagcatggtactagtagaaaaacagacacatagaccaatggaacaga33660 ataaagaacccaaaaataaatccacatatttatagtcaactgatttttgacaatgacacc33720 ccttcaataaatgatactaggaaaactggatatcgatatgcagaagaataaaactagacc33780 cctatctctcaccatatagaaaaatcaactcagactgaattaaagacttgaatgtaagac33840 ccaaaactataaaactactggtagaaaacataaggaaaaacgcttcaggacattggtcca33900 ggcaaagatcttatggctaaaacctcaaaaacacaggcaacaaaaacaaaaatggaaaaa33960 tagcactttattaaactaaaaagctcctgcacagcaaaggaaacaacagaatgaaaagac34020 aacctgtagaatgggagaaaatatttgcaaactatccatccatcaagggactagtatcca34080 gaacacacaagtgactaaaaCaactcaacagcaaaaaagcaaataatctggtttttatat34140 gggcaaaagatctgaataaacattctcaaaggaagacatacaaatgtcactatcattctg34200 ccagtaccacactgtcttgattacttgttagtgtataaatttttaaattgggaagtgtga34260 gtcatcctacactttgttcttgtttttcaagtttgttttggctattctgggagccttgca34320 agtataaaatagccaacaagtatgaaaaaatgctcaccatcactaatcatcagagaaata34380 aaaatcaagaccactatgagatatcctctcactccagttagaatggctactatcaaaaag34440 acaaaatataatggatgctggcaaagatttggagaaaggggaactcctatacactgtggg34500 tagggatgcaaattggtaatggccattatggaaaataatactgaggtttttcaaaaaact34560 gaaaatagaactaccatatgatccagcaaccctactactgggtatttatccaaaggaaag34620 aagtcagtatactgaagaaatatatgcactctcatgttaattgcaacactgttcacaaca34680 gccaagacagggaataaatctaaatgtgcatcaacagatgaatggataaagaaaatgtgg34740 catatacactcaatagaatactattcagccattaaagaagaatgaaatcctgtcatccca34800 gcaacatggatgaacctggaggacattatatttaatgaaataagtaaagcacaaaaagat34860 aaacagtacatgttctcactcagacatgggtgctaaaaagaaaatggggtcacagaatta34920 gaaggggaggcttgggaaaagttaatggataaaaatttacagctatgtaagaagaataag34980 ttttagtgttctatagaactgtagggcgagtatagttaccaataacttattgtacatgtt35040 caaaaagctagaagagattttggatgttcccagcacaaaggaatgataaatgtttgtgat35100 gatggatatcctaattaccctgattcaatcattacacattgcatacatgtatcaaattat35160 cactctgtacctcataaatatgtataattattacgtcaacaaaaaaaggaaaaaaaagaa35220 aattaagaeaacccacataatggaagaaataaaatatctgcaaattatatatatctgata35280 aatatttaatatttataatatataaagaactcctacaactcaagaacaacaacaaaacaa35340 cccaattcaaaaatgggtaaaagccttgaatatacacttatctaaagactatatacaatt35400 ggccaataaagacacgaaaagatgctcaacatcactagtcatcagggaaatataaatcaa35460 aaccacaatgtagaatgtagacaccacttcatatgcactaggatggctagaataaaaagg35520 taataacaaatgttggtaaggatgtgaaaaaatcagaaacctcattcgctgctgttggga35580 atgtaaagtgatgcagccactttggaaaacagtctggcagctcctcaaattattaaatac35640 agagttaccgtatgacccaggaatattcctcctgggtctataaccaaaaaaatgaaaaca35700 tatatccacataaaaacttgtacatgggcatttatagcaacattattcataacagcaaag35760 gtggtaagaacccatatgcccatcatctgatgaacaggtaaataacatgcggtattatcc35820 atacactagaatattatctgcccatacaaggagtgacatccagctacatgctacaaggat35880 gaatctcggaaaccttatgctaagtgaaagaagccagtcacaaatgaccacagattatga35940 ttccatgcatcggaaatgaccagaatagggaaatctatagagacagaaagtagattagtg36000 gttgggtggggctgggaggacaggtagtacactactttcccagaactactggaacaaagt36060 accacaaactggggagcttaaacatagaaattgatttcctcacagttctggagactagga36120 ctctgagatcaaggtgtcagcagagctggttctttctgagggccctgaggcaaggctctg36180 tcccaggcctctctccttggctggcaggtggccatcttctCCCtgCgtCttCaCatCatC36240 ttttctctgtgtgtgcccatgtccaaattttgattggctcattctgggtcatggccaatt36300 gctatgcacaaagtgaagtctacttccaaaagaagggaagagggaacactgactaggcta36360 aacttatagtcattttaatgtccgcttttcctatgagattgtgaacacacagaagtaggg36420 tttttatctacattgtgcaaagtttaataagaaaaatagaattcaagagaagcagttcaa36480 tagcaggaatttaatatgggaactaattacaaggtttagggcaggactaaaaagccagtt36540 gggatggtgagccaacccagagattagcaacagtgggaccccatctacctaccacccatg36600 _21_ aagctggaag gataaaggag gggctattat cagagtccac aagccagtgt cagagtcctt 36660 ggctggagct gggaccaccc tagagacact gtgcaaagca gaaaacaagg gggaaaaacc 36720 ctgacttctc ccttcctccc acctttcaat ctcccactag tgcttcctac tagccatact 36780 tggccagaga cagtgacaag gaacactgca aaatgaagtt tgtaggaatc atctccctct 36840 gagacagaga aatatggaag ggtagaaaat gaatcagagg ataaagagaa aaaaccctga 36900 gtactatctt atttatcttt gtatctccag tgcctaatct gtctctcaaa aaaggaaagc 36960 aattgagaga aactgaaaac tccaattgaa atgaaagaat ggagaattac tggactagaa 37020 gagaagagaa aaatttattc cgcatagagt aaacaagaat ggattcacaa aggacgtgat 37080 gaatgaaaag ctataatcag caaagatttg ccagagaaat taaaaagtgg taaactcagc 37140 cacgctgtac aacctgaagg cacaatgcat gaaaacgttt caagaaatga caagatttga 37200 agtcaaattc taagtgcttt tccagaatct ctcaagacga ttatatagct accccatttt 37260 attaaataaa atggaaactt actaaacttt ccccttgtat taaactaaca tatgtcctaa 37320 tagcaaacga ttctggaatt cctagagtaa aatatatttc gtcaaagtgt attgctcttt 37380 taatattctg ctgacctcct tttgctattt aggatatttg tatacacatc acacgtaaat 37440 ttggtctata gtttacatct acgggcttat actgttcttt ttttcatttt tttaaaattt 37500 ccaaccccca gtatccatat actgctctct atcagggtta ttttaacttt gtaaaatcag 37560 ctgagatgct ttccatgttt ttttttttta ttttctgcca catttgaata gcataggagt 37620 taccaccatc aaccttggat tatttaagca ttcacgattc cacgtgtgga ttttttattc 37680 agagtctttc ttgtcattcc tgctatcagc acagaaccca atctcagctt tccagctata 37740 ctctcacccc atggaatttg cagatgaagt tcaaaaggac ctttgcatta tcctgcctcg 37800 ccctcttccc ccttcattta gacatcacct tcttctagaa cgtcttacct gacatgccct 37860 gctcccaacc cctgctgccc aattgtgtgc tctcccgtgt cctggcctgc catcctcttt 37920 agtaattgcc tgctccctca tctgtctccc cacccagaca ttaagctgaa tagactggat 37980 ttgtgtcttg tccatcacta taatctcagc acctagtacc tagtaggtac ttaccatgta 38040 ttcattagca aaatgttatg tataaccttg caccttaaaa acaagagaag gaagacaaaa 38100 ttaagtctta agactatggt ttagaacatg gatcagaaac tacagtctgc agcccaaatc 38160 cagaccaaat gaagagacca tgttcattta catacaacct atagcagctt tcacactaca 38220 ggagcagagc taagtagttc caagggaaca cacggccctg caaagcctaa aatatttact 38280 ctatagctct tcacagaaaa agttttcaga tccctcgttt agaactcttg ttcatatgca 38340 atttcactaa accatagttt tttgggtttg tttggttttt tttggcaaaa aggaatgagc 38400 cgatccagaa aaggttgaaa agaatgaatc attactgctg aaagaatgtg cacacagtcc 38460 gtcagtattc tgctgccatg CtgaCaCCCa tccaatagtg tcatgagatg cagcagctac 38520 tactgtgttc tcaatgccga gtccacccac tccataacca tgtccaagca atcttgggaa 38580 catcatcacc atgcttgttt atccttaagg tattgcctca catacagcag tggctggtca 38640 taaagtcaaa tgacactagt ggccaggagg tcaagagaat gagtgaggac aggtgggtag 38700 gCagCCCagg ccctagcaac agcaggagct cacccctcag tcactctagc caggactgaa 38760 atacttttca ccctttcaag agagactagg aatctggatt tttatgtgaa atatcttgat 38820 tactaaatgt tgtcaacaga catgtcaaaa ggtaaaacta agtaagttca tggggcagat 38880 tgactattca ggttatagaa ttaaggattc ttatccaaca cagataccaa ccaaaaagct 38940 gacgtataac atattaggag aaactatgtg cactgtcgaa acatcaacaa ggggctaatg 39000 tctaaaatag tctatattgg attccagttg aaacatgggg aaaggacatg aacaggcaac 39060 ttatgtcaat ggaaactcaa aaagataaca agcatatata aaagcattct caaattcagt 39120 agtaaacaga cagatgcaaa taaaaagagg gaaactgctg ccgggcacag tggctcacac 39180 ctgtaatccc agcactttgg gaggccgagg cgggcggatc atgaagtcag gagatcgaga 39240 ccatcctggc taacatggtg aaaccccgtc tctactgaaa acacaaaaaa ttagccaggc 39300 gtagtggtgg gcaccagtag tcccagctac tcaggaggtt gaggcaggag aatggcatga 39360 acccaggagg cggagattgc agtgagccga gaccatgcca ctgcactcca gcctgggcga 39420 ctgagtgaaa ctccatctca aaaaatataa taataattat aattataata ataataaata 39480 gtaaataaat aaaaagagag agactgctaa agtctagaaa gttgaatgat gccaagcgca 39540 tgcaaagatc agggccttgg gatggccggg tgcagtggct cacgcctgta atcccaccac 39600 tttgggaggc caaggcgggc ggatcatgag gtcaagagat caagaccatc ctggccgaca 39660 cagtgaaacc cggtctctac taaaagtaca aaaaaatata tatatatata tatattatta 39720 tattatatat atatatatca gagccttggg aatccttgtg tgctgctggg gaaggtagtg 39780 gtgcagccac ccttgacagc aatctggcag tacttggtta tattaagtat aggcacacac 39840 cacgaccagg cagtcctact cctgggtcta aatcccaaag aattctcaca caagtccata 39900 aggagacatg tacgaggctc attcagcatt actgggagtg ggaatcaacc tgggtgtcca 39960 tctacaggag acgagatgga caaaatgtgg tggatattaa gaccagaatc accaagtaac 40020 agagatgggt ggtgagtgac aatcctaaga tacagaataa aggctagaac atgatgccat 40080 tcatgtaaat taaaaataga tgcacacaaa gcagtatacg cgtgaccctt gaatagcaca 40140 ggtttgaact gcctgtgtcc acttacatgt ggattttctt ccacttctgc tacccccaag 40200 acagcaagac caacccctct tcttcctcct ccccctcagc ctactcaaca tgaagatgac 40260 aaggatgaag acttttatga taatccaatt ccaaggaact aatgaaaagt atattttctc 40320 ttccttatga ttttctttat ctctagctta cattattcta agaatatggt acataataca 40380 catcacacgc aaaataaatg ttaattgact gtttatatta tgggtaaggc ttccactcaa 40440 cagtaggctg tcagtagtta agttttggga gtcaaaagtt atacacagat tttcaactgt 40500 gcaggcaatc agttcccctg accccctcat tgttcacggg tcaactgtat atacacaaaa 40560 gtattatatg aacctcatta gaatagctgt ctatagggag aagagaatga gagtgggata 40620 aaacggaatg aacaaataaa ccaacaaatg cattaacaag caaaacaaca gaggggcttg 40680 catgggccag tgatgataaa gggctaagaa tgagaatata attaattcaa ttcctcacac 40740 ctgaggtcta aaaccaagga aagggagggc caggcgtgga ggctcacgcc tgtaatccca 40800 gcactttggg aggctgaggc gggcggatca caagattagg agtttgagat cagcctggcc 40860 aacacagtga aagcccatct ctacaaaaaa tacaagaatt acccaggtgt ggtggcacat 40920 gcctgtagtt agctactctg gaggctgagg caggagaatc acttgaaccc aggaggcgga 40980 ggttgcaggg agccgagatc acaccattgc actccagcct gggtgacaga gtaagactct 41040 gtctcaaaaa aataaaaaaa ataaaaaaac agagaaaggg aggaaactag atccaggctg 41100 actagataca gcctttagag ttagaaaaga tgatttgaca atctaagccc acactcagat 41160 tgaatgaaat tgaaaagcct ttcaaactaa aacatttaat tacaccatct gctgcagaca 41220 gaactcagac aactcaaaca ggtaatgtca gcgtggtgtt ttatatcacc accctcaaca 41280 cagaataaaa atcagctgca tgtgaagcag tgactagaat gaagaaaagg ctgcttctta 41340 cttccttcta gtggttcttt ccgaaaacat taataggcac cagctctatg catgtcaccc 41400 tgcagggaga catggggtat ataactatga cttactgttc attcctcaag gaattcccaa 41460 tcttgtggaa gattatacac aatgaggcaa caaaaactat ccaataaaac cacggaaaag 41520 aagccagtga caaagaagcc agtgatgaaa ggccctgtga gcagagctga tggccatttg 41580 gggaagaaag accaacatgg atgggggtga tcagggtggc tccgtgggaa agctggaaga 41640 gaagtggcag atctctgagc tggatgatgg gccactacca tctgtatatg gctaattaaa 41700 gaccatgtgt ggatttttta ttcagctctt tcgtgtcatt cctgctatca gcacagaacc 41760 caatctcaac tttccagcta tattgagcta aacttctcac ctcatggaat ttgcagataa 41820 agttcaaaag gatccttgcc ttttcaaaat aattttgaat ggttgagtag tccctctgtg 41880 ctctctcact gacaccctct caaggctgct gagcacgtgc catgctatgg ctttctccaa 41940 catcaggaaa tgttctccac tcagtttcac cttaatacaa atgtgttctc tcttcagaga 42000 aggcaaaaaa attcatgacc atctgactgg gagaagtcat ttctaggtaa agtgtccatc 42060 tttttctgag gaacacagga ggaaaatctt acagaaaaga gttaacacag caggcctaag 42120 actgcttttt aaaataaata aataaataaa taaataaata aataaataaa taaataaata 42180 aataaatgaa tgatagggtc ttctgtattg gccaggctag tctcaaattc ctggcttcaa 42240 gagatcctcc caecttggtc tcccacagtg ttgggattat agacatgagc cattgtgctt 42300 ggcccaagac tgttattctt aaaaagtetc ataaaaagca tggttaatcc ttggctggca 42360 cctgggaact tagatttcag aagggttccc accatccaaC ctggaaagag ggactcactg 42420 tgcctaaatt attgtgtggt ttatgctgaa ctcctgcttt tcttcaggta gcgtggaatg 42480 tggtatgtgc tgggcaaagg gggcctgcat gaccagcccc caataaaaac cctgggtgtt 42540 gggtctctag tgagtttccc tggtagacag CatttCaCat gCgttgtCa.C agCt CCttCC 42600 tcggggagtt aagcacatac atcctgtgtg actgcactgg gagaggatgc ttggaagctt 42660 gtgcctggct tcctttggac ttggccccat gcacctttcc ctttgctgat tgtgctttgt 42720 atcctttcac tgtaataaat tacagccgtg agtacaccac atgctgagtc ttccaagtga 42780 accaccagat Ctgagcatgg tcctgggggc ccccaacaca gaaataaatt ataaaagacc 42840 aaggactggg catggtggcc catgccggta atctcagcgc tttgggaggc cgaggcagga 42900 ggaccagtta agcccaaaag ttcaaagtta cagtgaccta tgactgcgcc aatgcactct 42960 aacctgggag acagagcaag accctgtccc caaaacaata aactaaacac atacttctgc 43020 cttccaagtg tcttaaaatt caatggaatg gtagaaacat ttttaaaaca ctaaatcaaa 43080 agaaacctgg aaaacaagag tgccgatggc caactaaaat gtctaggaaa tttctgaaaa 43140 gtaaaaagta ctcagaacca gattacctga gcaaaccata gcccaataca agcttgggag 43200 gaggctgtta tgcagaagga aatggtaaca ggtttccagg aacagacttg taacagcaga 43260 tagaacagca gaggtagaac ctgacaaggt gattacctgg ggaactgcag tctgaatgac 43320 caggactgtt ggacccttcc cctcacatgg aatacacacg ccactcagca gcacaccaca 43380 gctcttcaac aatcacagga ggcacgctac gcctagtaag acaggaaaaa aggaattctc 43440 aaacttcgaa gatgaacaca taaagaatca ccaagttttt attcagtatg atgaaacagg 43500 gacactgaat caacagaaca caaacccaag caaagataat tactagagca catagaagaa 43560 attattagat attcttggga agacctaagg ggacattata aagagcaagc agttggtatg 43620 tgacgatctt tgtgatatac caagaaataa aaacacagga tgaagaccag atagagaata 43680 atgctactat ttgtgcaaaa aaggagaaat ggagaatctg attcatattt gcttgtattt 43740 gcatgaagaa actttggaag gtacataagt aactaacaac aatggttacc tacttgtaag 43800 gcgagagaag taagaggaca ggaatggtgg gaacaccttt tgtgtccgga attggtgggt 43860 tcttggtctg acttggagaa tgaagccgtg gaccctcgcg gtgagcgtaa cagttcttaa 43920 aggcggtgtg tctggagttt gttccttctg atgtttggat gtgttcggag tttcttcctt 43980 ctggtgggtt cgtagtctcg ctgactcagg agtgaagctg cagaccttcg cggcgagtgt 44040 tacagctctt aagggggcgc atctagagtt gttcgttcct cctggtgagt tcgtggtctc 44100 gctagcttca ggagtgaagc tgcagacctt cgaggtgtgt gttgcagctc atatagacag 44160 tgcagaccca aagagtgagc agtaataaga acgcattcca aacatcaaaa ggacaaacct 44220 tcagcagcgc ggaatgcgac cgcagcacgt taccactctt ggctcgggca gcctgctttt 44280 attctcttat ctggccacac ccatatcctg ctgattggtc cattttacag agagccgact 44340 gctccatttt acagagaacc gattggtcca tttttcagag agctgattgg tccattttga 44400 cagagtgctgattggtgcgtttacaatccctgagctagacacagggtgctgactggtgta44460 tttacaatcccttagctagacataaaggttctcaagtccccaccagactcaggagcccag44520 ctggcttcacccagtggatccggcatcagtgccacaggtggagctgcctgccagtcccgc44580 gccctgcgcccgcactcctcagccctctggtggtcgatgggactgggcgccgtggagcag44640 ggggtggtgctgtcagggaggctcgggccgcacaggagcccaggaggtgggggtggctca44700 ggcatggcgggccgcaggtcatgagcgctgccccgcagggaggcagctaaggcccagcga44760 gaaatcgggcacagcagctgctggcccaggtgctaagcccctcactgcctggggccgttg44820 gggccggctggccggccgctcccagtgcggggcccgccaagcccacgcccaccgggaact44880 cacgctggcccgcaagcaccgcgtacagccccggttcccgcccgcgcctctCCCtCCaCa44940 cctccctgcaaagctgagggagctggctccagccttggccagcccagaaaggggctccca45000 cagtgcagcggtgggctgaagggctcctcaagcgcggccagagtgggcactaaggctgag45060 gaggcaccgagagcgagcgaggactgccagcacgctgtcacctctcactttcatttatgc45120 ctttttaatacagtctggttttgaacactgattatcttacctattttttttttttttttt45180 tgagatggagtcgctctctgtcgcccagactggagtgcagtggtgccatcctggctcact45240 gcaagctccgcctcccgggttcacaccattctcctgcctcaacctcctgagtagctggga45300 ctacaggcaatcgccaccacgcccagctaattttttattttattttttttttagtagaag45360 cggagtttcaccatgttagccagatggtctcaatctcctgacctcgtgatccatccgcct45420 cggcctcccaaagtgctgggattacagacgtgagccactgcgccctgcctatcttaccta45480 tttcaaaagttaaactttaagaagtagaaacccgtggccaggcgtggtggctcacgcctg45540 taaccccagcactttgggaggccgaggcgggcggatcacgaggtcaggagatcgagatca45600 tcctggttaacacagtgaaaccccgtcgctactaaaaatacaaaaaattagccgggcgtg45660 gtggtgggcaccggcagtcctcgctactggggaggctgaggcaggagaatggcgtgaacc45720 tgggaggcagagcttgcagtgagccgagatagtgccattgCCttCCagCCtgggcgacag45780 agcgagactccacctcaaaaaaaaaaaaaaaaaatagagacccggaaagttaaaaatatg45840 ataatcaatatttaaaaacactcaagagatgggctaaagagttgacggaacaaatctaaa45900 tattagattggtgacctgcaaaaccagcccaaggaacatcccagaatgcagcccataaag45960 ataaagagagcatttccgctgggcacagtggtatggcaggggaattgcctgagtccaaga46020 gttgcaggtcacattgaaccacaccattgcactccaggcctgggcaacacagcaatactc46080 tgtctcaaaaaaaaaaaaaattaaattaaaaaagacagaatatttgagagaaaaaaatgc46140 ttatttcaagaaacatgaaagataaatcaagatattctaattcccaagtaagaataattc46200 cagaagcagaaaatagaatagaggcaaggaaacactcaaaacttctccagtgccatagaa46260 atgtgtattaatctttagaatgaaacggactaccaaatgctgagcaggaagaacaaaaga46320 gatccactcttaagccagtgtggtgcccaagcgcagtggctcatgcctgtaatcccagca46380 ctttgggaggccgaggcaggtggatcacctgaggtcaggagtttgagatcagtcaggcca46440 acatggtgaaaccctgtctgtactaaaaatacaaacattagctgggtatggtggtgcaca46500 tCtgtaatCCCaaCtaCttgggaggCtaaggCaggagaatcacttgaaaccaggaggtgg46560 aggttgtagtgagccgagatcatgccacactcccagcctgggtgacagagcaagattcca46620 tctcaaaaaaaaaatccactcctagacaaataatagttaaattttagaacaccaaggaga46680 aagaaaaaaaattgtaaagcttcagagaaaataaacattaactacaaagaaacgagagtc46740 agacgcgtgcacttcttcctagataccagcagataaagcaatatctccaaaattcagaag46800 gttttaacgtagaatcctatacccagtcaagaatattcacatggaaaagtgaaataaaaa46860 acattgtttaaacatgcaagggttcagaaagtttaccattcacagaatccctgaaaacaa46920 aaccaaataatcacttaaggactcattaagaaaacaaatgaaataaaagcaccaatgatg46980 agtaaataatcagaaaaatttacagtttacctaaataactgtttatgcataatgtatgaa47040 aacccaaaaatttaatatgggacagaattaaaatcatgataagattcttttttgctttac47100 tcatggagagttcacataaacagattatcttttaatagcaagagaaaaaaatgtttagat47160 atgtgtgaaaaactaagggtaccaaaacagtgcaaattcatttatcatcaggaaaatcca47220 aattaaaaccacagtatccaccagaataactaaaaggtaaaagacagaaattaccaagag47280 ttggcaagaatgtggagcaaccacatatacttctggggtaaataagttggtgcaaccggt47340 actgaaaactgtttgctagtatctactaaaaccgagcacatgcacagactacaaccaagc47400 agttccactcccagatacacactcaacagaaatgcacacactcactcaacaaaagacgtg47460 tactagagtgttcatgtacttactattcataatagtccaaaaatgcaaacaaccaactgc47520 caatcaaagtcaaatgtatatctatattagggatatatacaatggcatatacacagcaat47580 gagaatgaaatgaaccagctcggcacagtggttcatgcctgtaatctcagcactttgggc47640 gggtaaggcaggcagatcacttgaggtcagaaatttgagactagcctggccaacacggtt47700 aaaacctgtccccactaaaaacacaaaaattagccgggcatagtggttgcaggcctgtaa47760 ttccagctactcgggaggctgggttgggagaatcgtttgaacccgaaagccggaggtcgc47820 agtgagcggagatcgtgccactgcactccagcctggacgatagagcaagactccgtctca47880 aaaaaggaaatcaaaaatataaaataagatgacaggaataatccgcaaaagatcagtaat47940 caaaataaatataaatgggctaaagctacctattaaaagacaaagatttcacacccataa48000 ggatagctactatcaaaaaaagagagagaataacagatgttagcaaggatgtatggaaac48060 tgaaattctcacgcattgctggtgagaatataaaatggttcagcctctgcggaaaacact48120 atgctgggtcatcaaaaaattaaaaatagaagtactacttgatccaacaattctacttct48180 gggtatatacccaaataactgaaagcagggtcttgaagagatatttgtacacccatgatc48240 atggcagcattattcataatagctatgatgtggaaccaacataaatatcctttgataaat48300 atatggataagcaaaatgtggtgtatacattcaatggaatattaattagcaataaaaatg48360 aagaaaattctgacacatgctacaacatggatgaaccttgagggcattacattaaatgaa48420 ataagccagttataaaaagacaaatactatatgaggtactatattagatactcatgcaag48480 gtacctaaaataggcaaattcatagagacaaaaagcagaatggtggttgccaggggctgc48540 ggtaatggatacagagcttcaattttgtaagatgaaaaaattctggagattggttgcata48600 acaatgtgcacacacttaacactggggaactgtaaacttaaaagtagtaaatggtaaaaa48660 taaaaataataaataataaattttatgttattttaccacaatatttattaaaagacaaag48720 attaactaattaaacaaaatccagccataagctaatggtaagagtaacaattaaagaaga48780 cacagaaaattgaaaatcagtgactagaaaaagatattccatataaatgctaacaaaaag48840 caagtacagcaatataaagagaatgaacaaaaaaaaaattaaataagatggctcgtttat48900 tcccaaaaggtacaattcaccaagaagatacaagaattgtgaacctttaagcacataaaa48960 cagcttcaaaaatacaacatttaaagaaaaatatatattaaacatagaaatagtacaaaa49020 acccctacaagaatcataatgggagtcttcaatacaactctccatatcaacaggtcaaac49080 agagaaaaaaaataagttaaggatgcagaaaacctgaattaccatcaataaacttgagat49140 taatatagaactgtatacccaatatactaagagttcagggaacagtcgtgactgacagtg49200 gactgcaaattaatctgttcttaatctttgtttttctttcagcactgtggcagaatagag49260 atcctaaaaaccttccagctacaaaacatctttttaaaaatataaaaaaatacaaaaata49320 actctgaaatcaatagaagacacatggtgaaaccaaaattctagaatacagggagaataa49380 aggcattttcagatattacaaaaacagaaaattgatcattgctgaagtaatttctaaaga49440 atgtacttgagggagaagaaaaatgttccaaagaaaagtatctgtgatacaagaaggaat49500 ggaaagtgaagaaatggtaaacaggtagataaagctaataaatgttgacctagaaaataa49560 caaaaacaatagcaataatgtctcgttggaagggttgaagtaaaaatacaattaaggcca49620 aatgtgaggtaagtggaatgaaagaattagaagtccttgccttgttcacaggactgatta49680 aataaatgagccaggttttccattcaaacagttaaaacttgaacaaaataaactcaaatt49740 aagtagaaagataaaaaacagaaattaatgtcatagaaaaataaaaaatcaatagaatta49800 atcaataaatcctggttaataaaagctggttctttgaaaggattaataaaataatcatta49860 agcaagtctgatcaaaaaaaaagagaaaaggtaccaaaaaaagtactgtatcagaaagag49920 aacatacagatacatacagatatgtaagagtctgttttcttacaccagaatactatatac49980 aacattatgctagcatatattaaatttcaataatgttaatgattttctaggaaaacagaa50040 aatattaaatttactttgaagaaacagaaaaactgagaaaaataaatgatcatgaaaaaa50100 atgaaaaggtaattaaatactgatattaactgcctaaacaacaecagcagcagcccaggc50160 agtctgcagtcaagttctgccaaacttgagggaacagataattcttctattccagagcat50220 agaaaatgatggaaagtttcccaatttaatcagagaggacagcctgatccttgttatgaa50280 cacagataaaaatggggtaaactatatgccaaactcagataccaaaaccctaaataagat50340 gctagcttattgatgtgaacaatccaaaagtgcattttaaattagcccagggttttagag50400 aaagaaaatctagcaatgtgaCCa.CCaCttatgttaacaattttaagacgaaaatctaca50460 tgatcatatcaatgcatgctacacaaaagcatttgggcaaaaaacccaacacccaccctt50520 gactttttaaactcttagtaattaggcataaacagaaatgtacttaatgtgatagaatac50580 actcggtgaagatacagagggaatgctccctaaaaccaagcccaagacaaagattcctat50640 ttaacctcaatagtcaacactgcagcgagagtaatctatggaagacaaggaaaaaagtaa50700 aaacatgagagacatctgttgtttaacagacaataagatcacctacttggaagaggcaaa50760 cgaatcaagcgaaaaactattaaaactgagacaggctttagtatggaggctcagcttcag50820 ctgtagtttgggctaccaaattcaactcgcttgcttggagagttaatcctgcaaagctaa50880 tttctgttgaggtattaggattgacaagcctgtgCtCCtCCCtCCtCCCCCatCttCaaC50940 actgaaataacacggtgtttggaactggataacagaatcttccaaaaacaaaaattgtcc51000 tgaagggctgaCttgtgCCCttaCtCaaaaaaCaCtttatCtgCtgCCtgCagCtCCtaC51060 agttgctggtggataagcctgccaaccagctcggcgtaattcttcctgcagagggcaagg51120 aagagcactttcacaggaaaatttttttccgaactgtatgccgcttattacataaactta51180 cgtgctggcaaatggagctccagcaaaataagatattcagagtcaaacttccttaggaaa51240 aaaaaaaaaaaaaagcaagcacataacactaatttccttgcatgggcactggggaaggag51300 gtCgttaCttCCgCaCgCCCgCaggtCCgCaCCa.CCgggaaaCCCaCgggcaccgcgcgc51360 tgcccccgggccttccaggtgcactgcgccgcggcgccccagctgacccgggatgcgcag51420 ccctagcccttcccctgtcaccccggccaggaaggggcgggagcgcggcggacgccgagg51480 gcgaagggcttctcggtcctctgcaccacgcagcacccccaaggcacaacagggagggtg51540 cgggaggctcccgagacccaggagccggggccgggcgtgcccgcgcacctgtcccactgc51600 ggcgagggctggggtcgcctccagggccgcagctgtcgggagccacctggctctcagtcc51660 cgggtccctgcgacaaccctcgggcccggaggggaggaggcggccacctgccgctgccac51720 ctgcggcaccggtcccaccgctccgggccgggcaggacaggccaggacgtccctcctggg51780 ctggggacaggacacgcgacgaggggaccggggcccccgcggcgaagacgcagcacgcct51840 tcccagaaaggcagtcccgtgcccccacgacggactgccggacccccgcgctcgcccgcc51900 catcccttcagaccacgcggctgaggcgcaaagagceggccggcgggcgggctggcggcg51960 cggctagtactcaccggccccgctggctcagcgccgccgcaacccccagcggccacggct52020 ccgggcgctcactgatgctcaggagagggacccgcgctccgccggcgcctccagccatcg52080 ccgccagggggcgagcgcgagccgcgcggggctcgctgggagatgtagtacccggaccgc52140 cgcctgcgccgtcctccttcagccggcggccgggggccccctctctcccagctctcagtg52200 _25_ tctcatctccctatctgctcatcctctggtcgcacataatcgatgtttgggcgtcccaag52260 ccagatgtggaccccatttccgcactctacactggaggttttctaagggtggtgcccgga52320 ccagcagcttcagcctcatctgggaacttgagaaaatgcagattctccgtcccacccagc52380 ctattcggtttttcctgcactaaaaccatgaaggtggggcccagcagtccacattctcgc52440 aagcccgtcaagtgattctgaggcgccctccagtttgagagctatgctcacggcctcacc52500 tccgccccgcaaggagcccggtcttgcctgtggcgctagccgcacacggacacctcatcc52560 tgcggggcccgcccccccgctgcaccctcaccgcccaacgcctcctccgggatgcagcgg52620 aggcgcctggaagtcggcaaggtcaacatccccctcagcatCttCCCtaCCCtCaCggCt52680 CCtCCtCCaggggtgCCtCatggccaggggttagaaagagccactgtgtttcttgacatg52740 gaagtggcctaagaccttaatgaaaactgcaggagtggaatgacagaacctttggtcata52800 cttgagggcgtgaagctcaaatgaggaggaaggaaaggatccagggagaataaccaaccc52860 tggcaagttgtggcgcccaggtagaggggcgagcctaggctagcggttctcgaccagggc52920 cggtgttgcccctcctcgccgccccgcgtacatttggggaggtctggagacatttttggt52980 tgtcatgatgcgggagttgctactgttgcctaagtgggtagacacgagggtgctcctcaa53040 catcctacctgaaggacaggactgccccacaaggaagaatgatccggccccaaataagaa53100 accctgggctggtcagcaacaacccctttgttctgagaagagaggaggaaagaataaaag53160 aagtggggtgaagttttggtttggtagaggaaacttgaagacattttcactggaaaggaa53220 gagaggaagaggagggagatgtctgtaaggacgagcaaaccgggtgacagctgatttcct53280 catattgaagtaatgagtcctagttataataaattcctaataaaaacccagtttatccct53340 gcaataaacttgtcttttttttttaaatatactgcttgattctgtttgctaatattttat53400 ttacaggctttgcattgatatgcaaaaatgagatgggcaataattttctttttgaatgtc53460 taatgttgtttggtttcagaatcaatgttatgctcacatcataaaaaatttggaaccgag53520 gcaggaggagtgcttgaggccagaagttcgagaccagtctaggaaacacagtgagacccc53580 cccatctctacaaaaaaaaaaaaagaaaaaaaaatgggcatgtttgctttttccttttac53640 tctgaacaatttaaggagcattaaaattatctattctttgaggtttgatcatttcccagt53700 taaaaatgttcctcccagcctgatgctttctttggggagggtaaatcttttaaggctaga53760 aaagtttcttctgtggcaattttattatttacattttaaaaattattctagagttaattt53820 tgataaagcatgtatttcttaaaacaaattatcctttttttccagatgttcaagtgtatt53880 tgcataaagttgaggaaagtagtcttttgtgaatcttttaacttctcccaaatatcttat53940 tttgtgtatttttgcttetttattttgttaacttttaaaagtgtatttttttttcaaaga54000 atcagctcttaggtttatgtttttggttatactggagcttttttcttcttctttttaaaa54060 tattttttctcctttattttttagacgtattttgatctaacgtaatcggaagaaggtaaa54120 ttagaatcttttgttactattgtgtttttatttctccttatttctctgaagtcctgcttt54180 ataaatagtaccatgttatttgtgcataaatattcatttgtcttatattcttgggaattt54240 tcccacttcatcataaaatgaccttccttgtctcatttaatgtgttcaaactttgccctg54300 aatttaaCtttgtCtgatattttaCCatCCtgctgaattttgtttgttaccccaaacaac54360 ctttgctgttttcgtcttttctgaaccctttattttaggtaatcccttgaattagagcac54420 taagttttgctttgtgattaaatctgaaaatctttatcttgccatagatgagttgagccc544.80 tattcatgtgacagctatattatgctgtttcatagcccttttggtccttttttcactctt54540 gcattgcatattttgtgtttattgtgttttgtgtttcttctgataatttggaaggtttgt54600 atttttattcagggagttgccttataatcatactccgcaatacacatcgtcctcagtttc54660 ttcagactgtctgttaactccctattctgaataaaaatgacattgtaatttccctctttt54720 ttctttaccccttttcttctcctcacctaatgtaaatgattttatccttctttagtattt54780 gcttttttaattaactacatttataaatatctttatcacttgatttttaaatcagctttg54840 aatgagatatttggattcctagatataaaagatgttaattataccatttccacgttagta54900 ggtttataaaatcatacattctgctgtgtaaccataatcccacgtttgttttagttccac54960 tcctacagttaaaagattcagaagtattattaacagttattttgccatagttttttcccc55020 aacccattttgtggtaagttatgatcctgctttagtttcttaagaataatttatagagca55080 gagtgtggtggctcacgtttgtaatcccagcactttgggagacaagaggtagaaggatcg55140 cttgaagccagcagttcaagaccaccctgagcaacatagtgagaccttgtctctacaaaa55200 aattttaaaatttagccagacgtagtggcgtgtgcctatagtCCCagCtaCt CaggaggC55260 tgaggcaagaggattgctagagcccagaagtttgaggctgcagtgacctctgattgtgcc55320 actgcaccccagtctgggcaagaaagtgagaacctatctctttaaaataacaataataac55380 ttatgaaaattatattccctgagtttttcatgtttaaaaatatttgttgcctttatcctg55440 taaaagtttgagtataaattcttgggttatactttatttattgaagaatgtataagtatt55500 gtcttctagaattgagtgttgctgtaatgaaaccagaagtcagcctggtttatttttcct55560 cagaaatgaggtaattgccggccggacaccgtggctcatgcctgtaatcccaacactttg55620 ggaggccgagacaggtggatcacgaggtcaggagattgagaccatcctggctaacatggt55680 gaaaccccggctctactaaaagtacaaaaagttagctgggcatggtggtggacgcctgta55740 atcccagctacccgggaggctgaggcaggagaatggcgtgaacctgggaggaggagcttg55800 cagagagctgagatcgcgccactgcactccagcctgggcgacagagtgagactccgtctc55860 aaaaaaacaaaaaaaaaacaaagaagtgaagtaattgccatgatgctccaagaattatct55920 ctttgtctatgaaatccagaaatctcactgttatacattttggaattattattctgggcc55980 aatatttcctgggacacaatagattgactctatagatttaattttttttttttttttgag56040 acagagtctcactgcaatctcagcttactgcaacctctgcctcacgggttcaagcaattc56100 tcctgcctca gcctcccaag tagctgggac tacaggcgcg tggcaccatg cctggctaat 56160 ttttgtcttt ttagtagaga cagggtttca ccatgttggc caggctggtc ttgaacgcct 56220 aacctcaagt gatccacctg cctcagcctc ccaaagtgct gggattacag gcgtgagcca 56280 ccatgcccag cctcaattcc tctttctatc tggtaatttt tctgaagttg aaaacatttg 56340 ttctaatacg ttatttcagt gttcttctaa gatgtgtaaa gcaccctatt cccaggtcag 56400 cccccatctt gctagtgagc tcggctggtt cttcacaaga gctctggttt tctcctgctt 56460 aatctcaagt acctctgtca gcctccacct ggtttatgat ttggagtttt tggtttttg 56520 ttttttgttt ttgacagagt cttactctgt cacccaggct ggagagcagt ggcataatct 56580 cagctcactg caacctctgt ctcccaggtt tgagcgattc tcctgcctca gcctactgag 56640 tagctgggat tacaggcgcg tgccaccaca cccggctaat ttttgtattt ttagtagaga 56700 tggggtttca ccatgttggc cagggtggtc ttgaactcct gacctcaggt aatccacctg 56760 cctcagcctc ccaaagtgct gagattacag gcgtgagcca ccgcgcctgg catggtttgg 56820 agttttaatc tgtagtttta ataaagatag tgcttatgtt tgtgtttctt atatttcttg 56880 gtactcttgg gtaatttgta agatccccat atctacacaa gaagtccatt ttcaattctt 56940 ttcttcagac tgtttatttt attttatttt attttatttt tatgtttgag atggagtctc 57000 gctgtgtcac ttctggaggc tggagtgcag tggcgcgatc tcaggtcact gcaacctccg 57060 tctcccgggt tcaagcaatt ctcctgcctc agcctcccga gtagctggga ttacaggcac 57120 ctgccacttt ttaatttttt tagagacaga gtctcgcttt gttgaccagg ctggagtgcg 57180 gtggtgcaat catggctgac tataacctcc aaatcctggg ctcaagtgat cctcctgcct 57240 cagcctcctg agtagctggg actacaggca catgccacca tgcccagtta attttaattt 57300 ttttgtagag acagggtctc catatgttgc ccaggctggc ctcctactcc tggcctcaag 57360 taatcctcct acctcagcct cccaaattac taggattata agcatgagcc accatgccca 57420 gccttgttct actactttaa tttcatatgt taggtgacca tgtaattgat catccaaacc 57480 aggatactgt aagaatgaaa gaggctgaca gtagtatgat gctgggacta gcattgtgca 57540 ctgagattat ttctgggaaa gcaggagata cggtcaccct acttatagtg tgcttgtctt 57600 tggattgttg aatttggagt ttctatttgc aggcttattt caactgggca gccttgatcc 57660 gCCCtgCCCa gCaatgCtaC CgttCtCtCC aCCgggtCtC tgggaCCCCt tCagtCaCta 57720 taCttagCtC agttCCCCaC CCtCCCaCtC CCtaaaagCg taaCCaggaa tCCtgCCtCa 57780 ggtctactgc cgtcttccgt gggctgtttc agttcctatt acccagagtc aaactcccag 57840 cattccctac ctgattccag aCttggagtC CagagCttta aCCtCttCag gCCaaCtCCC 57900 CaCtttgCat ttCtgtCCCt atatCttagt CCatggagat aCatttcatg tCtttgagtC 57960 tacttacaaa gtaaattttg ctgtttttta attttttttt tgagatggag tcttgccctg 58020 tcacccaggc tgtggtgcaa tgacgccatc tcggctcact gcaacctccg cctcctgggt 58080 tcaagcgatt catctgcctc agcctcccaa gtagctgtga ttacagacag gcaccaccac 58140 gcccagctaa ttttttttat cttttagtag agacagggtt tcaccatgtt ggccaggctg 58200 gtCttgaatt CCtgaCCtCg tgatCtgCCC atCtCggCCt CCCaaagtgC tgagattaCa 58260 ggcgtgagcc actgtgccca gccaattttg ctttttttat atttcattgc tatatgttta 58320 gaggataagt ttacagtgct atatgcattc ecaaatatta gaccaaaaaa atctecaaaa 58380 aattagaaag aaaatccaaa aaatctcaaa aaataccaaa aagcaacaat ctcacagacc 58440 atactcactg acccccaata aaataaaatt agaaattaac Cacaacttaa caaaataaag 585OO
tactcaagtc agagaggaaa gaggaaataa acatcaaaat tacaaagtct aggcggtggc 58560 tcacgcctgt aatcccagca ctttgggagg ccaaggcggg cagatcacaa ggtcaggaat 58620 tcgagaccag cctggccaat atggtgaaac cccgtttcca ctaaaaatac aaaaattagc 58680 caggcatagt gatgtgtgcc tgtaatccag ccacttggga ggctgaggca ggagaatcac 58740 tgaacccagg gagacgaaga ttgcagtgag ccaaaatcgt gccactgcac ttcggcctgg 58800 gtgacaaagc gagactccat ctcaaaaaaa aaaaaattac aaactcttta gatagaaatt 58860 ttggtgtttt tttttgagac ggagtctcac tctgtcgcag aggctggagt gcagtgggac 58920 tatgtcagct caccgcaacc tCCatCtCCt ggattCaagC aattCtCCtg tCtCagCCtC 58980 ccaagtagct aggattaCag gCgCCCaCCa CCagaCCCag ctagttttta tatttttagt 59040 agagatggtg tttcaccatg ttggccaggc tggtctcaaa ctcctgacct caagtgatcc 59100 aCCtgCttca gCCtCCCaaa gtgCtCagat taCaggCgtg agCCaCCgCa CCCCaCCtag 59160 atagaaattt caacatgagg ccgggcacaa tggctcacgc ctgtaatctc agcacttcag 59220 gaggctgagg cgtgggagga tcacttgggc ccaggagttc aggaccagca tgggtgacag 59280 agacagaccc tgtctctatt tatttgaaaa aaaaaaaaaa aaagagagag agaaagaaat 59340 ttcaacatga aaagtatctc tcaaaccctt cgagatgttg gcaaaaagcg actcaaagga 59400 aaatgtatta ctgtgtgtga atttgcttga aaataagaaa gaggccgggt gtggtggcta 59460 acacctgtaa tcccaacact ctgggagtcc gaatcaagtg gatcatgagg tcaggagatc 59520 gagaccatcc tggctaacat ggtgaaaccc tgtctctact aaaaatacaa aaaattagct 59580 aggcgcggtg gctcatgcct gtaatcccag cactttggga ggctgaggca ggtggatcac 59640 ctgaggtcag gggtttgaga ccagcctggc ctacatggtg aaacctcgtc tcttctacaa 59700 atacaaaaat tagctgggcg tggtggtggg tgcctgtaat cccagctact cagaggctga 59760 ggcaggagaa tcgcttgaac ccgggaggcg gaggttgcgg tgagccgaga tcgcaccact 59820 acactccagc ctgggcaaca gcctgggtga cacagtgaga ctccatctca aaaaatacaa 59880 aaaattagct gggtgtggtg gcctgcgcct gtagtcccag ctacccggga ggctgaggca 59940 ggagaatgga gtgaacctgg gaggaggagc ttgcagtgag ccgagatccc accactgcac 60000 tccagcctgggcgacagagcaagactcttgtctcaaaaaaaagaaaaaaaaaggaaaaaa60060 gaaccctgataataaagaaaccaaatgttcaactctcaaagctcggacactttaaagaaa60120 taattaataaaggcagaagttaaagggaggatgataaagcaattttttttgttggttttt60180 ttgagatggagtcttgctctgtcacccaggctggagtgcagtgatgcgatcttggctcac60240 tgcaacctctgcctcccgggttcaagcaattctcctgcctcagcctcctgagtagctggt60300 actacaggtgcgcgccacctggcccagctaatttttgtatttttattagagacggggttt60360 caccatatttgttaggctggtctcaaactcctgatctcaggtaatctgcccacctcggcc60420 tctcaaagtgctgggattacaggcaggcgccaccgcgcctggcctaaagcaaaatattgg60480 ttctgtgcaaaaggtcaataaaaagagcaaacgtttacaaactggagccagcacccattc60540 agctcagtgtgtctggagaaaaaacaatctcgcttcagaattcatgattacgcagccctt60600 tttgcttcctaaaaatcctactatgttgctgttgaccattctctctctttctctctctct60660 tgctttctctccagaaaagctattcagacattCtCCtCtttCCtCaaaCCtccaacactt60720 cctcctccatccttagcctcagctgctgacctcacttctaatcattgagaaaccaggaga60780 agcatttaagagtgaaCCtCCgCCtCCCCgcacgggcaaaaccacccacccacagaattg60840 tgccccaattctgcgtcctctcctctcaccatggatggacggtccaggctccgagccaaa60900 gccaggcctcccctggagctctggatccaccacctgcagcttctcaggcagggccccagc60960 agctcccctgCtCCCttgtaCCatCaatCCCtCCCCtCaCtgggtcactcccaacaatat61020 atatatttagtgatgtttctcccatgtggtaaaatcacttagcctctctcctcccccagc61080 tactatcctatttgtttctttccattctctgcaaaacttctcaaagcattgtgtctatgt61140 gCtgaCtCCatttatCttCtCCCgttCtCtgctgagtccttCCCaCagaCtCtCaCCCCa61200 gttactccatgaaatgacctctgcactgccacatccaatggtgaatgttcagttcttaat61260 tttattcagtctttcagcagcatttgacctggccgatcactccctcttcttaaaaatact61320 tttctcagccaggcgtgatggctcacacctgtaatcccaacactttgggaggccaaggcg61380 ggaggatcatgagagcccaggagttcaagatcagcctgggcaacatggcaagaccctatc61440 tctacaaaaactaaaaagtagccagtgtgatggcatgcacctgtagtcccatctacttag61500 gaggctgaggcagtaggatgacttgagcctgggaaatcaaggctgcagtgagccatgatt61560 gC~CCa.CtgCaCtCCagCCtgagtgaCagCgagaCCCtgtCtCaaaaagaCaaaatagga61620 aacttttctcagcatattcctctgattctcctgctgcttctgtctgcacagattcagtct61680 CCtttgCCggttCttCCtCatCCtCCtgatCtCttgaCCttgaagtgCCCCagagtaCag61740 tctttttttttttttttgagacgcagtctcgtctgtcacccaagctggagtgcaatggcg61800 aggtCtCagCtCatgCaaCCtCtgCCtCCtgggttcaagcgattCtCCtgCCtCagCCtC61860 CCaagtagCCaggaCtaCaggCaCatgCCaCCatgCCCagCaaattgttgtatttttagt61920 agagacagggttttactatattggccacgctggtctcaaactcctgaactcgtgaaccac61980 ccgcctcggcctcccaaagtgctgagattacaggcatgagccaccacacccggcccagag62040 tacagtctttagacggcctctCtaCCtataCttgCtCCCCtCataaaCtCCtCCtgCCtC62100 atggCtttaaataCCatCggtagaCtgatgaCtCCCatatttCtCttttttttttggaga62160 cggagtctcgctcagtcccccaggctggagtgcagtggcgcgatctcggctcactgcaag62220 ctccacctgccaagttcacaccattctcctacctcagcctctccagtagctgggactaca62280 ggcacccgccaccacgcctggctaatttttttgtatttttagtagagatggggtttcacc62340 atgttagccaggatggtctcgatctcctgacctcgtgatccgcccatctcggcctcccaa62400 agtgctgggattataggtgtgagccaccgtgcccagccgatgactcccatatttctatct62460 cttgctgtgtgggagttctcctcagaactccatactcataaatccaactctcataaatag62520 tatctcaaatgggcaatatgctcaaaagtcaattcctacttttctccctaaacttgcttt62580 cctgcagtctccaccatcttaatgtccaatctaacattaggaggcaaaaactttgaagtc62640 attCttgaCtCttCtCtattaCc'.LC~.CCCtatCCaatCtttCtgCagatCCagtCgaCCCC62700 CaaatCCagttagCtCtCatCatCtCCCCtgttaCCCCCtggtCCaggCCatCttCCtct62760 ctcacctgaatcactgcagcattctcctcactggtctctttggttctgttttcactccac62820 cttagcatagtctccacagagcagtcagagggatccttttaaagtgtaattcccatcctg62880 tccctgctctgctcaaaaccctgtcgtgattcccgttttaatctgtcagattaaaagcca62940 gagtCtttCCagtgaCCtaCatgatctgcctattatCa.CCtCCCICttCtttCCCCttgC63~00 tCd.CtCCa.CtCCagCtCtgCagCtgtCCtttCtgtttCCtgaacagcccagattttgctt63060 ctttagaacctttgtatttgctgtcccctctgtctggaatgtttttccaggaagtcacct63120 ggctctctcctgcacttccttcctgaccaccatgtttaaaaatcactcaaacacacttca63180 ggccggacatggtggctcacgcctgtaatcccagcactttgggaggccaaggtgggtgga63240 tcacctgaggtcaggagttcgagaccagcctggccaacatggtgaaacttcgtctctact63300 acaaatacaaatagtagccaggtgtagtggcacacacctgtaatctcagctactcaggag63360 gctgaggcaggagaatcgcttgaacccagaaggcagaggaggtgcagtgagccaagatca63420 cgccacaacaccccagcctgggtgacagagcaagaccccatctcaaaaaaaaaaaaagaa63480 aaaaaaatcacacaaacacacttctcttcatattccttttccaagttttatttttctcca63540 gaatactttacattgttttaatggaagttctCCgtttCCCCCCaaCtagaatggataCtt636OO

cctgcaggtaggcactctagtcctcccatccaagtactaaccaggctcaaccctgcttag63660 cttctgagagcaggggagatcaggcctgttcagggtggtatggcccaggaattttgattc63720 tgttttattcattgctgttctgttgattctcttttgttcctcctcctagtgctgagaaca63780 ctacttgtacataataagcattcaataaatatttgttgaatgaatgacttgttgaatgaa63840 ttaatctcagaaatgcaggactggttctacattagaaaatttttcaaggtcattctctgt63900 tgtcgtaaca cattaagaga ggaaaatttt gtactctaaa tcatttgata aaatacatac 63960 tgatttctgt tttcaaaaac tcttagtggc tgggcgaggt ggctcacatc tataatccca 64020 gcattttggg aggacgaggt gggcggatca cttgaggtca ggagtttgag accagcctgg 64080 ccatcatggt gaaaccctat ctctactgaa aatagaaaaa ttagccgggt gtggtggcgc 64140 atgcctgtag tcccagctac ctgggaggct gaggcaggag aatggcttga acccgggagg 64200 cggaggttgc agtgagccaa gatcatgcca ttgcactcca gcctgggtaa cagagtgaga 64260 ctccatctca aaagaaaact cttagtgagt ttaggaatcc aaggaagacc ctcaaactaa 64320 atagataatc tagctaccag aagccttcag taaaccttaa cactccatgg tgaaacatta 64380 gaaacattcc tactaaaaga caggctaaga atgcctgcaa tcttcacggc tagtccaaga 64440 agtcaaaaag aagaaatgag cgctgattta aaaaaataaa caaacaaaaa actaccgatg 64500 cagaggctgg cagcaaggac tgaaggactg tacagtactt gcctggagca ggcggatggc 64560 cacacccctg cgaagcctgc tcagctggct gggggacgct ccagtgtgtg agtggcagga 64620 tgcagggtac ttcctctgcc agggagttgc actggggaga tCCtCCCCCa CtCa.CaCttt 64680 ggcagctggg gctttggaat gtgacttagc ttctgtcaaa gggtcaatcc accctttgat 64740 atatgatgca aaggcgaaca tatgatgcaa aggtgagaga acagcccaaa ttaggacttt 64800 taccacagct gtggaggtgg acagcgacag tggtgggccc tggccagact tttcatgctc 64860 aaaggtggtg gttgttcttc ctacttcttg tccctccagg gcttcctttg cctgtgtgct 64920 gaacctgctt cttttaattt tttttaactt ttttaaattt ttaattgttt taattaaaac 64980 aaattttgaa aactgtctga acctgctttt gaaccctgct atgatttgaa tgtttgtccc 65040 ctgccaaact gattttgaaa cttaatctcc aaagtggcaa tattgagatg gggctttaag 65100 cagtgactgg atcatgagag ctctgacctc atgagtggat taatggatta atgagttgtc 65160 atgggagtgg catcagtggc tttataagag gaagaattaa gacctgagct agcatggtcg 65220 ccccttcacc atttgatatc ttacactgcc taggggctct gcagagagtc CCCaCCaaCa 65280 agaaggctct caccagatac agctcctcaa ccttgtactt ctcagcctct gtaactgtaa 65340 gaaataaatg ccttttcttt atgaattacc cagtttcaga tattctgtta taaacaatag 65400 aaaacgaact aaggcaaact ctcatgattc tactgccatg ccattccaat aaactccctt 65460 tatgcttaag agagccagag ttggccaggc gtggtgactc acgcctgtaa ttccagcact 65520 ttgggaggcc gaggcaggtg gatcacaagg tcaggagatc gagaccatcc tggctaacac 65580 ggtgaaaccc cgtctctact aaaaatacaa aaaaattagc tgggcgtggt agtgggtgcc 65640 tgtagtccca gctactcggg aggctgaagc aggaggagaa tggcgtggac ccaggaggcg 65700 gagcttgcag tgagtcgaga tcgtgccact gcactccagc ctgggtgaca gaatgagact 65760 ccgtctcaaa aaaaaagaga gccagagttt atttctgttg cttgcaacca agaaatctgg 65820 ctggtgcact gaagtttcca taaataatag caatttaaag actctttcca agccaggcaa 65880 tgcctagcct tgtgtagtcc ttgtggtaat acattcattc attcatttgt tcaaccaact 65940 gtgctccaga gactaagaat acaaaaatgg gggccgggtg tggtggctca cacctataat 66000 cctagcactt tgggaggccg aggcaggtag atcacctgag gtcaggagtt cgagaccaac 66060 ctggccaaaa tggtgaaacc cctactctac taaaaataca aaaaattagc tgggggtggt 66120 ggcggacacc tgtaatccca gctactcgtg agactgaggc aggagaatca cttgaacccg 66180 ggaggcagag gttgcagtga gccgagatcg caccactgca ctccagcctg ggcaacaaga 66240 gcgaaactcc acctcgaaaa aaaaaaaaaa aaaaaaagag ggccgggget gggcgcagtg 66300 gctcacgcct gtaatcccag cactctggga ggccaaggca ggagaattac gaggtcagca 66360 gatcgagacc agcctgacca acatggtgaa accccatctc tactaaaaat acaaaaatta 66420 tccgggcgtg gtggcgcaca cctctagtcc cagctacttg ggaggctgag gcaggagaat 66480 cgcttgaacc cgggaggcag aggttgcagt gagccgaaat catgccactg cactccagcc 66540 tgggtgacag agtgagactc cgtctcaaaa aaaaaataaa aaaaaaaaaa gaattcaaaa 66600 attgtagagt tatagtgtgc ttctagttta gttgagagga catctgtcct tcaaggaagg 66660 ctagaatcta taccctgagt ccttactgaa atcaatccag cagtcaaaac atgggaccaa 66720 cgatcacagc agtaagatag gaagagcacc tttgtacatt tagctcatgt tgagataagc 66780 cactgacaga gctgaaggaa gctcacagtt ctgggttcca tcctttggca tttaaaaaga 66840 aaagtgctaa gaaaattcgg ttggtcacgg tggctcacgc ctgtaatccc aacactttga 66900 gaggccaagg caggcagatc acgaggtcag gagttcgaaa ccagcctggc caacatggtg 66960 aaaccccgtc tctactaaaa acagaaaaat tagccgggca tggtggcgca tgcctataat 67020 cccagctact caggaggctg aggcaggaga attgcttgaa cccgggaggg ggaggttgca 67080 gcgagtgaga gcaggccact gcactccagc ctgggagaca gagcaagact ctgtctcaaa 67140 aaaaaaaaag aaaaaaagaa agaaaggaaa aaaagaaaga aaaaaaaaga aaaaagaaaa 67200 ttcaggccag gccaggcctg gtggctcaca cctgtaatcc caacactttg ggaggctgaa 67260 gcgagacggt gccttagccc aggagtttga gaccagcctg agcaacatag cgagaccctg 67320 tctctataaa aaaaaatttt tttttggcca gacgcagtgg ctcacgcctg taatcccagc 67380 actttgggag gccgaggcag gtggatcacg aggtcaggag atggagacca tcctggctaa 67440 cacggtgaaa ccccatctct actaaaaaat acaaaaaatt aaccgggcgt ggtggcgggc 67500 gcctgtagtc ccagctactc gggaggctga ggcaggagaa tggcgtgaac ccgggaggcg 67560 gagcttgcag tgagccgaga ttgcgccact gcactccaga ctgggagaga gtgagactcc 67620 gtctcaaaaa aaaaaaaaaa aaaaaaaaat taattgtcag gtgtgctggc atgcagctgt 67680 agtcctagct actcgggagg ctgaggtaag aagatcgctt gagcccagga gttcaaggct 67740 gcagtaatag tgcctctcac tctaccctgg gtgacaatga gaccctctct caaaaagaaa 67800 gaaaaaagggaaagaagaaaagaaagaaagaaagagaagaaaggaaggaagaaagaaaga67860 aaaagaaaaggaaggaaggaagaagaaaaaaaaagaaagaaagaaaagagagagaagttc67920 aaagaccaaagggtcaggatcccaaaatagtttttatgttttatttatttatttacttat67980 ttatttttgagacagtatggctctgtcgcccaggctggagtgcagtgatgcgattgcggc68040 tcactgcagcctccaaactgggctcaggtggccctcccacctcagcctcccgagtagctg68100 ggaccacaggcgcgtgccaccatgcccagctaattttttaattctttgtagagatgaggt68160 ctctatatgctgcccaggctggtctcgagctcctgggcttaagccatccacccgcctggg68220 cctcccaaagtgctgggattacagaagtgagccaccgcgcctaatcgggtggtttgtttg68280 tttattgacggggtctcgctgctgcccaggctggagtgccagtggctgttcacaggtgca68340 gtcctggagcattgcatcagctcttgggctctagcgatcctccagagtagctgcagctgg68400 gattccaggcgcgccaccgcgcggggctcagaatgggtttttatattgagggttatgctg68460 ccacctagaggatatatgtagtaccgaactgtgtgcgcagggaggctgaggttgcagtga68520 gccaagatgatgccagggcactccagcgtgggtgacagagcaagatttcatctcaaaaaa68580 aaaaaaaaaaaaaaaaaaaaaagaattgaaagtaaggtcttgaagagatatttgtgcctg68640 tatggtcatagcagtattaactttgacccactagctaaaacacaaaagcaacatgtgtct68700 gtcagcaggtgaacggataaacaaaatgtggtatatatgtacaattgaatattattcagc68760 ctttaaaaaggaataaaaggctggatgcgggggctcacgcctgtaatcctaacactttgg68820 gagactgaggtgggtggatcacccgaggttaggagtttgagaacagcctggccaacatgg68880 tgaaacttcatctctactaaaaatactaaaattagccgggcatggtggcacttgtctgta68940 atccaagctactggggaggctaaggcaggagaattgcttgaactcaggagccggaggttg69000 cagtgagctaagatggcaccactgcactccagcctgggcaacagagtgagactccatctc69060 aaaacaaacaaacaaaaaattattatttccaaagaaacaagaccctgggtccatttccca69120 gcccacacctgatgttgactcacaacacacagcctggtttgctatgagcctgcttcattt69180 aattgtcaccttaacttcacatcaccctcaagtcctggaataactctttgctgacctttg69240 tgtgCtgagCCatCtCCatgtCgCtCaaCgtgCagtCCCtctcactgcactgagtcaata69300 gccagacgtggtctgactgc.agggtcatccttggtggcttaggctgactcgggcatagca69360 gggtgctctgagacctcaccgcatataggctttgCCCCCaataaaCtCtatataatattc69420 atattatgtggtctgggtgtgtgtagctttgcactgtcttctcgtgacagtgccctcaac69480 ctctttcccaggatttcctcctctacctcctcaagtcccactgctctgcaaagaccaaaa69540 gCtgCagagtCCCagCtCCCtCCtttaCa.CCCCaCgaCgCagCCtCCCCtCtCagaaCCC69600 tttaaaCagagtCttttaCtgCagatCCCaagaaCagCCaCaCCCCtCtCtCCGaL'CCaC69660 tccagacacacccaggtaattatagcacccagggtaactatgtagatggagtccctggaa69720 catgtggatagtgccccctgggagtatgcaaaagcaacattgctggcacctgcagagaac69780 agggtgacatccaggaatcagagcatgggcctctgggaggtagggatgtggccaggcagg69840 ctgccaaaaattggtagagcaaggccacaggatctttctgaccttccttccaaacagagg69900 CtCCtgtaCtggtgatCCCtgtgttgattgaCCa.CtCCCttCCtgggggtCgtggtCtCt69960 gtcccagttgcccggacttctgtgagtgtcctactgaggtccttttcatgagaagcatgc70020 tgtccttccacctgctgggagcaagagtgacaacttcaatactataatagcagtggcata70080 cagagaagaagaaagatgaagtggcaagaaaaacaggcttccaagcaggagtttttctat70140 aaaaacaaaaacgtttacaagcaaactttttataaagggctagatagtaaatattttagg70200 ctttgagagccacatagacttgtttgcagggactcaatgtcgctattgtagtttgaaagc70260 agccatcagggttatgtaaatgagtgagtctgattttgtttcagcaaaattttatttacc70320 aaaacagacaatgagtgggctggatttggcccatgatccttagtttgccaactcctgctt70380 tgggctcacccagatctgattttgaattctggctctgctactggttagctgcaggagctt70440 ggaaggctctctgagcctgtttcctcatctgtaaaattaaagcaataatttctaacactc70500 aagagtgttacctcacgcctgtaatcccagcactttggaggctgaggcaggcggatcacc70560 tgaggtcagaagttcaagaccagcgtggccaacgtggcaaaaccctgtctetactaaaaa70620 atacaaaaagtagccgggcatggtggcgcgcatctgtaatcccagctacttgggaggctg70680 aggcagggatactgctagaacctgggaggtggagcgtgcagtgagtggagatcacacctc70740 cacactccagcctggccgacagagcgagactccatctcaaaaaaaaaaaaaaaaagagtg70800 ttagaaggttttgagataatgaataaaagatgccttgtgtatactaagtattcaacaact70860 gatagctgcattggtctaattataacagtttagaagcgattgagtcaacaaatgctggat70920 ttgtcagggaggacttcctatcaggaggtagatcttgggctgagtcctgaagcaaagata70980 ggcattggatagaggagttgagagaacaccctaggactgttattattattattcgacacg71040 gagtctcttgctctgtcacccaggctggagtgcagtggcgcgatctcggctcactgcaac71100 CtCtgCCtCCCaggttCaagcgattctcctgcctcctaagtagctgagactacaggtgtg71160 tgccaccacacccggctaatttttatatttttagtagagacagagtttcaccatgttggc71220 catgctggtctcgaactcctgacttcaggtgatccacccgcctcagcctcccaaagtgct71280 ggaataacagatgtgagccaccgcacccagcccagaaccatttttcaatccttggctctg71340 ccttttattagctgcaagatctcaggcaatttatttaacctctccaaagactcattttct71400 cattcacaaaatgaggcaaataataatatctactatcccaggttgtcatgagaattaaat71460 gcaacatgacatttaatgaaatgagaagtcccttggacattaactggctaaagtatgtgc71520 tcgacaaggatatcattttaggtggatacttagcatctcagaactgatgctcacaatgga71580 atatcattgaaacgcattaaaattcattttaaatgattgtaggtagtgaggcaattgaaa71640 gaagaagacaagaggactgattataatgcttcaggctcactagtctccttttaggaggga71700 aaaacaatttcaagttaaattttaggctctagatttttacccctgctgctcattagaatc71760 acccagattgatgaaatcagagcccatctgaggctgtgtttttcatctccagaatgagag71820 ctgttgtggggattaagtttttgaaaaagtacatctaacaggtgatcgaaaatgatagtg71880 atattattgcagtgatggtcattattgttgttattattatactgaaagaggcttcagttt71940 tctgatccataaagtgagggaattgcatgagaccattgctaagattccttctagctctgt72000 ttttttgtttttgttttttagacagagtctctgtcgcccaggctggagtgcaatggcatg72060 atcttggctcactgcaacctccgcctcccgggttcaaatgatcctcctgtctcagcctcc72120 gaagtagctgggactacaggcacacaccaccatgcccagctaacttttatatttttaata72180 gaggtggggtttcaccatattggtcaggctggtctcaaactcctgacctcaggtgatcca72240 cccgcctcggcctcccaacatgctgggattacaggcatgagCCa.CtgtgCCCaaCCCCtt72300 ctagctttcttgatcactgattctagggttctctgctgaaatatatttgagacatcctgg72360 ataaaagatcatgcaagagctcccaatatggtattaataattgattctggaggcttagct72420 actcctgatggattagacatgactcaactgcctctcttatgtgtacaacacaacaacaca72480 accaagaaaggttattctggcattccatttattcagtttatttacagcccttacttccag72540 cagcacgttaaagatatggccagggccgggtgcagtggctcaagtctgtaatcccaggac72600 tttgggaggccaaggtgggcggatcacaaggtcaggagtttgagaatctggcaattcttc72660 agacttagaagcaaccagctcgataacacagtcttgtgtgggctctccctctgtccctcc72720 CtCgCttCCCtCatttCtCatCCCtgCCCCtgagactgtgCc~.CCttcacatagccctgcc72780 atgagaccttcatctcaggctttgctttctggggtaactgaggctaaacactgagtggcc72840 ctaaaagaggattgggatttggaagttagattattcaccagagaacagactttgctgatg72900 atcaggcccaggttgtaattgttgaaaaaaagagaggatgcatagtcttatctcatctcc72960 tagtcaaagtcaacaccatgataaataagagtcaaatcctgagatgtgaattggggacat73020 ttgagtggttaaccctgagaagcttgcaccttcagacccctcaatacccctgctccccag73080 agaaggctggacattgacctcagcacaggcaggagccctgcaagatgccatttgtcctac73140 taaagatggacccctccactctgtttctaggtaaataaccaaagtcaagtctccacacag73200 cctgagcaagaaagtcagagcctgctacaggagaaaataccacactggccaaaggattca73260 ctagccctggccactgtgtgtgggaggaaccagggaatcatgtgtgggagtcaatgttga73320 agctgttggactgggggtggggtggaatataagcctggccctggggagtttttcccgttt73380 gagggcctttacccacaactcaagatccagtgctatagcaggagatcccagagctagtcc73440 taacagatggtcaggattgaacttggcctagagtaaaatgaggaggatagtgccagaact73500 ttctcaacatactattgaggaagaggtcagaaggcttaaggaggtagtgtaactggaaag73560 gggtcctgatccagaccccaggagagggttcttggaccttgcataagaaagagttcgaga73620 cgagtccacccagtaaagtgaaagcaattttattaaagaagaaacagaaaaatggctact73680 ccatagagcagcgacatgggctgcttaactgagtgttcttatgattatttcttgattcta73740 tgctaaacaaagggtggattatttgtgaggtttccaggaaaggggcagggatttcccaga73800 actgatggatccccccacttttagaccatatagagtaacttcctgacgttgccatggcgt73860 ttgtaaactgtcatggccctggagggaatgtcttttagcatgttaatgtattataatgtg73920 tataatgagcagtgaggacggccagaggtcgctttCatcaccatcttggttttggtgggt73980 tttggccggcttctttatcacatcctgttttatgageagggtctttatgacctataactt74040 CtCCtgCCgaCCtCCtatCtcctcctgtgactaagaatgcagcctagcaggtctcagcct74100 cattttaccatggagtcgctctgattccaatgcctctgacagcaggaatgttggaattga74160 attactatgcaagacctgagaagccattggaggacacagccttcattaggacactggcat74220 ctgtgacaggctgggtggtggtaattgtctgttggccagtgtggactgtgggagatgcta74280 ctactgtaagatatgacaaggtttctcttcaaacaggctgatccgcttcttattctctaa74340 ttCCaagtaCCa.CCCCCCgCCtttCttCtCCttttCCttCtttCtgattttaCtaCatgC74400 ccaggcatgctaCggCCCCagCtCaCattCCtttCCttatttaaaaatggactggggctg74460 ggcgcggtggctcatgcctgtaatcccagcactttgggaggccgaggcgggcggatcatg74520 aggtcaggagatcgagaccatcctggctaacacggtgaaaceccgtctctactaaaaatg74580 caaaaacattagccaggcgtggttgcaggtgcctgcagtcccagcggctcaggaggctga74640 ggcaggagaatggcgtgaacctgggaggtggaggttgcaatgagccgagattgtgccact74700 gcactccagcctgggtgacagagcgagactccgtctcaaaaaaaaaaaaaaaaaaaaaaa74760 tagctgggcatggtggcgcgtgcctgtaataccagctactctggaggctgaggcaagaga74820 atcgcttgaacccagtaggcggaagttgcagtgagccgagatcttgacactgcactccag74880 cctggtgacagagtgagactctgtctcaaaaaaaaaaaaaagaaaaaaaaagacagaaag74940 aaagagcacagacagagtcacaggtatttgcagtaggaagctgtcaggttagagtgcacg75000 gaaatagaaagtatattttacacttacagcacatcttcgtttgattagccacatttaaaa75060 tactgaatagcaacgtgtggctatttagtattcactaaaatcttggacagtgcaagtcta75120 aagaatccttgatccgtccggcatggtggctcacgcctttaatcccagcactttgggagg75180 ccaaggtggaaggatcacttaaggtcaggagttcgagaccagcctggccaacatggtgaa75240 acctcgtctctactaataatacaaaaaaaattagccgggcatggtggtgcatgcctgtaa75300 tcccaggtacttgggaggctgaggcaggagaatagcttgaatccaggaggcgctgcagtg75360 agccgagatcatgccatgccactactgcactccagcctgggcaacagagtgagactgtct75420 caaaaaaaaaaaaaaaattgttgggcgtggtggctcacgcctgtaatcccagcactttgg75480 gaggctgaggggggtggatcacctgggttctggagttcgagaccagcctggccaacatgg75540 tgaaaccccatctctactaaaaatacaaaaattagctgggcgtggtggtgggcacctgaa75600 atctcagcta ctcaggaggc tgaggcagga gaatttcttg aacccaggag gcagaggttg 75660 cagtgagcca agatcgcgcc tctgcactcc atcctgggtg gcagagcaag actatgtctc 75720 aaaaaaaaaa aaaaaaatac ttgattgtct ggacattctg cagaacatca tatggagaca 75780 ctatgttgac gacatcatgc tgattgtaag caagaaatgg caagtgttcc agaaacacag 75840 tcaagacaca tacatgccag aaggtgagat ataaactcta ctaagattca gtggcctgcc 75900 acactggtga catttttaaa cctgctagat gtttgtgtag aaaaggattt aaccttgccc 75960 aaagaggggt ctggcctttg tccccagcta ctggacataa tctctttaaa ctcttgaaat 76020 atcattcctg atagaagtat ttttgttttg actaggggcc ttgggccagc cagatagcaa 76080 caatgtgatc tgggttgggg gctttggatc aggtggcatc agtgtgacct cctgagtggc 76140 tagagactag aatcaaccac atgggcagac aacccagctt acatgatgga attccaataa 76200 agactttgga cacaagggct tgggtaagct ttcctggttg gcaatgctct atactgggaa 76260 acccattctg actccatagg gagaggacaa ctggatattc tcatttggta cctccctggg 76320 ctttgcccta tgcatttttc ccttgtctga ttattattat tattatgaga tggaatctcg 76380 ctctgtcacc caggctggag tgcagtggaa tgatctcaac tcactgcaac ctctgcctcc 76440 ccggttcaag cgattttcct gtctcggcct cccgagtagc tgggactaca gatgcatacc 76500 accacacccg gctaattttt ttgtattttt agtagagacg gggtttcacg ttagccagga 76560 tggtctcgat ctcctgacct catgttccgc ctgcctcggc ctctcaaagt gctaggaata 76620 catgtgtgag ccaccgcgcc cagccccctt ggctgattat taaagtgtat ccttgagctg 76680 tagtaaatta taaccgtgaa tataacagct tttagtgagt tttgtgagca cttctagcaa 76740 attatcaaac ctaaggatag ccttggggac ccctgaactt gcagttggtg tcagaaataa 76800 gggtgctcat gtgtgtacca tgccctctaa ttttgtagtt aattaacttt cacaacttta 76860 ttattaccgc ttacactcaa tgtttattca catttatcca cataccactt attctagtgc 76920 cttgcatcaa agactttcta tctcatgtac tttattctgc ttgaagtaaa tcctttagga 76980 tattcttttt tttttttaaa ctttgcacat acatactttt attttttatt tatttttaat 77040 tttgttattt ttgtgggtac gtagtagata tatgtattta tggagtacat gagatgtttt 77100 gatacaggca tgcaatgtga aataagcaca tcatggagaa tggggtatcc atcctctcaa 77160 gcaatttatc cttcaagtta CaaacaatCC aattacactc tttaagttat tttaaaatgt 77220 acatttaatt ttgtattgac tagagtcact ctgttgtgct atcaaatata attttttttt 77280 tttttgagaC agagtCtCaC tCagtggCCC agaCtgaaag tgcagtggca caagctcggc 77340 tcacttcaat CtCtgCCtCC CtggttCaag cgaatctcct gcctcagcct cccacatagc 77400 tgggattaca ggcacacacc accatgccca gctaattttt atattttttt agtagagacg 77460 ggttttCgCC atgttggCCa ggCtggtCtt gaaCtCCtgg CCtCaaatga tCtgaCCaCC 77520 tcagcctccc aaagtgctag gattacaggc atgagccacc acacctggcc aaaatagaat 77580 attctttagt gaggtctgct ggtgacaatt tttttctttt ttttgagact gagtctcgct 77640 gttgtcagct tgggctggag tgcaatagca cgatctcagc tCaCtgCaaC CtCCaCCtCC 77700 cggattccag caattctcct gcctcagcct cccaagtagc tgagagatta caggcaccca 77760 ccaccacacg cggctaattt ttgtattttt agtagaaatg ggggttcacc gtgttggcca 7a82o ggctggtctc gaactcctga cctcaggtga tccacccacc ttggcctccc aaagtgetgg 77880 gattacaagc atgagccacc acgcacagcc aattttttcc gtttttgtct gaaatcttat 77940 tttgtgtcat ctttgaaata tatttttgat ggatataaaa ttgttggttg atagttatta 78000 tcattattat tattattttg agacagggtc tcactctgtt gcctatgctg gggtgtagta 78060 atgtgatctc ggttCaCtgC agacttgacc tCCtagggCt CaggtgatCt tCCCaCCtCa 7812~
gCCtCCCtag tagCtgggaC tacagatgca tgCCaCCata CCCaaCtaat ttttCtattt 78180 tttgtagaga tgaggctttg ccacatttcc caggctggtc tctaactcct gagctctagc 78240 aatccaccca ccttggcctt acaaagtgct gggccatgac tagccagcag ttacttttta 78300 tagcatattg aatatttaat atgaatcttc tggcatccac tgtaactgtt taaaaaatca 78360 gCtgtttaCt tggCa.CtCtt tttttttttt ttttttttga gacagagtct tgccctgtcg 78420 cccaggctgg agtgcagtgg cgtgatcttg gctcactgca agctctgcct cccgggttca 78480 CgCCattCtC CtgCCtCagC CtCCggagta gCtgggaCta aaggCgCCCg CCaCCaCgCC 78540 cggctgattt ttttgtattt ttcgtagagt tggggtttca ccgtgttagc caggatggtc 78600 tcgatctcct gacctcgtga tctgtccgcc tcggcctccc aaagtgctgg gattataggc 78660 gtgagccacc gcgcccagcc tctttttttt ttttttttag acggagtctt actctgtcat 78720 ctaggctggt gtacagtggc gtgatctcag CtCagtgCaa CCtCCd.CCtC CtgCCt CagC 78780 ctgccaaata gctgggatta caggtgcgta ccatcacgcc cggctaattt ttgtattttc 78840 agtagagatg gggtttcacc atgttagaca ggctggtctc gaactcctgg cctcaagtga 78900 tctgcctgcc ccagcctccc aaagattaca ggcatgagcc accgcacccg gccaagtagc 78960 actcctttga aggtaatctg cttcccctac ccctagcaat ttttaacaat ttttcttcat 79020 ttttatttcc tgaagttttg ttattaataa tctgtgtgca gatttctttg tatttctttt 79080 gtttgcagtt catagtgatt cttgaattag tgtgttggtt tctgttatca ccacaggaaa 79140 attgtcagcc gttagctttt caaatatttc cttgctaaat tctctcttct cccctttcgg 79200 tacaattgat ttgattaaaa ctaaaaccag ggccgggtgc agtgactcat gcctgtaatc 79260 ccaacacttt gagaggctga ggcaggtgga tcacctaagc tcaggagttc aagaccagcc 79320 tggccaatat ggtgaaaccc cgtctctact aaaaatacaa aaattaccag gcatggtggc 79380 acacatttgt agtcaggagg ctgaggcagg agaattgctt gaatccagga ggtggaggtt 79440 gcagtgagct gagatcccac cactgcagtc tggcctgggc gacagagtga gatgagaatc 79500 tgtctcgaaaaaaaaagttatgaatgtttgataaactatatttgttagaatgtttgttgt79560 agaatactattcattgatttttaaacaatgttagattaaaccattcactggatttgtgat79620 aattaacttactgattttacctcactgatttgttgtaattaatacaactggtataaaaag79680 actgtgacgaggccgggcatggtggctcccgcctataatcccagcactttgggaggctga79740 ggcaggcggatcacctgaggtcaggagttcaagaccagcctgaccaacatggtgaaaccc79800 catctttactaaaaatacaaaattagccggtcgtggtggtgcatgcctgtaatcccagct79860 cttcgggaggctgtggcaggagaatcacttgaacccgggaggtggaggttgcagtgagcc79920 gatatcgcgccattgcactccagcctgggcaacaagagcgaaactccgtctaaaaaaaaa79980 aaagaaaaaaaacacataaaacaaaacaacactgtgacggttcccaaaaattaggagcat80040 aattaaaggaactcctgataaaaattaattttatcttacatgtaaactaaaatgacttta80100 tgaagttaattcagaaatacaatgcagggtattagtttgccacagctgcgtattcagcct80160 aatgtaatattcttgttatttttaaattcttcttttaactttactcatatgtggatcatc80220 aaatttcaaaagattaaatgacaatactcttagcagcaagcttccctaagcatataaaca80280 ttttaatgggtgatgattcagaaggtacccgaagaatatgtactgccagatatcattcac80340 ccccatatacctgcccgacagacatcccattttgggaccctggataaatgtgtgggtgga80400 gagaaagataggagaaagtggtataagcaaatggctttggagtctgattgacagcgattg80460 aaatcctgtctctacctcttaacagcctcatgatcctacataagttaccccgatcctcag80520 ggccacatctgtaaattgggggttgcgatggcagccatctcacagggtctcttttcgggg80580 aagggcaggaattatggattaagtgagctagtaattgtaaagcacttaatacaaggaggg80640 cgcataataagtacttcataaataatgacggccattatcatgactgaggtgtatgcagct80700 gtcggggattacggcgacttcagaatttctggtgggcagggctcaaaggcagcaaatcac80760 actggaagtcgaggtgaggcactgcttctgcacagactgcttagctggagagaatgagga80820 aggcttagaggagatttagaggaacttagagtCCtCCgCCtCCaaCtCtgtgggatCtgC80880 tcccgtgccagagacattcaggggatttctcgcactctcccctcccctacgtccctcccg80940 ccccatccaactaaccacacaacacatacaaaatagcccctgcgaggttctgcacgctgg81000 aagggaacaggagaagggcgCtgCgCtttCttgCtgatgCCCtgtaCttgggCCCCtggt81060 agacacagccacttgtcccctcagcctgcagagaaatcccacgtagaccgcgcccgggtc81120 cttggcttcagccaatctccctttggtgggggtgggatgcacgatccaaggttttattgg81180 ctacagacagcggggtgtggtccgccaagaacacagattggctcccgagggcatctcgga81240 tCCCtggtggggCgCCgCtCagCCtCCCggtgCaggCCCggCCgaggCCaggaggaagcg81300 gCCagaCCgCgtCCattCggCgCCagCtCaCtCCggaCgtCCggagCCtCtgccagcgct81360 gcttccgtccagtgcgcctggacgcgctgtccttaactggagaaaggcttcaccttgaaa81420 tccaggcttcatccctagttagcgtgtgaccttgagcagttgactttatttttcagtgcc81480 tagttttccagataccaggactgactccaaggactattactcatctggagggtttagcac81540 agtaccgtcgcatagtaaatttccatgtcagttttggttacctttcatgcacttgcaaac81600 atgccatgctctgaaacgaaataggcacatCttttttttttttttttttaaggagtcttc81660 ctctcgcccaggctggagtgcagtggcgcgatcttggctcactgcaacctccacctcccg81720 tgttcgagattctcctgcctcagcctcctgattagctgggactacaggcatgccacgacg81780 cccagttaatttttgtatttttagtagagacggggtttcgccatcttggccaggctggtc81840 taaCtCCtgaCCtCaggtgatctgactgcctcagcctctcaaagtgttgggattacaggc81900 ataagccactgcatctggccagaaatgaaataagtaaatcttttaacctgctctaacaat81960 atagtgaaaagaccatattattattagagcaggttaagggatttgcctatttcgggttct82020 agttatagtcttaaacttggacattcttgtagaaagtaaaaagtttcctcttcaaagttc82080 cccttcttgttaaagaatacatcataagtgttagaagtaatagtttattttaaagactaa82140 ctttcttcaagCCtCCttgCtttgtgctaataactctttgttaagccctatcctatgtaa82200 ctgttggacatgctcacaggcacgttccagttcacagcctatgccccttccttatttgga82260 aatgttattgcttccttaaacctttcggtaagcaacttcctctccttcttcgttcttcct82320 tgcacttacctatttagaaagttttaggctattagcaaatcggctatcagtttaagagtg82380 tgaggtcccgctccagccaatggatgcaggacatagcagtgaggacgacccaaatgcgta82440 agggataaatatgtttgcttttcctttgttcaggtgtgctC'tCgaCatCgttCCatCtgC82500 gattgagcaccctttctgcagaaagtaaagattgccttgctggagatcttttgtctccgt82560 gctgacttttcttcgtggcaccgattatctatttctaacaattttggtatttctaacatt82620 ctgaacaatcttgggctagttgtctcttctgggcctgtttCCCCatCCgtcacatgataa82680 acttcattggtttaaaaaccccagcgaacatttattgagttactattaccttcctgccct82740 ccccaaccccaaccccagggagcagttacaacctcagccgctgagcgcactcgccgggtg82800 ttaagaagcaccaaagacagggaggcttgattgattttgctttgggagtagagggtcaga82860 agattcacaggaaaatggcatttgagcaaggatgattcactggagctagcttttaaatac82920 tggcgaggcttttatgttgcagtcccttacaaagttgagcattcgcagggactgcactcc82980 gaaataagcccgcttccccttttcattcgctaatgatccagggagctgctggttccgcat83040 gcggcaggttgtgccttttcctaatcagggttctgcatcgcctcgaacccgcaggccgtg83100 gcgggttctcctgaggaagcagggactggggtgcagggtgaagctgctcgtgccggccag83160 cgcctgtgagcaaaactcaaacggaggagcaggaggggtcgagctggagcgtggcagggt83220 tgaccctgccttttagaagggcacaatttgaagggtacccaggggccggaagccggggac83280 ctaaggcccgccccgttccagctgctgggagggctcccgccccagggagttagttttgca83340 gagactgggtCtgCagCgCtccaccgggggccggcgacagacgccacaaaacagctgcag83400 gaacggtggctcgctccaggcacccagggcccgggaaagaggcgcgggtagcacgcgcgg 83460 gtcacgtgggcgatgcgggcgtgcgcccctgcacccgcgggagggggatggggaaaaggg 83520 gcggggccggcgcttgacctcccgtgaagcctagcgcggggaaggaccggaactccgggc 83580 gggcgggttgttgataatatggcggctggagctgcctgggcatcccgaggaggcggtggg 83640 gcccactcccggaagaagggtcccttttcgcgctagtgcagcggcccctctggacccgga 83700 agtccgggccggttgctgaatgaggggagccgggccctccccgcgccagtCCCCCCgCaC 83760 cctccgtcccgacccgggccccgccatgtccttcttccggcggaaaggtagctgaggggg 83820 cgccggcggggagtcaggccgggcctcaggggcggcggtggggcaggtgggcctgcgagg 83880 gCtttCCCCaaggCggCagCaaggCCttCagcgagcctcgacctcggcgcagatgccccc 83940 tgagtgccttgctctgctccgggactcttctgggagggagaaggtggccttcttgcgcga 84000 ggtcagaggagtattgtcgcgctggttcagaagcgattgctaaagcccatagaagttcct 84060 gcctgtttggttaagaacagttcttaggtgggggttagtttttttgtgtttctttgagga 84120 ccgtggatcaagatcaaggaaatctctttagaaccttattatggaagtctgaagtttcca 84180 aatgttgagggttttatgtctaaaagcaacacgtgaaaaaattgttttcttcacccagtg 84240 ctgtcttccaatttcctctttggggggaggggtagttactgctgttactaaaataaaatt 84300 acttattgctaaagttccccaacaggaagaccactacttttgatgactttggcaagtttg 84360 ctaactactggaaccctaacttacaaacgaactacttacatttttgatttccagttgtat 84420 tacctgcccaatgtttacgtagaaacagcttaattttgattctgggtaacgttgttgcac 84480 ttcattaaaaatacatatccgaagtgagcaagtatgggtctgtggacagcagtgattttt 84540 cctgtcaattcctgttgcttcagataaaatgtaccagacagaggccgggcgcggtggctc 84600 acgcctgtaatcccagcactttgggaggcttggcgggtggatcacctgagatcgggagtt 84660 caagaccagcctgaccaacatggagaaaccccgtgtctactaaaaatacaaaattagcca 84720 gggtggtggcgcatgcctgtaatgccagctacttgggaggctgaagcaggagaatcgctt 84780 gaacctgggaggcggaggttgcggtgagccgagatagcaccattgcactccagcctgggc 84840 aaaaagagcgaaactccgtctcaaaaaaaaagtaccagacagaaatgggttttgttttct 84900 ttttttgttttgagacggagtttcgctcttgttgcccaggctcgagtgcaatggcgcgat 84960 CtCagtCtCggCtCaCtgCaaCCtCtgtCtCCCaggtttaatCgattCtCCtgCCtCagC 85020 CtCCCaagtagCtgggattaCCCatgCCCCaCCatgCCCggCtaatttttgtatttttag 85080 tagaaacggggcttcaccatgttaggctggtCttgaaCCCCtgaCCtCaagtgggCCtCC 85140 Cc'~.CCtCggCCtCCCaaagtgCCaggattaCaggCatgagCCdCCgCggCCagCCagaaat 85200 gggttttggaaaaagcactaaacaaaatcgaacttggtttcatatgacagctctgctgct 85260 aactgtaacaggggcagaccagttaacctacttttctgtettctgtcagctgagaattag 85320 atgattcccaaaggcccattgaactctgaatgactttaaatacttcttcttaagtgggta 85380 cacggttttggtaactgatgccaggtgatgaatgcatgaaagtgcttaatgaatgaaacc 85440 ggtaaaatagtaggaggaagctttattggtaaggcaggggtatacctaatagctctctaa 85500 tttattggtattgaagtggttaacttttgtttttttaaggggggaaaacattctaagaat 85560 aatgaggcaaactgcatattgeacaagagactgttgtctctattcaacaaataccttttg 85620 agtgtccagagtctgccaggtgctgtgctaggccctcacgattgagtagtgaaccagaga 85680 atgtccctgcacceatggagcttattgtctactggggtagacagataataaataagcaaa 85740 caaatcttctctcttctccctttcgctccatgtaagtgtgtgtgtataggtgtatactta 85800 caagttgagtaaagtgttatgaaagattaagaggagaaatgcattttggttagatgttag 85860 aggactcagcaggtgaccttgaaacttagagctgaaggatcagtaggaggtaactagaga 85920 ggccagggaatcgcatgttcaaaggccaggaggcaagaaagagcatggtgCCCttCaaga 85980 gaggaaagaaggctactgtgactggagcatagatgtaggcaagtgttgggtgattgagag 86040 ctctacgggccatggttaggttttattcctaatgccgagatgccaaacatggtggttcat 86100 atctgtaatcccagtattttaggaggccgaggcaggaatatagcttgaacccaggagttc 86160 aagaccagcctgagcaacatgagacctgtacaaaacatttaaaaaattgctgggtatgat 86220 ggtgcacacctgtggtcccagctactcaggaggctgaggcagaaggatcacttgagccta 86280 ggaggtggaggctacaatgagccatatttgagtcactacactccagcctggatgacaaag 86340 tgagaccatgtgtcaaacaaaatacagaaagaatattaatttaaaattttgaaagaggag 86400 tgatctgaacttatatcttaaaaagatcattctagggcatggtggctcatgcctgtaatc 86460 aagggctttgggaggctgagacaggaggatcacctgaggccagttcgagatcaacctgta 86520 cagcatagagagactccatctctacaaaaagaaaaaataaatagctgggtgttgtgagtt 86580 attcaggaggctgaagcagaaagatcacttgagcccaggagtttgaggctgcagtaagct 86640 atgatcccaccactgcaacacagtgagatcttgtctcaaaaaaaaaaaaaaatcattcta 86700 ggtgctttttggaggctggatgtggtaagagtagaagctggagatggtcctgttagggat 86760 tcgattcagactttaaataccatcaatgcattgagtcccaaatttacatcactacgttgg 86820 atccttgcccctgaatccagactggtatatccaactttaggttcagtttgtatctctacc 86880 tgaccaatatagaggtgtccagtcttttggcttccctaggccacattggaagaagaattg 86940 tcttgagccacacatagagtacactaacgctaacaatagcagatgagctaaaaaaaaatc 87000 gcaaaacttataatgttttaagaaagtttacgaatttgtgttgggcacattcagagccat 87060 cctgggccgcgggatggacaagcttaatccagtagataccttcaacttacaatatctaaa 87120 attttatgccagatttagtcattttaaacctgctcatcagtttttctcaagaagtagtat 87180 tttggctttttttcttttcttttttttgagatggagtttcgctcttatcgttcaagctgg 87240 agtgcagtggcggatcttggctcactgcaacctccgcctcctgggttcaagtgattctcc 87300 tgcctcagcctcgcaagtagctggaattacaggcatgcgccaccatgaccagctaatttt87360 tggagacagggtttcaccatgttggtcaggctggttttgtactcctgacctcaggtgatc87420 tgcctgcctcggcctcccaaaggctgggattacaggcatgagccaccgctcccggctgca87480 tttttggatttttagttgctcagcccaaaactttagtacatctttgaacctcttctttcc87540 tcctactctatatctgatccatcagcaaatctgttaggtctacctcacacatatcgaaat87600 cctaccacgtctcaccatctgtgacaattaacaccctggtctaggcagtcatctctgtta87660 agattgagtggttaaggatgtcctctaaggagatgacattcaaatcttagcttaaatgtc87720 aagagggagctggttttataaagattgaggaggcagcattattttgccataggcttccat87780 ttggtttccattccattcttgatacttatggtatatattcaaaacaaatgcacagaaaca87840 gacccaggtatattgggaatttcggatatagagttcctagttgggaaaagatagactgat87900 ctgtaaatgatgctagttatccatcatctggcaaaaaataatttcctgcctcctctcata87960 tatctcagatcaacagactttttctgttaagggccaaatcataaatattttaggctttcc88020 agaccatatggtttctgtcacactctcctttatccttgaagccatagacaatatgtaaac88080 aaatgggcatggctgtgctacgataaaactttacttacaaaaactggtagtgggccagtt88140 taggcatggccagcactttgggaggctaaggcagatggatcacttggggtcaggagtttg88200 agaccagcctggccaacatggtgaaaccctgtctctactaaaaatacaaaaaatagctgg88260 gcatggtggtgggtgtctataattccagctactctggaggctaagacacaagaatcactt88320 gaacccaggaggcagaggttgcagtgagctgagatagcaccactgcactccagccagggt88380 gacggagtcttaaagcaaaacaaaacaaaaggtagtgggttgtatttggcccatgggctg88440 tagtttgccaatccctgatgcagaaacaaattccaggtaaataagagcctggaatgttaa88500 aaaaacaaaacttgaagtcatgtagaagaacaggtagggggaacaatcctgatctcagga88560 taggaagggatattgcttaaaataagacacaggaaaatataatccatgttgtgtaaattt88620 gactacgttaaaacttaaaactttcgccaagcgcggtggctcacgcctgtaataccagta88680 ctttgggaggccgaggtgagcagatcaccaggtcaggagattgagaccatCCtggCtaaC88740 acggtgaaaccccgtctctactaaaaatacaaaacattagccgggcgtggtggcgggcgc88800 ctgtagtcccagctacttgggaggctgaggcaggagaatggcctgaacccgggaggcgaa88860 gcttgcagtgagctgagatcgcgccactgcactccagcctgggcgacagagtgagattcc88920 gtctcaaaaaaacaaaacaaaacaaagcaaaaaacctaaaactttcatacaataaagtat88980 acctaagatacttctagaagagaagatttacatccaggacgtgtatggaatttctgcaag89040 taataagtaaaagacaagggacatgaagaggcagttcacaaaagaggaagccaaaatgac89100 caataaacatgaaaggatgtttaacctcaaaggaaacaaggaaatgaattaaaaacatca89160 aatgccatttcaaaactagtaagttggcaaaattaaaaataccaaggatgagaatatgaa89220 gcatggctatatgagtgcatggaatggtacagtcactttcattaaaaatgcacataattt89280 gttttttatttatttttttgagacagtctatgtcgcccaggctagaatgcagtggcatga89340 tCtCggCtCaCCaCaatCtCtgCCtCCtgggttCaagCaattCtCCtgCCtCagCCtCCt89400 gagtagCtgggattaCaggCaCatgCCaCaaCGgCCCggttaagttttgtatttttagtag89460 agacagggttttgccatgttggccaggctggtctcgaactcctgacctcaggtgagctgc89520 ttcccaaagtgctgggattagaggcgtgagccaatgctcctggctgaaaaaaatgcacat89580 aatttgttacctagcaattccatgtctagaggcttatcctagagaaattcttgcttatat89640 gcataggaagacgtgtactagaatgttcactagttgaatgtttaagtgaaaattaggaaa89700 taaagtaaatgttcattaacaggaaaatgagtaaaggtatatttataaaacaattaagta89760 gctaaaatgaataaactagagctgcgtgaatgaactagaactggttcaatagtcatgtca89820 gattattgaatgaatacaggtcagatatgtatagagtgtcatttgtgtaattaatttttt89880 ttttttttttgagatggagtctcactctgttgcccaggctggagtgcagtggcgtgatct89940 CagCtCaCtgCaaCCtCCaCCtCCtgggttaaagtgattctCCtgCCtCagCCtCCCgag90000 tagttgggattaCaggCatgCaCCa.CCatgCCCagCtCattttCCtatttttagtggCCa90060 cagggtttcaccatgttggccaggctggtcttgaactcctgacctcaagtgttccaccca90120 acttggcctcccaaagtgctaggattacaggcgtgagccaccgtgctcagccatttgcgt90180 gatttttaaagatgtgcagaataatgccattaaaaaaaatacacatacatgtatatatat90240 acacgtttggctgggtgtggtggctcacacctgtaatcccagcactttgggaggctgagg90300 caggaggatcacttgagcccaggtgtacaagactagcctgggcgagatagcaagacccca90360 tctcaacaacagaaaggataattaggtatggtggcatgagaggatcacttgagcccagga90420 gttcgagtgttatcaggccactgcactctagcctggacaacaaagcaagaccgtgtctca90480 aaaaaataaaaataaaaagtatttgtatgtggtcatagtcaaaaaacgtacatggaagga90540 aaatgtctttatttatttatttatttttttttttttaagacagagtcttgCtCtgtC2.CC90600 caggctggggtacagtggtgtaatctcagctcaccgcaatctcggcctcccgggttcaag90660 cgattcttctgcctcagccttctaagtagctgggactacaggtacccgccaccacaccct90720 gctaattcttgtgttttcagtagagacagggtttcaccatgttggcaaggctggtctcga90780 actcctgaccttaagtgagccacccgccttggcctcccaaagtcctgggattacaggtgt90840 gagccactgcgcttggccaggaaatatctaatttagtaagtatttatatctgggaaagga90900 agggtcaggtggtgattcataggaactctaaagtctatgtataatacttagggggacaga90960' aggaaataaagcaaaatgctgatatttgattgttgagttgtgtatatgttagaagtataa91020 cataggagatctgattgatagtaggagaatgtttttaggtggtaaaagtggaaccgtggt91080 ggtttgttttggcagtagaatcagttggtcatagtttgtatgtggaaggtaataaacaga91140 ccatgttaaggatgacttccggaattttggtctgagtagtgggtggatgacagtgtcatt91200 catgagggaagatgaagactgaggtaggaacaggtttgggagaagatgacatgttccctt91260 ttagacaagtggaattatggaagatggcaggtaggtggttagctatatgaatttgagata91320 aaagatttaggatggagatataaatttaggagtaacagcgtatctatggtattgtaagcc91380 ttaagaatgggtaggatcagccaggaaatacagatgtatatgcagaagagaggagtcaag91440 gaagccaagacaagttaatgtttaaagtgagtgatgtagtccatgggcagatgctgctga91500 gagggctgcaaacaccagtgaccctacaacatttttaaatgtcgtcttcctgacagcagt91560 gatcagtacctgcaacgatcttatttatttttttcatgttagtctccacacacttgaatg91620 tagactttttgaaggcaaaatcattgccttttctgagctgggagcatgtctggcacatac91680 caagcactcaacagttgatgtattgacttcatccagatactctgagggcgagttatttcc91740 tgctactagcctttcacctttcaatgtttaagagcacaaatacagagatgggcacgtttt91800 ggcatttcttattttgataaccttttcctggtaagattttttaatgttgaaaaaaaaaaa91860 caagaaaagagggttaaaaatagtcttatgtcagatcctgtgatagaattcacacttggc91920 ttaagctgctgggcaccttcctatcttggatgtcatattagcttatctacagcagaattt91980 ttactgttttatgtagtaaggaagcaattatatgattattttacagacaaattattcttt92040 atcttttatttttttagacggagtctctctttgtctcccaggctggagtacagtgtcgcg92100 atCtCggCtCaCtgCaaCCtCCgCCtCCtgggttcaagcaattctctgcctcagcctccc92160 aagtagctgggcttacaggtgtccgccaccacacccagctcattgttttgtatttttagt92220 agagatggggtttcaccatgttggccaggctggtcttgagctactgacctcaggtgatcc92280 acccgccttggcatcccaaagtgctggaattacaggcgtgagccaccgtgcctggcccag92340 acaaattattatactctgagtgttagaggcttaggatgttttcacttgatgctatgggag92400 gaataagtaataagatatgatacacaaccaaagacctttcttcactatgcttctagtagc92460 tagtactatggatgacacatggtaataatattggttagcatttgtcctcaatttactgtg92520 ctagttactcttctaagccccttacaggtatatattttttttcatcaataatcctctaag92580 gtagtttttattattgacctaattttataaatcaagaaaattaagacccagagaagtaag92640 taacttgtccaagatcacatggcttataagtggtagagccagaatttgaccccagatgtt92700 gtgactacattgtctctccataagcaggttcaactcttttgactggatgctgttccaagg92760 tCaCttCCttagagaagCCtttgCtgaCaaCtaCCCtCCtgtgCCCtCCtCCaaggCtgt92820 ccattgttctagaactttgaatactcatcttagaataaagctggtctaatttttacagtg92880 ttatagaatggatctctgactgcaaaagttggtcataattatctttttatgttctagtga92940 aaggcaaagaacaagagaagacctcagatgtgaagtccattaaaggtaagttctgccctt93000 ggCagtCCa.CtgCattaaaaagtgatgtgCtttgcatttgtgagttctttaatCCtgtta93060 tactctctcttttggcattaatcatttctgccttattttataattacttatgattttgat93120 ttatttccctctttaacctgtataatgctttaacatctagcatataataagtaggctttt93180 tttttttttttttttttggagacggagtcttgctctgttacccaggctggagtgcagtgg93240 cgcgatcttggCtCdCtgCaagCtCtgtCtCCCgggttCaCaCCattCtCCtgCCtCagC93300 CtCCCCagCagCtgggaCtaCaggtgCaCggCgCCa.CgCCtggCtaattttttgtatttt93360 ttagtagagacagagtttcaccatgttagccagtatggtctcgatctcctgaccttgtga93420 tccgcccgcctcggcctcccaaagtgctgggattacaagcgtgagccaccgcacccggcc93480 gtaagtaggctttttttaccttaattttatttttttgagatggagtcttgctcttatccc93540 CaggCtggagtgCagtggtgCCatCtCggCtCaCtgCagCatCCaCCtCCCgggttCaag93600 cgattctcctgcctcagcctCCCgagtagCtgggattacaggtggccgccaccatgccca93660 gctaatttttgtatttttagtagagacagggtttcaccgtgttggccaggCCagtCtCaa93720 aCtCCtgaCCtCaagtgatCCaCtCgCCttggCCtCCCaaagtCCtgggattaCaggCgt93780 gagCCa.CCatgCCtggCCataagtaggCttttactgagccttgtgtgtattggctatcct93840 agtgattaCagtgaaCCagtgCCCttCttattaatCaCaCatttaattgttCCCtaaaag93900 tgattagttcactttatttatttagtaagacaaaaaatgaagaatactcttaactgagca93960 gtctgttaactgtaggaaagcactgacacttataaggcttagttttctgtcatttatcca94020 gaagtatggttgattacagtttttacttttttatttgaatgaacaaccttaatttaaaat94080 atattttgtttattttttgttgggatcgatacattgtccttgtttatagattagagcatg94140 ctttttaaagatgctgtattactcactgattttatttgtccagtgtacagagattgaagt94200 gggaaaattataatggaaattgtttccatagtcattacatattaatttcatcaatttatt94260 tccataaaatctgtagattgctacttatttagatttttccttcaaatgtttttatgttgt94320 attgcttgcactgagtatttattctatatgctcaatttgctggagaagaagactaattat94380 aacttaggcaagttgtaaaattagggaaaaaagtaaggtaccttacagcctagtttactt94440 atttcttatgtaaagccagttagattccacattagttcaaactgccttctttgagcaaaa94500 cttgattggcagtgataaaggcttaaagcccttctcaagcagagacctgtaaagactaga94560 tctgactgtagtagaaggaaggaacttagatgtttcaggcagtgagaacaccagtcttcc94620 actctaaactttgccactaacagtatgaccttgggaagttgtaactttcttcagattctt94680 catttgttgaatggggggattggcctagctaatttctaaatctctactgggctaaaaaat94740 tctgtgcttatactctgattatgaagtacataatctgtgcttaacattcactgacttatc94800 cttaggataatacagaagcagtacaagaaacagcccctcaagatgtttgcagtctggtta94860 gaaagacaaacttatacacagaacagtagcaaatagaccaaaataataatagctgccatt94920 tatagaacacttcttctgttctgggcattagacaaaaactgactataacggtgaacaaaa94980 aagacttaggtcctgccctcattgaacttacagattagtaggggagaggaacattaatca95040 agtaattccacagatggcttagcctagattggtagtgatggaagtaaagagatgtgaacg95100 gacttgaaaaaaaattcggaggcaaaatggatagaagtttattattgattaaatatgagg95160 tgtgagagagagggatatttaagattgatacctaccttctggcttgcctaacagaaccaa95220 aacaggaaattatatgttcagttttgttatgttgggtgggaggtgcttttgagtcattca95280 tttatatatgttatatatgttattttatatgcatagtaattttaaggtctgagttttaaa95340 ccaaaggttagagagtgattttttagagtctagcaaacctaagttgaaatcctgcctgtt95400 gaaatggctgtttactagctcattaacctagggcaaagtattcaacttgttttcattttt95460 gtcttcatctctaaaatgaggaaaatatggtcttacaagattgtcctgagagatagatga95520 aataatatccaaaaaaaaaaaaggtacatagagaaactcgtatagtgcctggtatatagt95580 aggtcctccattggtagctatcattatctagttttaacatagccttcagtttgttgaatt95640 agtcaaactgagtgaagcactgcaaggaattcagaggaatttgagatcaacaaatgattt95700 ctgaagtttagggaagacttcatggcaatgacacttaccttgtataaaagttgaagaata95760 agaaagatttgaatgagagattctttctcttctccctaccagcccagcttcttatttgag95820 gatatattgggcaaaggggccttcagacaagtagagggagatttttacagaaagattgag95880 atgaaggtatagaaggctgtaaagaccagaaaagagaattgagacagaggaagcaggaag95940 ccactgtaggtttttgagcaagatattgatgctgtaagtatggtgtttatgaaaggttag96000 tctggaagagatttgcaggatggagaccccggaagtttttttgttataatacagaaagac96060 ttgcactgagggtgaggtgttaaaaataaacaggtaagtaaatgtttaaacatcttgaag96120 gaaaagtcaacaaatcttggcaagtaaacagataacagtgaaaaagaatgggaccaagat96180 tttgagttttggagactggtggattgaacagacagggaaattgagaggagaatcagatga96240 tgatgttttaagttgatatttagacagattgtgcttgagatggtaaagtcaatgtgggtg96300 ggaatgcttagtagcgagtaatcagtgatacaagaccaaagcccaggtcaaagacaagtc96360 acagatacagatcagggctttttcatctgctccacagaggtgtaccctaggagctgttgc96420 aaacagtccatgtggagggtgtgagtaagatgtttcccttgaatttgccagaattacttt96480 tttgttgttgttgttgttttttctgagacagattctcgctctgttgcccaggctggaggg96540 cagtggcgagatcgcgcagctCc'LCtgCaaCCtCtgCCtCtCgggttCgagtgattCtCCt96600 gcctcagcctcccaagtagctgggattacaggcttgtgccaccaagcccagctaatttct96660 tttgtatttttagtagagatggggtttcaccatgttggccagactggtctcgaactcctg96720 gcctcgtgatctgcctgcctcagcctccaaaagttctgggattacaggcgtgaaccactg96780 cacccggtcccttgttaagtttattttggtgggaagcaaaggaggtttcagcttttaaaa96840 agtttgaaaattattgctctggtaataattaaagatttgagagtaaatatgctttctagc96900 agaaagaataaaagaagaacagatagcctcaagaaggggagccaaagaagcaggctatat96960 ctgacacactgggtgttgataaatgggtattaaaagaatgagagcaatgagcagatagaa97020 gaggaaattaggagagtataataccatggagaccaagaaagatagactatcaggaaggag97080 tggtaaaaataagttactagttctaagagagatgttaagagggaccggggaaagccttgt97140 acaaatgagttagtagcattttacattatatacatctaattaagaaacaatgcgagagtc97200 tcaccattcctatagactcttacttgtacttgtctgaacacgaaaactggcttttgttta97260 taaataagctaaaaattattttgctccaatttctcatgaaaataaaaataaaccttcttt97320 taacattgaaaaaatagtttgaagacagtcactcttcattttgtaattcccacaactatt97380 attgaatgactgaaattatctttattctgaagccaaaggggtgatactgatatttcttca97440 gactactaaaaatatattttatgaatttttagtgtgctttatctttttttgttttttttt97500 ttgagatggagtttcactcccgttgctcaggctggagggcagtggtgcaatctcagctca97560 CtgCaaCCttCgCCtCCCagattCaagCaattCtCCtgCCtCggtCtCCCaagtagCtgg97620 gattacaggcacctgcccccacacccagctaattttttgtatttttagtagagacagggt97680 ttCaCCatgttggtcaggCtggtCttgaaCtCCtgaCCtCaggtgatCCaCCCa.CCttgg97740 CCtCCCaaagtaCtgCgattgcaggcatgagccaccatgcctggcctgaggaatattttt97800 ctaggttccccccaccccaagcatttattctgcaattttagttttgttcctaaagcaagc97860 aaggtttaaggatttaaaaataatccgtattttagaatgctttctggctttgttactttt97920 tatccacagtagaagttctcagagaatgatctccctcttttaatttaactttttggcaca97980 gtattttgagaattataaataatattagaatgttttctggctgggtgtggtggctcatgc98040 ctgtaatcctggctacttgggaggctgaggcaggagaatcacttgaacatgggaggcaga98100 ggttgcagtgagccgaggtcatgccactgcactccagcctgggtgacagagcaagactct98160 gtctgggaaaaaaaaaaaaaaaaaaaagagtgttttctttcctattttccaccacttgat98220 taagttacttttcctcttaagtattttttgctgagtatgctgacttaagagtaatgttac98280 aaaatttaatttttaaagttctctgaaagcccctttatgagagttttaggctatcaaatt98340 gtgtttaattcttaacaattttttgaaaaattatagcttcaatatccgtacattccccac98400 aaaaaagcactaaaaatcatgccttgctggaggctgcaggaccaagtcatgttgcaatca98460 atgccatttctgccaacatggactccttttcaagtagcaggacagccacacttaagaagc98520 agccaagccacatggaggccgctcattttggtgacctgggtaagtaactatcatttttta98580 ttaacttgtattagaaggatttgagtacaatatgtgaaacttctgtcataggatacagaa98640 ctatataattggaaagtgctttggaaaaaatgtatttaaaataacagctacaagtataat98700 gggtagctgtgttgtgttcctgtaaatatagaatataaagcatgcccagtagaaaaacaa98760 gcatttccagaagaaatatatctgatcactaaatataaatatatgaaaaagatgtctcac98820 tttattactgagggaagtgcaaattaaaataatcagttaatgttctcctaacacattagc98880 atattttttaaagtttgacaatttgaatgtcagtgaagatgcagggaaatacccctccta98940 tttagtgataatataatctggtgaagactctttggaaagcaatttggaaatcagtataaa99000 atatgcatgt catttaggcc actctttcta agacctagcc ctcagatatg ctcattcata 99060 tgtgcaggtg tgtatgtgtg tgtgtgtgtg tgtgtgtgtg tgtatatgta tgtatgtatg 99120 tatgtatgta tgtatgttga aggctattca ttatagtatt gtttgtgata gcaaaaaatt 99180 atggacaaca tataaatatc tgttataggg aaataaccaa attgtggtat acgcatgctc 99240 tggagtataa tatagccatt tgtttctatt tatttatttt cttgagacag ggttttactc 99300 tgttgcccag gctggagtgc agtggtatga tcatggttca ctgcagcctt cacctcctgg 99360 gcacaagcca ttctctcgcc tcagcctcca gagttactag gactgcaggc atgtgtcacc 99420 acacccagat aattttttaa ttttttgtag agacagggtc tcactatgtt gcctaagctg 99480 gtctcaaact cctggcctca agcaattctc ccacacaggc ctcccaaagt gctgggatta 99540 ccaacgtgaa ccaccacacc tggttcagtg tagccattta gaaatctaaa aaagacgtgg 99600 gaaaatgtct aaggcatgtt taaatgtgag aaaagcaagt cacagtatgc atggtaaaat 99660 ccgttatatt aaaataagtt cttccaaaac aaaaacatat gcaggagacc tttattttgt 99720 cagtatttct tacccaaatt tctgcactta gaaaattgca tgtcatgttg tcataagttg 99780 aaaaaaagat ccatgaacca atggacttct aataaaatca gtcctgcttt tgacatctct 99840 ctctactttt gtgtatattc aaaccagagt gtcaatgtgt ttgtggggca cacttagcaa 99900 taatacatag cagacaaaat gcatatagct cagagagtaa aattgtaagt tttgctagat 99960 cactcataaa ttgctgatga gaatttaaaa tggtgcagat gctctggaaa acaggcagtt 100020 tctttctttc tttttttttt tctttttgag acagggtctc actctgttgc gcaggctgga 100080 gtacagtggc gtgattacaa ctcactgcag cctcaccctc ctcaggttca ggtgatcctc 100140 cctcagtctc ctgagtagct gggactatag gcatgcacca ccacgcctgg ctaatttttg 100200 tatttttttt tttttttttt gtagagacgg ggtttcgcca tgtttcccag gctggtctca 100260 aactcctgga atcaagcgat ccacttgcgt aggcctccca aagtgctggg attacgggcg 100320 tgagctactg tgcctggcct aggcagtttg tttgtttgtt tgtttgtttg tttatttatt 100380 tgtagacgga gtctcacagg ctggagtgca gtggcccaat ttttggctca ctgcaacctc 100440 cgcctcccag gttcaagcta ttctcctgcc tcagcctcct gagtagctgg gatgacaggt 100500 gcctgccata atgcctggct gatttttgta tatttagtag atatggggtt tcaccatgtt 100560 ggtcaggctg gttttgaact cctgacctca ggtgatcagc ccgcctcggc ctcccaaagt 100620 gctgggatta caggcatgag ccgtcatccc tggctggtgg tttcttatga cgtgaaacat 100680 gcaattacca tatgacctag cagttgcact Ctgtatttat cccagataaa tgaaaactta 100740 ccttccaata aaaacctgtg cacaaatgtt catagcagct taatattgaa aaactggatg 100800 ttcttcagca ggtgaatgaa ctggttcatt cataccatgg aataccattc agcaataaaa 100860 aggaacaaac tgttgataca tttaaccacc tggatgaata tcaagggaat tatgctgtca 100920 gacaaaaacc agtccctaaa gactacatat agtatgattc cgtttggata atattcttga 100980 aatagagaaa ttaagagaaa tgaaaagatt agtgtttgcc agatgttaga gacagggagg 101040 tgagaggggt aagtgggtgt agttataaaa gtgcaacatg agggatcttt gtgatgttga 101100 agttgtatct tggcagtgga tgcagaaatc tcaatgtgat aaaattacaa agaactaaaa 101160 acaagaatga gtatagataa aactggggaa atctgaacaa gttagagtgt tgtatcactg 101220 tcagtatctt agagtgatat tgtactatag ctttgcaaga tgttaccatg ggagaaacta 101280 aagtgtacaa gggatctcta ggtattatta tttttttaga gatggggttt cactatgttc 101340 cccaggccgg tcttgaactc ctgggctcta gtgatccgcc tgccccagcc tcctaaagta 101400 ctggaattac aggcgtgagc gaccatgcct ggccctttca gtattgtatc ttagaacttc 101460 atgtgaatct agcattatct catagaattt aattaaaaga aattgtaaac ctcacagaag 101520 atcagaattt cctcaagttt gtgatgttga caaagatgaa ctagttgaca ctgacagtaa 101580 gactgaggat gaagacacga cgtgcttcaa aaaaatgatt tgaatatcaa tggattaaga 101640 agaactcttt tgacaaattg atgaaaccct cagtcagttt tataagaatg cccatcttta 101700 tgatcatgct atgaaagcca atttttaaaa aaattttttg tctttcctaa caattagctt 101760 gtggttataa tttaaattta gttaaatata agataaatga ttttttatta agtttagttt 101820 catttttcaa ggtacgatct caaagctact ctttaaccta ctatgaatga ataatgctga 101880 gttcataaca tctttgtaga tatatccaca attttccctc aggataagtg cctacaagtg 101940 gaattactgg actgaaaata atgcagtttg ctaagacttt gctatctgtt cctgaatgct 102000 cctccaaaaa ggttttgcca gtttacatcc tcatgaccag cgaatgagag tgttgcctat 102060 tttcctgtgc ccttgttact gcttaataat ttttgaaaaa aatctaattt gacagacaaa 102120 aatgcatttt atgttaattt gcttttctgg gatttttaat gaggttgagt atagttttta 102180 atatttttat tggccccttt ggaactagta tcataagttt tttttcttaa gaatttatgt 102240 agtctgggct gggcgcagtg gctcacgcct gcaatcccag cactttggga ggccgaggtg 102300 ggtggattgc cgaaggtcag gagtttgaga ccatcctgac caacatggtg aaaccgaatc 102360 tctactaaaa gtacaaaaac tagctcagcg tggtggcggg tgcctgtaat cccagctact 102420 taggaggctg agtcaagaga atcgcttgaa cccgggaggt ggaggttggt tgcattgagc 102480 cgagatcgcg ccattgctct ccagcctagg caacaagagt gaaaagtctc aaaaaaaaaa 102540 aaaaaaaaaa aaaaaagaat ttacatggtc tgaattgcca ttaaaagaga tatgagaatt 102600 attgagtaac aaataacttt ttaataattt aggcaagttt tggacgattg tactttgttt 102660 agaaaccaaa agcatagtat ttgtagtttt tttatttact ttagttgcta ggaagtaaac 102720 tttattcaag gtctctggta ccagttgttg ctaaaagtga ttgactaatc tgtcaatctg 102780 aaattatttg ttgctgaact gctaattctt ttgcttctat cttttaggca gatcttgtct 102840 ggactaccag actcaagaga ccaaatcaag cctttctaag acccttgaac aagtcttgca 102900 cgacactatt gtcctccctt acttcattca attcatggaa cttcggcgaa tggagcattt 102960 ggtgaaattt tggttagagg ctgaaagttt tcattcaaca acttggtcgc gaataagagc 103020 acacagtcta aacacagtga agcagagctc actggctgag cctgtctctc catctaaaaa 103080 gcatgaaact acagcgtctt ttttaactga ttctcttgat aagagattgg aggattctgg 103140 ctcagcacag ttgtttatga ctcattcaga aggaattgac ctgaataata gaactaacag 103200 cactcagaat cacttgctgc tttcccagga atgtgacagt gcccattctc tccgtcttga 103260 aatggccaga gcaggaactc accaagtttc catggaaacc caagaatctt cctctacact 103320 tacagtagcc agtagaaata gtcccgcttc tccactaaaa gaattgtcag gaaaactaat 103380 gaaaagtgag tatgtgattt tcttgtgtgt acatatgtgt ctcactttct ttttttaatt 103440 tactaagcag aacttcagat gaggaataaa atgattggaa tatttttttt ctcctctaac 103500 tacttgtaaa tttgggagaa tttggagagt gtagtagagt cagatcagtg tatggaaaag 103560 gagcaggagt gactggacct tctaagaagt gtgttatcag aattagtaaa tgaagggtca 103620 aatgtcctac ttttcccctc cactgatttt gacatcaaac cattatccac atagccttat 103680 ttcctccctc ggtcttaatt ttattaatat tttactgcac tttgcagata aaatttttaa 103740 aaaattttta aaaattgcca ataagtgaca tttattaagt tcagtgctta gtgtatattt 103800 ggattttatt tattagtcac aagacctttg tgcaggtagt aggcatgatt atcttttttt 103860 ttttgagatg gagtcttgct ctgtcgccca ggctggagtg caatggcgcg gtctcggctc 103920 actgcaacct ccgggttcat gccattctcc tgcctcagcc tcccaaatag ctgggactac 103980 aggcgcctgc caccacaccc ggctaatttt tttgtatttt tagtagagac ggggtttcac 104040 catgttcgcc aggatggtct cgatctcctg actttgtgat ccgcctgcct cggcctccca 104100 aagtgctggg attacaggca tgagccaccg cgcccggact gattatctta tttacacatg 104160 agaaaaccag ggcttagaaa ggttaggtaa cttcctctag gttgtacagt aaatgtggac 104220 ctagaagcat tttgacaaga gcacctgttt ttttttcttc tctattagtt tagaaattat 104280 atactcttaa ttatcacctg ggattttgat tagacagcct tcatgttctt tttcatctta 104340 aatgttcttt gtgtcttaaa gggctaagtg atttcttcag atcttttagt tcactcattc 104400 tcagtgaact aaaatgaggt ctaatctgct actgaatcaa gttttcagca tgttatttcc 104460 ttcctccctc cctccctcct tccttccctc aaccaggctc ccgaggagct gggattacag 104520 gcgcccgcca ccactcctgg ctaattttta tattttagta gagacggggt ttcaccatgt 104580 tggtcaggct gatcttgaac tcctgacctc aagtgaccca cctgcctcgg cctcccaaag 104640 tgctgggatt acaggcatga atcaccacac ctgacggcat gttattttca tcgc2aagtt 104700 actgtaagct gggagaagtg gcacacactt gtactcccag ctactcagga agcttaaggt 104760 gagaagattg cttgagccca ggagttttga gaccaacctg ggcaacacag caagacccca 104820 gctcaaacaa agaaaaaaag ttattgaatt ttttatttct atggatcatt ttttgtagtt 104880 tcttattcct ttcacccttc attcccactt ttgatcccat cttttattta tttagtttta 104940 ttaaatgtat atttgtctga taattctgct atctacagtt ttttgtggac ctgactcagc 105000 atttctttgt ttcttcggat tcagactgtt ggtggcttgt gattttagtg atttttggcc 105060 gtgaacatgt ttcttggact tttgtctgtg ggaattctct gtgtactctg tataaattaa 105120 gttacttcag gtgttttgca ttttcttttg ccatgcacct ggggcctggg tcacta_CCCt 105180 tctggtacca cttaaaactg aatttttgtc ttgggtgctc gtactgatcc tgtatgagta 105240 caggtttata cttactgtag aaatatggtg tttgattatg gggtattgtc ccagatggtg 105300 ctggagtatt aatatgctct ctgttaaact taatgtgttg tccctgtaaa actccaaaat 105360 tctgaattcc agaatactac tggccccaaa tgtttaagat aagggcactg cctgtatttg 105420 tttctgcctc ccactatttt ccttagttta acacaaactc ac,ctttttaa aaaacatttt 105480 gagagaattc agtattggga agagtttcta acctgtttct ggaaatggaa gtccaaagtc 105540 tgtttctgta attgtttttt ttttgagatg gagtctcact ctgtcaccca ggctggagtg 105600 caatgacgta CtCtCagCtC aCtgCaaCCt CCa.CCtCCCg ggttcaagcg attctcttgc 105660 CtCagCCCCC tgagtagCtg ggattaCagg tgCCCaCCdC CatgCCtggC tgatttttgt 105720 atttttagaa gagatggggt ttcgccatgt tggccaggct ggtcttgaac tcctgacttt 105780 gtgatctgcc cacctcagcc tcccaaagtg ctaggattat gtttctgtaa ttgtaataca 105840 tttattgttt ttagaaactg tctttgcttt agtggtaatt ttcaataaaa atagaaatag 105900 cagtggagtt attaaaagag cattagttac atttttccct ttttcattat cttcaaatat 105960 tatatatagt aagtttgacc tttttaaaat gtatacttgt atcagtttta acacatacat 106020 agattcctgt aactgtcacc actataaggg taaagaacag ttagttcctt cacctttgaa 106080 gtCaagCCCC aCCtCtatCC CaaCdCttgg CaaCCgCtga tCtttCtCCg tCtCaatagC 106140 tttgcctttt ctcttttttt ttcttatttt tttttttgag acagcgtctt gctctgtcgc 106200 ccgagctgga gtgcagtgag gcaatctcgg CtCaCtgCaa CCtCCgCCtC CtgggttCaa 106260 gcagttctcc tgccttagcc tccctagtag ctgggattat aggcacgcac caccacaccc 106320 ggctgatttt tttgtatttt tagtagaaat ggggtttcac catgttggcc aggctggtct 106380 caaactcttg acctcaagtg atccacctgc ctcggcctcc caaagtgctg ggattacagg 106440 cgtgagccac tgtgcccaat caggactttt tttttttaaa tttacattca acttgtcatt 106500 tttttcttgt atggattgtg ccttcagagt cacacctaag agccctttgc ctaagcaaag 106560 gtcatgaaga ttttctcata tgtttccttt taaaagtatt gtggttggcc aggtgccatg 106620 gcttatgcct gtaatctcag cactttgaga agctgaggtg ggcagattac gaggtcagga 106680 gatcgagacc atcctggcta atgcggtgaa accccatctc tactaaaaat acaaaaaaaa 106740 aaaaaaatta gccgggcgtg gtggcgggca cctgtagtcc cagctacttg agaggttgag 106800 gcaggagaat agtgtgaacc cgggaggtgg agcttgcagt gagccgagat cgcgccactg 106860 cactccagcc tgggcaacac agtgagactc catctcaaaa aaaaaaaaaa agtattatgg 106920 ttttacactt tacgtttaga tatatatctt ttttgagtta atgtcgtata agtatgaggg 106980 ttacgtcaga ttttttgttt tttgtttatt tttacatatg gatgtctagt tgttctaata 107040 ccatttgttg aaaagacaac ctttactcca ttgaattgcc tttgtacttt tgccatattt 107100 gtctaggcct gtttttggac tcctttttct gtttcatgat gtgtgtgtct attcctttgt 107160 taataccaca tggtcttaat tactgtatag taagtcttaa aattgggtaa tgctggcctt 107220 ataaaacgaa ttgggaagtt tttattttta ctcttatttc cattttctag aagagattgt 107280 gtagaattgg tgtcatttct tctttagata tttggttgaa ttgggaagtg atgccatctg 107340 ggcctagggt tttgtttttt gtgtgtgaga cagagtctca cttctgtcac ccaggttgga 107400 gtgcagtggt gagatcttgg cttactgcaa cctctgcctc ccaggttcaa gttatcctcc 107460 tgcctcagcc tcccaaatag ctgggattac aagcgtgtgc caccatgccc gactaatttt 107520 tgtattttta atgcagacag ggtttcacca tgttagccaa gctggtctcg aacttgtgac 107580 ctcaagtgat tagcccacct tggcctccca aagtgttagg attatagatg tgagccaccg 107640 tgcctggcag gggcctaggg ttttcttttt cagagtattt taaactatga attcagatta 107700 tttaatagat ataggactat ttaagttatc tgtttcttct tgagtgaatt tttactgtag 107760 tttatggcct ttgagtaatt aattgtattg aattgtcaaa tttatgagcg tgtaattatt 107820 tatagcattt cgggtttgta gtggtatccc tcttttattc ctggtgttgg caattgtgtc 107880 ttgtttttct ttgtcagatt gtatagggat ttattagtct tttcaaagaa ctagcttttg 107940 ttttgatttt tctgttgttt tgttttcaat tttattgatt ttctgctctt tattatttct 108000 tttctattat ttctgcttgc tttgggttta ttttactctt ttttttttct ccaagttgct 108060 taaagtagaa acttagattt ctggtttgag acctttcttt tctaagataa gcatttaata 108120 ctgtaaattt ccttctaacc actgctttag ttacaccccc acaaattctg gtattttgaa 108180 ctgagcacaa atgaaatgtt ctaatttccc ttgaatctta ttcttttacc aatgaattat 108240 ttagaaatat gttatttagt ttgcaagcaa ttggagactt ttttcctgtt atttttctac 108300 catttatttc tcatttcatt atattatggt cagagaatat attttgaatg atttcattta 108360 ttaattttta aaaataacat taaaaaattt tttaaaatgt gaatatacca catacagtat 108420 aaagattgta cattctgttt ttggacagtt ttctataaat gtcaagttga tttagttggt 108480 taatgatggt gttcagtttt tctttattct tgctgatact ttgtatgcag ttatatcact 108540 ttattactca gaagagtgtt gaactttcca actacaattt ttttttccaa ttttactttc 108600 agctctatct ggttttgctt catgtatttt gaggctctgt tgttaggtgt gtacacattc 108660 aggatgatat cttctgggtg aattgcctgt tttatcatta tgtaattccc tctttatggt 108720 aattttcctt gttctaagat cagaaatatc tgttgtccaa tttatataga cactgcagct 108780 ttcatttgat tagtgcttgc atggcatatc tttttccatt tttttacttt tgatctacct 108840 ttataattct atttaaaggg ggcttcttgt aggcagcata tagttgggta gtgttattta 108900 tttatttatt tatttattta tttatttatt tattgagaca gagttttgct cttgttgccc 108960 aagctggagt gcagtggtgc aatcctggct taccacaacc tccacctcct gggttgcagt 109020 gattctcctg cctcagcctc ccaagtagct gggattacag gcacgcgcac catgcctggc 109080 tgattttttg tatttttagt agaaacggat tttcaccatg ttagccaggc tcgtcttgaa 109140 CtCCtgaCCt CaggtgatCC aCCtgCtttg gCCt CCCaaa gtgCtgggat taCaggCgtg 109200 agccactgca cccggctgag tcatgttatt tttaatcttt tctcacaata cagggttttt 109260 gttggtaaat ttaattattt taatataaat tttagtataa ttatttacat taaatgtaac 109320 tgttgCactg gggtatttat aatgtgtaaa tataattatt ggtattaata taattatatt 109380 actcataata atattaatat ctttggattt agattaccag tttagtatat gtttttctgt 109440 ttctccctct ttgatttccc cttttttgct tttttttttt ttttaattct tatttttttt 109500 tagtatttgt tgatcattct tgggtgtttc ttggagaggg ggatttggca gggtcatagg 109560 acaatagttg agggaaggtc agcagataaa catgtgaaca aggtctctgg ttttcctaga 109620 cagaggaccc tgcggccttc tgcagtgttt gtgtccctgg gtacttgaga ttagggagtg 109680 gtgatgaCtC ttaaCgagCa tgCtgCCttC aagCatCtgt ttaaCaaagC aCatCttgCa 109740 ccacccttaa tccatttaac cctgagtggt aatagcacat gtttcagaga gcagggggtt 109800 gggggtaagg ttatagatta acagcatccc aaggcagaag aatttttctt agtacagaac 109860 aaaatggagt ctcccatgtc tacttctttc tacacagaca cagtaacaat ctgatctctc 109920 tttCttttCC CCaCatttCC CCCttttCta ttCgaCaaaa CtgCCatCgt CatCatggCC 109980 cgttctcaat gagctgttgg gtacacctcc cagacggggt ggcagctggg cagaggggct 110040 cctcacttcc cagatggggc agccgggcag aggcgccccc cacctcccag acggggcagt 110100 ggccgggcgg aggCgCCCCC Ca.CCtCCCtC CCggatgggg cggctggccg ggcgggggct 110160 gaccccccac ctccctcccg gacggggcgg ctggccgggc gggggCtgaC CCCCCaCCtC 110220 cctcccagat ggggcggctg gccgggcggg ggctgccccc cacctccctc ccggacgggg 110280 cggctgccgg gctgaggggc tCCtCaCttC gcagaccggg cggctgccgg gcggaggggc 110340 tcctcacttc tcagacgggg cggccgggca gagacgctcc tcacctccca gatggggtgg 110400 cggtcgggca gagacactcc tcagttccca gacggggtcg cggccgggca gaggcgctcc 110460 tcccatccca gacggggcgg cggggcagag gtggtcccca catctcagac gatgggctgc 110520 cgggcagaga cactcctcac ttcctagacg ggatggcagc cgggaagagg tgctcctcac 110580 ttcccagacg gggcggccgg tcagaggggc tcctcacatc ccagacgatg ggcggctagg 110640 cagagacgct cctcacttcc cggacggggt ggcggccggg cagaggctgc aatctcggca 110700 ctttgggagg ccaaggcagg cggctgggaa gtggaggttg tagggagctg agatcacgcc 110760 actgcactcc agcctgggca acattgagca ttgagtgagc gagactccgt ctgcaatcct 110820 ggcacctcgg gaggccgagg caggcagatc actcgcggtc aggagctgga gaccagcccg 110880 gccaacacag cgaaaccccg tctccaccaa aaaatgcaaa aaccagtcag gtgtggcggc 110940 gtgcgcctgc aatcccaggc actctgcagg ctgaggcagg agaatcaggc agggaggttg 111000 cagtgagccg agatggcggc agtacagtcc agcctcggct ttcacaactt tggtggcatc 111060 agagggagac cggggagagg gagagggaga cgagggagag CCCCtttttt gctttctttt 111120 ggattatttg aatttttcct taaatttatt tatcttactt atttatttat ttttttgagt 111180 gattctcctg ccacagctcc caagtagctg ggactgcagg catgtgccac tacacccagc 111240 taattttttt gtatttttag tagagacagg gtttcaccat attggccagg ctggtcttga 111300 actcttgacc tcaagtgatc cacctgcctc ggcctcccaa agtgctggga ttacaggcgt 111360 gagccaccat gccctgcctt tttctagaat ttatatattg agttcttgat tgtatctttt 111420 tatgtaggct ttttagtggc ttctctagga attacaatat acatactttt cacagtgtac 111480 tcacatttaa tattttgtaa cttcaagtgg aatgtagaaa acttaaccac cataaaaata 111540 gaactaggga tgaggttaaa aaagagagag aaaagaaatg taataaagat ttaataacac 111600 cgtttttttt tttttttctc tttttttttt gagacagagt ctctctttct gttaccaggc 111660 tggagtgcag tggcgtgatc ttggctcact gcaacctccg cctcctgggt tcaagtgttt 111720 ctcctgcctc agcctactga gtagctggga ttacaggtgc gcgccaccat gcccagctaa 111780 tttttgtatt tttagtagag acggtttcac tgtgttggcc aggatggtct cgatttcttg 111840 accttgtgat tcgctctcct cagcctccca aagtgctggg attacaggcg tgagccaccg 111900 cgcccggcta agtctttaaa tatttttttg acattgcact ttttctcttt tccttctagg 111960 attttagtaa cccaaatgtt agttttgtta ttgtttggca ggttcctgag gctttcctta 112020 cttctttaaa tttttttttc ctgttgttca gcttcgaaaa tttctattca tctgtcttca 112080 aattcactgg ttctttcccg ttatttccat tctgttattg agtctttgta gtgaatttta 112140 aattttgttt attatgtttt ttagttctaa aattttcttt ttttgtgtat gtcttatact 112200 ttgctcctga aactcttatt tgtttcagga gtgatcttat ttcttagagc atggttttag 112260 tagctactta aaatttgttt tatcatccca gcatatgtgt cctcttgatt gtcttttctc 112320 ttgtgagata atgggatttt ctggttcttt atatgacaat taattttgga ttgtatcttg 112380 gacagtttga cttacgttac atgattctga atcttgttta aatcctgtgg aaaatattga 112440 agtttttgct ttaacaagca gttgacctag ttaggttcag tccacaaatt ctaagcagca 112500 ttctgtcggc tctggttcca tcatcagttc agttttgtat cttatctgct tatgtgcctt 112560 tctgtgtcca gtctgggacc tggccaatgg tcaggtccca aagcctttgt acacttttag 112620 aagcagggcc atgcacaccc agctcacgag tggccccggg agtgcacata caactcgacg 112680 ttttcatggg ctccttcttt tctgtgatgt ccctgacacg ttctgccttc taagaacctc 112740 CCtttatCCC tttCCtgttg tCtggCtaga aagtcagggc tttagattCC CtataCttCa 112800 gCaCaCttCC tgtagCtatg tCaaCCtCtg tggCCa.CgaC ttCttCttCt tgggaCtgCa 112860 gtttctcttg tcagaaagta ggattcttgg agctgctgtc attgctgctg tggctgctct 112920 gatgctgcct gggagtcgaa ggagagaaag gaacaaaaca aaacaaccca ggggatttcc 112980 tccactctct ttgatccgtg agagccccct ttcctgttcc tcagaccaga aatagagggc 113040 ctgtcttgga acttcttctt tgtgcatctg gtgtgcagtt tcagcttttg agtccaggcc 113100 aggaggtgct ggacaaactt gtcaggagta cggaggtact gcaagttctg attacttttc 113160 tCagtCCaCC tgcttccaag tccttggatg catttgtcca ttgttttgag ttgcattcca 113220 tgggagagac agaagagtgt gcttatttca tcttgacata cttattagga tttcatatca 113280 aatcaacgga tgatattctc tatattaatt tgctgttttc cctttagcaa gcacattagg 113340 aaaataacac tttaacaccc gcctttggtg gtttctgtca taattattaa tacttgactt 113400 tttttttttt tttgagacgg agtctcactc tgtcctttga ggcattgtcc ccataaactt 113460 ttggtaaagc atcaataatt ttatctttca tccacacaag cttcaccata aatttgatgt 113520 ttattcttcc attttagcag aattcatgtt gctccaatag gggctgtctt caaactgatg 113580 ttttctcctt cttagtgcct cagagtagat cctgttcaga tacgttataa caggttaata 113640 tgagtttatt ttggtgtaaa agtactttga aattcatgca tagttttttc atcatatgca 113700 ttttccatag ctttgaacac ccccatgtaa ctctcctctt ccacaaacca aacaatgaaa 113760 aagcaccttt gtgatggaag tttattttgc aataggaact cacagtgatc taagccctgc 113820 tattcatgaa tataattcat tactggagtc caagttgctt tttggttttt gaagttctct 113880 tcttcccttg caggtataga acaagatgca gtgaatactt ttaccaaata tatatctcca 113940 gatgctgcta aaccaatacc aattacagaa gcaatgagaa atgacatcat aggtaagcag 114000 tgcttgaaac tatggcaaaa aaaaaatgac aaaaaatgca cagaactgac aattttcgtt 114060 attgactaag ataatttttt cttaacatgg aatttagcag ttcccttcct aatttgtttt 114120 ctgagtattt tttatatcgg attatagctc actttaaaag tttctcggct gcattcggtg 114180 cgagggtctt tgcctgggcc agatgggctg cagtgtagcg ggtgctcagg cctgcccgct 114240 gctgagcagc cgggccggcg ggcggctacg ctaaccggca cagaccaccg gatggactgg 114300 ccggcagccc cgcaccagtg cacgaagtgg gcgggacaga aacttctggg gttggaagtc 114360 cagtgaggct aaaagccggt accaaagtct ctaggcatca gggctgcagc ccaagagtct 114420 cacgaccagt gggcaactgg atggccagac aggtgtctca gtggtggcct ctccgtctca 114480 gggcttcatc ccacttctca gtgggcctga cgtccctggg caccctggat gtctacctgc 114540 attagccaga gccatcacat ggcctgtgac ttgccttttt ttgccagttg attgtgccac 114600 acacagtgtc atttctgtgt catttggcac agctggaggt gcaaggagga gggcagcctc 114660 atgtccagtc ccagtttcac gtaactttat tcttctgaat aaagacaatt tgctaacctt 114720 aaaaaaaaaa aaaaaaaaaa agtttttctt atatgttgga cccaaattct taggctttaa 114780 cctgaataac aatgacagca agatcaataa atagtacaca tttattaaac actcactgtg 114840 tcccagacaa tattccaagc actttttatg gatagactca ttttaacttc taaagaactt 114900 tgtgggataa atacagttat tttatagatg aagaaactga agcacagaga agttaagtgc 114960 tttgtccagg gtaacagctc agatatggca gagtcaggat ttgaaactag accctcacat 115020 accttaactg ctgtgctgtg gcagtgtttt tcatactgta ggttgggacc agccttctct 115080 tatgccctca ccccctgcca aaaaaaaaaa aaaaaaaaaa aaatatatat atatatatat 115140 atatatatat atatatatat aatatatata tatataaaat atatatatat ataaaatata 115200 tgtattagta tatatgcata tatagtatat attatatatt agtatatata ctaatatata 115260 atatacatat tagtgtgtgt atatatatat atactagaat aaaaaaatca aagtatctca 115320 gagtagtaag gacaaacatt tcagaaaaat gttttcatta tatatacatg tatgtatgtg 115380 tatgctgatt caacaaatat atttcttata ggttatagca aaatagtttg aaagctttta 115440 ctgtgtttta tcaggaagac cttaggtgaa cgtatattca cagataaaag aggttattta 115500 ttcattcaat aaatattaca ttctcataag tcctaatatt atgtattttt attcttcaaa 115560 aaagttagta tttgtgattt atgaaataag acatgttctt gcacttttag cagatctgtc 115620 ccgatgttgg gcttctttaa tccttagtgt gggtgctttg cactcactca ctgctgggga 115680 cagcaagacc cctgttagtc tcagctgtgt ttcttaaatt ggcccactgt accttccagt 115740 tagctattct ggggtccatg tcatgttggc tccattttcc ttttctttct cccacacaga 115800 taCCtataaC ggctataaca taggcctggt ggctgttggt ggcttatccc tatctgcttg 115860 tatttaaggg gtactgtttc actgagtttt gctgacagat gttgtcatga gatttgaggt 115920 tttctgtgtt gttgctctat ttttatgtgg gaatttgcta ctatcatcat ccctagacca 115980 gcttttccta gtaatacaac agggatgttc tgactgatta gagtttgcct gtttgaagaa 116040 ttggttggct agtgattttt ttttgagggg agtctgtacc agttaatagc ctgactggcg 116100 tgtggataaa aaggaagcag tttcaagtca aataaaacac ttaaaatgaa accacactgc 116160 aactctcttt cttttactta agcttaatca aattaatgat gatgtaatcc catgaaggaa 116220 aagtcttctg aaggatcaag ttgataacat tttgtgatca aagaatttga gaaaacctct 116280 atcccagtgt ctatcattat atattttagg atgttaatta cctgtgtggc tttaggcaag 116340 tcatttttcc tccttgagcc ccattcttaa tcctgtccaa attatttgtc tcctcttgca 116400 gttggactat tttaatatag ctgtccttca agtgagtttt gttcaaagga gccttcactt 116460 tagctcttac tgtgtaccca ctttgcatag tcttgtttta aatgtaatcc ttggattttt 116520 ggtgttgcta actaattact gtttttatgt gaggatttag agtgatccag aatctatact 116580 tgcactacct ccttcatctt ccacaaatgt ttgaagtggt agaattttta aaaactttga 116640 aggtacagct gacagaattt gctgatggtt tggaagtgag tggtatgaga gggaaaaaaa 116700 ggaataaagc atgactgcat tttttgtttg tttgtttgtt tgtttttgag acggagtctc 116760 actctcgcca ggctggagtg cagtggcgtg atcttggctc acggcaacct ccgcctcctg 116820 ggttcaagcg attcccctgc ctcagcctcc caagtagctg ggactacagg cgctcgccac 116880 cacgcctggc taattttttt ttttgtattt tagtagaaac ggggtttcaC cgtgttggcC 116940 aggatggtct ccatctcctg acctcatgat ctactcacct tggcctccca aagtgctgag 117000 gttacaggca tatatataag catataaagt gtgttatagc atacaaacag gtatatatat 117060 aaacatgcag tccacacagc tgataggaat gaggcagtag tgaaggagaa gttgatgtag 117120 gagaggggac agttgttaca ggaaagaagt ctggaggcag aagggatgaa ttccagtgct 117180 cacatagaag attgcttaga tgggagcaag gacaatttat ctagagtcac aggaaagaat 117240 gcagtacacg ggtagagatg caggtgagtt gaaagatgtg agagatgatg gaaataattt 117300 tctgattgct tctatattct caaggaagca ggaagcaaag tcctcagcaa agagaataga 117360 agaggtgtta aatatttgag aaaggagatg tactgtagaa aaaaaaaaaa ctcagtttct 117420 ccttctgaac tctcacaaaa cagaaccctt ccatgactct agttgtgtgg ggttttttcc 117480 CtgtCagCta CCaattCtgC agatgattgt tCagtgaaCa CCaaCtgggt gtCCtCtaag 117540 tcagttcagt tctcacactg tttacctgga gatagcatca gatcccacag attgaggact 117600 ctgtcccaca agactgcctc cacttcagat gccagtctca agtacaagtt gtggcctgtg 117660 cttctgactg accttctata aattggagtt cccacagtcc cctccttggg ttcaataaat 117720 ttgctagagc agctctcaga actcagggaa atgctttaca tatatttacc catttattat 117780 aaaggatatt acaaaggata cagattgaac aggcagatgg aagagatgca tgggcaaggt 117840 atgggagagg ggcacagagc ttccatgcac tctccaggtc atgccaccct ccaagaacct 117900 ctacagattt agctattcag aagcccccct ccccattctg tccttttggg ttttttgtgg 117960 agacttcatt atataggcat gattgatcat tggctattgg tgatcagctc aaccttcagc 118020 cccctcatcc cgggaggttg gtgggtaggg ctgaaagtcc caaacgtgta attctgcctt 118080 ggtctttctg gtgattagcc ctcatcctaa agctctttag aggccacagc cacaagtcat 118140 ctcattagcc ttcaaaagaa tccagagatt ccatgaattt taggcgctgt atgctaagaa 118200 actggctaaa ggccagttgc aatgtctcag gcctgtaatc ccagcacttt gggaggctga 118260 ggcaggagga tcgtttcagg ccatgagatc aaaaccagcc tggtcaacat agtgagaccc 118320 ccttacaaaa aatttaaaaa ttggccaggc gtaatagctc ttgtctgtag tctcagctac 118380 tcagaaggct gaggatcact gagccctgga gttgaaggca gcagtgagcc atgatcgtgc 118440 cactgactcc ggcttgggtg acaaagtgag accttgtctc agaagaaaaa ggaaaaaaaa 118500 aaaactgggc aaagactaaa taacatattt cacagtatca cagatttgta ttgtctagga 118560 aagtgaatgt aaacagacca ggacactagt atgatccctt ggtttcatga aggtcccact 118620 aaagtcatga acacaaagtg agactaggca tcatgttata tggtttttcc agccatgttt 118680 aacagctagc taaatagcta attgtttcgc tgcagtttat tttagcagtt ccttatttta 118740 gcacatttca tgttttaaaa tttctaccaa taacatttta ataaactttt ttacagataa 118800 cttcacaaat ccataatttt ttaagttaca atcccagaaa tagaattgct cattgaaagg 118860 gtatgttcat ttttaaagtt atgctagaaa ctgccaaatt gccttcagaa aaaggtgttt 118920 gtatccccac taacactagt gttagttttc ttgtgccctt gctcaagtat acatattatt 118980 aaaaacaatg ttgggccagt ttactagata aaaggtgtag tgcctcctta ttctaatcta 119040 tttgattact agtgagtatg tatgtctttt cacgttggtc attttatgtt tgttcctttg 119100 tggattgtca tgtcctttgc tcatttttct tttggaacat ttcttagtag tttataagag 119160 ctcttggtat tttaatgata gtaacctttt aactgtcatg catgctgcaa atcttttttc 119220 tgtttgtttg cctttgtatt ttgtttttgg agggtttcta tgtataggaa ttaaatttta 119280 tgttgttaaa tcttttgatt tctgcttttg catatgtact tcaaaagact ttctatttta 119340 agatcaagtg ttacctgtat tttcttttag ttctatttaa aacctcttaa tttatatgcc 119400 tgtgctgtta actcccaagt tgattcacaa gtgtgtatac atagtttgaa tttagtggca 119460 atttaattat ttacaacttc ttttgcagca aggatttgtg gagaagatgg acaggtggat 119520 cccaactgtt tcgttttggc acagtccata gtctttagtg caatggagca agagtaagtt 119580 agttcatatt ttcacattgt gcatcctagg gaatttgggt tcattgttag gaatgggctt 119640 cactcagcta aaaacaaagt atttttgaga atttaaatat tttggatatt tacaagatca 119700 tataaagcat actctatctt ggttaacagt ttcttttaaa tataaattat gtgaactctt 119760 aaaattttca ttttcatttt caatgttaat atttcctaag ttaaaataat ttgtttttag 119820 ttctgaaata atttggggag tgattgagtc tgtagtgatt atgactatta gaattggttt 119880 atttatttaa ataatgcatg tcttcagatg gctctcctaa tttgttagtt aggctttaag 119940 ctaaatggat gctatataac taaatccaca tagatttgtt gaaatggctc cagaggtttt 120000 ttagatttat tactgctatg tgcccttaaa aaaaatctat tcattctttc acttaacatt 120060 tatcagaaga gtgctctgtg taagacgtgg ttaggcatag tgccagtctt gaaggaagtt 120120 acagcctaat aaaagacata gggcatgttg tttggttact gtaatatgaa gtggcatgtg 120180 ttaaatgtca ggggagaact acaaagtcat aaaaaggtgg gagagattac atacaggtaa 120240 aggaatcagg aatgacacca tggggagtaa ggtagtgttg acctaggcct ttaagataca 120300 atagggacag tatggaaaga gtatattttt cccacttaaa ctctttcctt ggtcgttccc 120360 tcaaattttc ccttttgtcc atgtgcaggc actttagtga gtttctgcga agtcaccatt 120420 tctgtaaata ccagattgaa gtgctgacca gtggaactgt ttacctggct gacattctct 120480 tCtgtgagtC agCCCtCttt tatttCtCtg aggtaaagtc tgcatttctt ttcacactct 120540 attcgagcat tccagcctct aactatcaat gctggggccc tgtctatagg aaataacaca 120600 gaagagccaa gtcatttcca aaaagatgta tcattgtttc aagttgtttc tgatggcaag 120660 agtaatttaa taatatatta gagagaacat gaaaattcaa tgtattaaat aactctaatt 120720 ttgagaaacc taattaaact actgcatgta agagagtgca tgtttttaat tatttggagc 120780 tattttaaaa ccacagaatt tgaaacttgc ttccagtgca taaattgcag accagacttc 120840 agaagagaaa aaaagtagta aattttttct tatgctcatc atttttactt tagtcacttg 120900 ataggattgc ccagtgaaga agcatttgca acagacaatg agtatattaa tctttttgag 120960 gcatacagtt tagtataatg ctctttgtta ggcttcaaca agtgaaatta ttttgttgga 121020 aagcaaatga ctattaagta gaaagaggat tcccagtctc acaaagcagt aatttagaca 121080 ctcgattctg cctctttaca agaatacagg tactcagttg atttgttttc tcactccctt 121140 tctttgctat aagtttaaat caacaatttg tttaggttaa tatgtcctca tggaatggtg 121200 gaaatgatca gatataaaat atttggtttg gttagtttac tctttatatg tttgctggca 121260 aggaaccaca aatccagttt agtataattt ttactctagt tcactaaaag tttgcatcca 121320 gctgtgtagg tagtgtttgt ttcttgttaa cttttttttc gtctaaaaga atactttaaa 121380 acttttcaat ctcaaatgac tgtaacttgc tgacaggtgt taacagaaga agtagatctt 121440 tttgtttttt gcttatgacc tgtattttaa tatttgagct tatagattag agattgtgag 121500 agaaatctgt ttatagtctt attttccctt gtgtattttt tcttcctagt acatggaaaa 121560 agaggatgca gtgaatatct tacaattctg gttggcagca gataacttcc agtctcagct 121620 tgctgccaaa aagggccaat atgatggaca ggaggcacag aatgatgcca tgattttata 121680 tgacaagtga gttatattga tagatggatt cagcagatac ttattgaaca tttgatatgt 121740 tttgtggaaa taaagatgaa taaactcagt ctctgttgtc aaggagctca caggaggcag 121800 cataaaagct gcttttatat ggtgtttgta aagctttggg ggttcttaga acaaaagttt 121860 ctgctgggaa aggggaggtg tatgtggggt aaacaggatg gcaatggtgg tgttcaagga 121920 gtgtttccca gaagagagat tttgtttgga tcccaaagaa agaagggaat tttgctaccc 121980 agagaaggca gaaaacaaca ttctaggcaa aggcattggc ccagaagcca tggaaacgta 122040 ggggaaagtg gcactttcaa gaaacttgag tttagataat caaaggagtg gggaataaat 122'100 atgaggatgc tggtactaat tggaatagat tgtaagggac cttgaatgcc tatttatggg 122160 tatattatac tttctgtata aatctgctca ggcacgttgt taattagttt tttattagtt 122220 ttcactgaaa atgagaggat ggaaacatca tacagtaaac aaaattgaaa atatctggtc 122280 aggcagatga tgagcttgtg gccagctctg taacgtatgg tattcttttc atttaacttt 122340 tcttactctg taaaaaaagt aattcgtggt cgggcacggt ggctcactcc tgtaatcaca 122400 acactttgag aggcagaggc aggtgaatcg cttgagccca ggaatttgag accagcctgg 122460 gcaacatggc aaaacccgcc tttactaaaa atacaaaaat tagctgagcg tgatggcgtg 122520 cgcctgttgt cctagctact taggggcctg aggcagaagg atcacctgag ccttgggagg 122580 tcgaggctgc agtgagctgt gatccactgt actccaccct gggcagggca gtagagtgag 122640 accctgtctc caaaaaaaaa aaaaacaaca aaggtaattt gttatttgta tccttaagca 122700 aatgctaaag gggtaacttg gggatagaga aaagtccaca gatgttaggg tttgaagaca 122760 ctaatagtat ctaggccagt ggttcctgaa cattagtctg tgggctcttg ctgggctgtc 122820 tgcataggaa tcacctgaga gcttattaaa aataggtttt caggctggtt gcggtggctc 122880 acgcctataa tcccagcact ttgggaggct gaggcaggcg gattacttga ggtcaggcgt 122940 tcaagaccag cctggccaac atggtaaaac cccgtctcta ctaaaaatac aagaattagc 123000 caggcatgat ggcacacacc tgtaatccca gctactcagg aggctgagga aggagaattg 123060 ctcgagcccg ggaggtggag gttgcagtga gcggagatca tgccactgca ctccaggctg 123120 gctgacagag ggagactctg tctcagaaaa aaaaaaaaaa ataggttttc agtctgggta 123180 ccggtggctc acacctgtaa tcccagcact ttgggaggcc aaggcaggca gatcacttga 123240 ggtcaggagt ttgagaactg cctggccaac atagtgaaac cttgtctcta ctagaaacta 123300 caaaaaatta actgggcatt ttgacgggtg cctataatcc cagctactag ggaggctgag 123360 gcaggagaat tgcttgaacc cgggaggcag aggactgcat ctcaaaaaaa aaaaaaaaaa 123420 aaaggtttcc agtccccctg tctcagaaat tctgattctg caggtttgag gtgtgaccag 123480 gaatctttat ttttagaaga cataccagat aattctgata aatagccagt ttagggatgt 123540 agtctaattt tcctattttg caagtaagga aaataaggcc cagagaggta atgattttct 123600 caaagtcaca gaacaagtta gtggcagaat ttggactgga atgcagttct taatgttctg 123660 tccagtgttt attctggtac agtatgtttg tagaaggtat tacgtaagaa acattgttat 123720 atagatgttg agataggaag agtttacatt tagaaatttg gtctaaaatg cctgaacatt 123780 caagtcgtgg aggagtattg accaacttac tcaatacaac ataggagatt cacattttgt 123840 tacaaaaatg ctgatttaaa aggagagttt tctttttttt cttctttttt attttttgag 123900 atggagtctt getctgteac ccaggctaga gtgcagtgac acgatctcag ctcactgcaa 123960 cctccacctc ctgggttcaa gcggttctcc tgcctcagcc tcctgagtag ctgggattac 124020 aggtgggggc caccacgccc agctaatttt tgtattttta gtagagacag ggtttcacca 124080 tgttggccag gccggtcttg aactcctgac ctcaagtgat ccacccacca ctgcctccca 124140 aagtgctggg attataggcg tgagccactg tgcccagcct gcttgttttt gtatcatata 124200 tatgcatcat cataatcatg cattatcaac ctttgtattt ctgtcaggac atagaaacca 124260 ttagagtgct tggaagagag cctttttttt tttctcgcat ttaatgcttt ttttggtatt 124320 catttcataa tcagcttacc aaaacattac ctgcattata ccccatcaag gtagaaatct 124380 ttgtgttatc aatattggtt actccctttc cacaccgagt catcagtaag tcctgttcta 124440 tccaaatagg tcatatgcat ctagctcacc cctcagtgct gttttgtttt gaatttgtac 124500 atgtttactc ctgatgcctt gtagttatga tgatgtgttc ttattttatt ctgtgcatac 124560 aagttctcag ctcgcttttt agggaaaatg accatgtctt cctttcctat aaattecttt 124620 ctatctatca agtcctcaac agagaatagg tacccataaa tatgtgattg ttagtttctt 124680 tgcctcagtt gtagtctgat ccttacagct tttaaacaac agtagagttc accgtcaaga 124740 actaaggatg gttggcaggc agatagaaag gtagcaagtt gacccaacta tctctgggga 124800 agtgggaaca aagaaaggtt acatcagcac tgtcatcaca tagctctata gttctaggcc 124860 tgcaggctca atcaagtagc cttgtataag attctctgga ggaggtgctg aaagttgctt 124920 atacttgcta tggaatttga ttttacttcg gatatctttt taccataggt acttctccct 124980 ccaagccaca catcctcttg gatttgatga tgttgtacga ttagaaattg aatccaatat 125040 ctgcagggaa ggtgggccac tccccaactg tttCacaact ccattacgtc aggcctggac 125100 aaccatggag aaggtaaccc agaacttcaa acgtatcaaa ctacaagaag ttttattggt 125160 agaactcata aaatataagg tgggaaaacc aagcagaata gcacagtgga aattgaagca 125220 gtccagcaaa gtgattaaga gcagaggcct tgagtctggc ctggtatgta cagtcacgtg 125280 ccacataaca ttttagtcaa cagtggactg cgtgtacgat ggtcctgtac gattataatg 125340 gatcaaagct ggtagtgcaa taataacaaa agttagaaaa aataaatttt aataagtaaa 125400 aaagaaaaaa gaaaaactaa aaagataaaa gaataaccaa gaacaaaaca aaaaaaatta 125460 taatggagct gaaaaatctc tgttgcctca tatttactgt actatacttt taatcattat 125520 tttagagtgc tccttctact tactaagaaa acagttaact gtaaaacagc ttcagacagg 125580 tccttcagga ggtttccaga aggaggcatt gttatcaaag gagatgacgg ctccatgcgt 125640 gttactgccc ctgaagacct tccagtggga caagatgtgg aggtgaaaga aagtgttatt 125700 gatgatcctg accctgtgta ggcttaggct aatgtgggtg tttgtcttag tttttaacaa 125760 acaaatttaa aaagaaaaaa aaaattaaaa atagaaaaaa gcttataaaa taaggatata 125820 atgaaaatat ttttgtacag ctgtatatgt ttgtgtttta agctgttatg acaacagagt 125880 caaaaagcta aaaaaagtaa aacagttaaa aagttacagt aagctaattt attattaaag 125940 aaaaaaattt taaataaatt tagtgtagcc taagtgtaca gtgtaagtct acagtagtgt 126000 acaataatgt gctaggcctt cacattcact taccactcac tcgctgactc acccagagca 126060 acttccagtc ttgcaagctc cattcatggt aagtgcccta tacagatgta ccatttttta 126120 tcttttatac tgtattttta ctgtgccttt tctgtatttg tgtttaaata cacaaattct 126180 taccattgca atagtggcct acgatattca ttatagtaac atgtgataca ggtttgtagc 126240 ccaaaagcaa taggttgtac catatagcca aggggtgtag taggccatac catctaggtt 126300 tgtataagta cactctgtga tgttagcaca atggcaagca gcctaacgga aattctgttt 126360 attgattgat tgattgattg attgattgag acagagtttc actccattgt ccaggctgga 126420 gtgcagttgc acagtcttgg cacactgcaa cttctgcctc ccaggttcaa ccaattatcc 126480 tgcctcatcc tcccaagtag ctgggattac aggcaggcac caccatacct ggctaatttt 126540 tgtattttag tagagacagg gtttcaccat tttggccagg ctgttctcga actcctgacc 126600 ttaagtgatc tgcctgcttt ggcctccgaa agtgctggga ttacaggcat gagctaccat 126660 gcctgggcag taactgaaat tctctaatgc cattttcctt atctgtaaag tgacgataat 126720 atgcacgttt acctcaaagt tactttgatg attaaagtaa ggtaatgtat ataaaataca 126780 tattaacata gtacctgaca catggtaagc atcaaaaaat gttaactact tttattacta 126840 ttattattac gtatttttaa ataattagag agcagtatca aaaattagct gggcgtagtg 126900 gcatgcacct atagttccag ctactcagga ggctgaagct ggaggattgc atgagcctgg 126960 gaattaaagg ctgcagtgag CCgtgttCat gCCCCtgCaC tccagccttg gtgacagagc 127020 aagaccctgt cttgaacaat taaagaaggc attatgccgc aacgttagct tagaaatgat 127080 ccacatatat caccagtaac tgtcaacagg attggaaccc tagttttggg tattatgatc 127140 acaaggtatt attaatagct tattaataat aaagcgttgg ctaggcacgg cgactcacat 127200 ctgtaatccc agcactttgg gaggccgagg tgggtggatc acctgaggtc aggagtttga 127260 gaccagcctg accaacatgg agaaacccca tctctactaa aaatacaaaa ttagccgggc 127320 gtggtggtgc atgcctgtaa tcccagctac ttaggaggct gaggcaggaa aatctcttga 127380 acccgggagg cagaggttgc agtgagctga gatcgcacca ttgcactcca gcctgggcaa 127440 caagagcaaa actccgtctc aaaaatataa ttataataaa taaataaaag taaagtattg 127500 atgtttgtga atgatttatt cttctaatga actagaggag atttttccag gaatttcaga 127560 gccagtgagg ttatgttgct tgtatgtgtc atgtgtatcc aggtgaaaaa acttaattaa 127620 acgctattat ataataccat acataaaaac tgaattttag gaatactgaa gaatgacata 127680 tagaagtcaa atcattaaat agctagtagt aaacagaata gagtgtcagc tgttacccaa 127740 tgatgataat attttcacga ttaaaattaa accttttctg attttaaagg aaaagttcag 127800 atctgtatca tataaagaat gtaaattttc agggtaataa aattaaaatg cagagagaaa 127860 aatgcaaaaa tagttcttac tagatgtgtg tatgtaagga acttagacta attttaagaa 127920 cactgtcaag accctggtag ttaggtagga aaaaagacat gaatgattca ttcaacaaaa 127980 actttgagta tttctgtgct agatggtagt gttacagtgg taaacaaaat aaatgtgttt 128040 ctgctatcct ggagcttagt ctacaaaaaa ggtacatatt ggccgggcac ggtggctcac 128100 gcctgtaatc ctagcacttt ggaagatcga ggcgggtgga tcacctgagg tcaggagttc 128160 aagaccagct tggccaacat ggcgaaaccc cgtctctact aaaaatacaa aaattaactg 128220 ggtgtggtgg cggacacctg taatcccagc tactcgggag gctgaggcag gagaatcact 128280 tgaacctggg agacagaggt tccagtgagt cgagatcatg ccactgcatt ccagcccggg 128340 ggacaaaagc gaaaatacgt ctcaaaaaaa caaaaacaaa caacaaaggc acgtattaaa 128400 tacgaacata aatatttaca aattatactg aataagttct catgtttatt atttgcttgt 128460 ccagttacaa acttttcctt cgtagaatta gaaatataaa taataaacat gagaactcat 128520 tcagtataat taataattat taaatgtaaa taaaaacatc tatgtacaat taggcattta 128580 tttaagaatt atttgaaaaa aaaacaatgt ggaaacagat attttgatat attgctagtg 128640 attgaaattg ataatgttct tttgaagagt aaagtgacca tatatattaa agttaaaatt 128700 taactcagca atcacacgcc tggtgagtta tcttaaggaa atcagtttga aagtaaaatc 128760 aatatatgca caaagacttt aacatttatc ataaaccaga aaaatcgagt ttcaaattat 128820 atcctatgga ctattttctg ctaaaaagta ttaatatcaa ctttatgtaa tactttcgtg 128880 acaaatattt tgggggagaa aacccaacaa aattacatgc attgtaattt tttttttttt 128940 ttttttttta gacagtcttg CtCCagCgtC CaggCtggag tgcagtggtg CaatCtCggC 129000 tcactgcaac ctccatctcc caggttcaag caattctcct gcctcaggcc tcccgagtag 129060 ctgggattac aggcgctcac caccatgcct agctaatttt tatagttttt agtagagatg 129120 gggtttcatc atgttggcca ggctggtctt gaactcctgg tctcaagtga tccgtctgcc 129180 tcggcctcct agagtgctga gattacaggt gtaagccact gcacccagcc ttatgcatta 129240 taattttaat ttgtaaactg tacaaaggga taatacttgt agtacaacaa gaagtaaaaa 129300 catttgttat aggtagttaa catttgtaac cagtagaatt ataggtaaaa tttatttatt 129360 taaaacagtt ttagttggat ttgatttcaa ctttaaaata atgcttttca tctctatcag 129420 gtctttttgc ctggcttttt gtccagcaat ctttattata aatatttgaa tgatctcatc 129480 cattcggttc gaggagatga atttctgggc gggaacgtgt cgctgactgc tcctggctct 129540 gttggccctc ctgatgagtc tcacccaggg agttctgaca gctctgcgtc tcaggtattg 129600 actgattgcg tctgccatta gggagaaaag catacacatc ctttccttca catcccagta 129660 acagatccta ttatttgtaa attttaagtt gtggaaaaaa aagataaaag ccaggcacag 129720 tggcctgtgc ctgtaatccc agcactttgg gaggctgcgg tgggcggatc acacgaggtc 129780 aggaattcga gaccagcctg gccgacatgg tgaaacccca tctctactaa aaatacaaaa 129840 attagccggg catggtggca ggcacctgta atcctagcta cttgggaggc tgaggcagga 129900 gaatcgcttg aacccaggag gcagaggttg caatgaacca aaatcacgcc actgcactcc 129960 agcctgggtg acaaagtgag actgtgtctc aaaaaaaaaa aaaaaagaga gaaataaaat 130020 tagcctactt actatcttct aatcaaagca tttgtggtaa cttaaaatat actgtattgt 130080 aaagtatcat gctgtttcat ttaggccatt attctatttg aatctgtggc tgtttctctt 130140 aataaatcaa gtaatatgga atatattcat agcctctgaa gagctcttta tgtaagtatt 130200 tatttaggat actttttgta aaataagtga atgaattctt aggtctcctt tttttttctt 130260 ttcttgagac agggtctcct cgctgcaacc tggaaattct gggctcaaat aatccaccca 130320 ccacagcctc ctgaatagct gggactagag gcatgcacca ccacgcctgg ctaatttgaa 130380 attttttttt ggccaggcat gatggttcac gcctgtaatc ccagcacttt gggagaccga 130440 ggcaggcaga tcacgaggtc gggagatgga gaccagcctg gccaacgtgg tgaaaccccg 130500 tctctactaa aaatacaaaa attagctggt tatggtggct catgcctgta atcccagcta 130560 cttgggaggc tgaggcagga gaatggcttc aaccagggag tcggaggttg cagtgagccg 130620 agatcacgcc actgcactcc tgcatggtga cagagtgaga ctccatctca aaaaaaattt 130680 tttttttaaa tgatggagtc ttgctgtgtt gctcaggctg gtcttgaacc cctgacctca 130740 aatgccgcct gcttcagcct aagtttcttt tttttttgta aagagacagg gtcttgctat 130800 gttggccagg gtagtctcaa actcctggct tcaagcagtc ctcccacctt ggcctctcaa 130860 agtgctggga ttacaggcgt gaaccactac ctataatgtt gtgtttcact caaggccttt 130920 tgatttcgtt ttgcattacc gtgccacatt gtgcatttcc ttgacctttt ttgggttttt 130980 tggagtgctt tcatatgtta aaccatacct gattctcctc aaaatcacac aaagtagaat 131040 atcctaagac aagaaatcta aggaggcata aagaagttaa ctggttttat taaactcaca 131100 cagtaaatga tagagccaga aatattcccc ttctagtgtt cttcaccatc agcttaatgt 131160 agcataataa ttttctaatt actgttgaca aataaataac cctttgaatt ttcaatactg 131220 ggccttggat aaattttcct aatttgtaag agagtattat cgtattgcca tttacaaagc 131280 tctcctgagt atctttttct tctgttaagt ttacctagga gataaactgc tgagtatggt 131340 tgccattttg gttttttgat ataggttaga atgtcttggt tttttttttt tttttttttg 131400 gtttttgttg ttgtcattgt ttgagacagc atcttgctct gtcgcccagg etggagtgca 131460 atggcacgat cgtggctcac tgcaacctcc acctcccggg ttcaagcaat tctcctgcct 131520 cagcttcctg agtagctggg attacaggca tgtgcaacca cacctggcta atttttgtgt 131580 ttttagtaga gaaggggttt caccatgttg gtcaggctgg tattgaactg ctgacctcat 131640 gatccacctg cctcggcctc ccaaagtgct gggattgcag gcatgagcca ctgcacctgg 131700 ctgaatgtct tgtttttgat taggcactta agaaaggcct aggtactaac cataaaatat 131760 atttttatac cttttgttga tactatatat atagaaaact gcacttatca taaccttaga 131820 caccttgaag aatgttcaca agcagaacta acccatgtga cccagcatcc agatcaaaaa 131880 CagCattatC agCCCCtCta gaagCCCtCt tgggCCCCtt CCattCaCtg tCCttCttgt 131940 CaCCagggta gCtaCtatCC tgaCttttga tggCatagat tagCattaCC tgttCttgtC 132000 attttataaa taaaaccata ctgtgtattc ttttcttgta cagctttatt gtgctaattc 132060 acatttacat catacaattc agtggttttt atatggtcac agagttaggt aaccattacc 132120 acatcgattt tagaacattt ttttcactcc agatagaaac cccctttact taaactccaa 132180 atcccccact ccaccagccc taggcagcca ctagtctact ttttatctct atagagacaa 132240 tagatttgct tattctggac atttcataaa catggaaccg tatattatgt ggtcttttgt 132300 tgccaactgt ctttcactta gcatcatgtg ttcaaaagag catcatgtta tccatgtttg 132360 gcatgtatca gaattttatt cctcattatg gccaaatatc ccattgcaag gatttatgac 132420 attttatttg aattgtaccc tcctttctgc catttatcaa taatgctact gtgaccattt 132480 gtgtacaagt ttttgtgtgg atacaggttt tctttttgtt tttaaatttg aggtggagtc 132540 ttgctctgtc gcccaggctg gagtgcagtg gcacaatctc ggctcactgc aacctctgtc 132600 tcctgggttc aagcagttct cctgcctcag cctcccgagt atctgggact ataggcacgc 132660 accaccacgc ccagctaatt ttttagtaga gatggggttt caccatgttg gccagtctgg 132720 tctcgaactc ttgacctcaa gtgatccacc catctcggcc tcccaaagtg ctgggattac 132780 aggggtgagc cactatgccc ggctgtggtt ttcatttctt ttgttgtata tacataggag 132840 tagaattgct gagtcaagag gtaactctta aacttattga aaaactgcca gattgttttc 132900 cgaaaaggct gcaccatttt gcaatcccac cagcagtgta tgagttttac agcttctcca 132960 catttcattg gaacttatta tctgtttggc tgtttttaaa aatgatagtc attccaataa 133020 gttctacttc agtgtggttt ttgcacttct ctgatgagta atgatgttga gcatcttttc 133080 atttgcttat tggcctttgt tctagctttg gaaaaatgtt tattcaaatc ctttggccat 133140 ttttattttt atttttattt atttattttt ttttgagacc aagtctcact CtgtCagCCa 133200 ggctggagta caatggtgtg gtctcagctc aCtgCaaCCt CCgCCtCCtg tgttcaagtg 133260 attCtCCtgC CtCagCCtCC CgagtagCtg ggattacatt tcaggcacct gccagcatgc 133320 cgggctgatt tttgtatttt tactagtgac agggtttcac catgttagcc aggctggtca 133380 caaactcctg acctcaggtg atctgcctgc ctaggcttcc caaagtgctg ggattacagg 133440 cgtgagccat tgggcccagc ctagattttc ttttttcttt ttttttttga gaaggagtct 133500 tgctcttgtt gcccaggctg gagtgcaatg gcacaatctt ggctcactgc aacctctgcc 133560 tcctgggttc aagcgatttt cctgcctcag cctccccagt agctgggatt acaggtgcct 133620 accaccacac ccagctaact tttgtatttt ttttagagac agggtttcac catgttggcc 133680 aggctggtct caactcctga cctcaggtga tccacctgcc ttggcctccc gaagtgctgg 133740 gattaccggc atgagctacc aggcccagcc aattttctca ttatattgcc caggctggtc 133800 tcaaactcct gggttcaagt gatcctcctg ccttggcctc ccaaagtgtg gggagtacag 133860 gcgtgagcca ccttgctcag cccctttgcc catttttaaa ttagattgcc tttttatatt 133920 gagtttcagg agtcctttat atattctaga taaatgtccc ttatcaaatt atattatttc 133980 caggtatttt cttcattctg tgagttgtct ttcctctacc ttttaaaaaa ggtgggtttt 134040 tgtttgtttg tttgtttgtt tttttaagat aaggtctcat tctgctgccc aggctggagt 134100 gcagtggcac aatcacagct cactgccacc tcaacttcct gggccgaagt gatcctctta 134160 cttcagcctc ctgaatagct agggccatag atacacacta tcacacccag cttttttttt 134220 ctgtttgtag agacagatct tactgtgttg cccaagttgg tctcaaactc taggctcaaa 134280 gtgattCtCC Ca.CCtCtgCC tcccagagtg ctgggattac aggtgtgagc cacacgcaac 134340 ctgtcttttc actattaata gtgtcttcct gcttcagcct cccgagtagc tgggattaca 134400 ggcacccacc accatgcctg gctaattttt ttgcattttt agtagagaca gtgtttcacc 134460 atgttcaccc ggctggtctt gaactcctga cctcaggtga ttcacctgcc atggcctccc 134520 aaagtgctgg gattacaggc gtgagccact gcacccggcc aaaatattgc cttcttaaca 134580 gtattgtctt ctaatttgtg aacatggatg tatcttcatg tatttatgtg ttctttcatt 134640 tcagcagaat tttgtagttt tcagagtaga agcctttcac ctccttgggt catttattcc 134700 tatgttttaa gttcttttcg attccattat aaatagaatt gttttcttaa tttcattttc 134760 agattgtttg atgagagagc atagaaatac aagtgatttt tacatgttga tcttgcaact 134820 tcaactttga taaatctgat tgttagctct aatagttttc ttgtggattc tttaggattt 134880 tcaatatata agatcatgtc atttatggat agagatagtt ttttttctgg ctagaactta 134940 cagagcaatg atgagtagaa gtggcagaag caaaaatctt tgtcttgttt cctatctgac 135000 agggaaagct ttcagtttca tcatttaata tgatgttagg tgtgggtttt caataaatgc 135060 cttttttcag attcaggaat ttccctatca ttcctgattt tttaaggctt tttttttttt 135120 ttaaatcatg aaagggtgtt gaatattgtc atgttctttc tgtatcagta taaatgatcc 135180 tatggatttt gggttttatt ctgttgatgt gaaatattaa ttgattttca gatgttaaac 135240 caaccttgca tacctgagat gaatctcact tggtcatggt gtataatctt ttcaatatgc 135300 tgctggattc catttactgg tattttgttg aagattttgt atctgaacgc ttaagataac 135360 atttacactc tatcagaaat gaattgacca taaatgtgag agtgtatttg tgggttcttg 135420 attctcttcc attccaaaga tagacataca tccgtctgta tgtctgtctt tatgccagta 135480 ccatactctc ttgattacta ttgctttgta ataagttttg aaatcagaaa gtataaatga 135540 gattttggta tctgagtaac agtcctcata gaattagttg ggaaatattc cctctttatt 135600 ctggtccctc tttctttttt gtttaactgt gtatcttgga gattgttcct tctcaacaca 135660 tgagagccgc tttccctacc ctcccacccc tgctatagag aggtctataa gtgtctgttc 135720 aattatttta tttacttaac ctattactta gtcggggaca ttaagcttgt ttatgtcttt 135780 tattttaaac aatgctgcag tgaataatct tgtatataag tcattttcca tcaatataag 135840 tctctctgta actgaatttt tagaagtgga atttctaggt caacctatgg ctctgtattt 135900 cacaaaaata ccaattctgg tttttcttgt ggaggtgggg agtaggaggt agaatgctgg 135960 aggagaactt gctgtactca gctggctagt cattttagaa aggtttcctt agcttctttt 136020 tgtcatatgg cctcaccaag aatcaaaaac attcctattt accctgtaaa catggggctt 136080 tactacccaa gatacatatt tctggatgta tgacagcttt tcatattgaa gaaataatgc 136140 tgtgagtaca gcacatttgt tggaacttag gtcgttaaga atgtcttata aattcataca 136200 ttatacattt tattttattt tattttttag tttttgatac agagtcttcc tctgtcgccc 136260 aggccagcgt gcagtggtac aatcttggct cactgcgacc tccatctcct gggctcaagt 136320 gattctcatg tctcagcctc cagagtagct atggttacag gcatgcacca ccatgcccgg 136380 ctaatttttt tatttttagt agaaactggg tttcaccata ttgaccatgc tggcctcgaa 136440 ctcttggcct caagtgatcg gcctgcctca gcctcccaaa gtgctgggat ccttgtattg 136500 ggtaaaagat gaatattgag ggctgcatgg tggctcatac ctgtaatccc agcactttct 136560 gagactgagg tgggaggagt cctggagccc aggagggtga ggctgcagtg agttgtgatc 136620 gcgccattgc acttcaacct aggaattata ggcttcagtc actgtgcccg gcatgtacat 136680 tttaatattg tgctttcctc ttttagctat agtatgaggt tacatttcag agtcattgtt 136740 gttaagcatc ttaatagtga tgaggttgag tgaaagttac ttctatttca aacactgaag 136800 aaaattttgt acaaatctgt cacattccaa gcccaggact gattgtttca tatacttcta 136860 attttacaat ttctattgta gtccagtgtg aaaaaagcca gtattaaaat actgaaaaat 136920 tttgatgaag cgataattgt ggatgcggca agtctggatc cagaatcttt atatcaacgg 136980 acatatgccg ggtaagctta gctcatgcct agaattttta caagtgtaaa taactttgca 137040 tcttttaaat tttttaatta aattttacat ttttttctaa tctattatta tatgcccaga 137100 actttcactt agagtgtgca gtataatgtg gtggttaagt ataaaggctc tggagtgact 137160 tcctgggttt taatcttggc tctgccattt attggcagcc gctaacctct tggtatctca 137220 gtttcttcat ctgtaaaatg agaataataa agtgaaaaga tgccaacatc atttactctg 137280 ggctgcataa ctgatacttg gaaaaagtat tcctttgagt ttaagaatta agttggttat 137340 tcattttagc ttgtaataaa aagatagtga ttcataggat atgccactta ctgaaattta 137400 ccacagatcc aatcataaaa tcactttctc ttccctaaag atagcttgat taacatgtaa 137460 aggtgtgtaa aggcttgatt acactaccct gatccgtacc ccagttccca gcagcaccat 137520 gaaaaaggga tttcaacata tttaattact ttcagtagaa agtaacagtg gtaggccagg 137580 cgcagtggct cacacctgta atcccagcac tttgggaggc cgaggtgggc ggatcacgag 137640 gtcaggagat tgagaccatc ctggctaaca cgatgaaacc ccgtctctac taaaaataca 137700 aaaaattagc cgggcatggt ggcaggcacc tgtagtccca gctacttggg aggctgagac 137760 aggagaatgg cgtgagcccg ggaggcggag cttgcagtga gcttagattg tgccactgca 137820 CtCCagCCtg cgcagtggag cgagactctt gtctcaaaaa aaaagaaagt aacagtggta 137880 ttgggagact gaggagccta gaaagtactt gaaggaagta aaaggtttgt ttgaccacat 137940 tgtatttgga aagccagctt tttcagctgt gtcagctttg tgtagtgatt tttagttctt 138000 cttttagaaa ataacggaca aggccgggca cggtggctca cgcctgtaat cccaccactt 138060 tgggaggccg agacgggcgg attacctgat ctcaggagtt cgagaccagc ctgggcaaca 138120 tggtgaaacc ccgtctctac taaaatacaa aaagttagcc gggcgtggtg gcgtgtgcct 138180 gtagtcccag ctactccgga ggctgaggca ggagaattgc ttgaacccgg gaggcggagg 138240 ttgcagtgag ccaagatcac accattgcac tgcagcctgc gcgacagagt aagactctgt 138300 ctcaaaaaat aataataaaa taaaaaagaa tggacagtaa acctaaatga gttcattccc 138360 aaagatgatg ttattcttaa gggatggttc atttatttaa gaccttacat aaagtctatc 138420 aattgcgtga tttttcactt ctgtaattgt gtgtatgtat aatgtaaata tatatgtttt 138480 tgttttgttt tggttttttg agacggagtc tcgctctgtt gctcaggctg gaatgcagtg 138540 gtgcaatctc agctctctgc aacctctgtc tcccaggttc aagcgtttct tctgcctcat 138600 cctcccaagt agctgggact acaggcacgt gccaccacgc ccggctaatt ttttgtattt 138660 ttagtagaga tggggtttca ccgtgttagc caggatggtc tcaatctcct gacctcgtga 138720 tccacccgcc ttggcttccc aaagtgttgc tattacaggc atgagccacc acacccagca 138780 tgtatttttt aaatgtataa aatgaagcag aaaagagaaa tgataatttt tcttcatctt 138840 gaaagattat cttcaccagg cgcagtggct cacacttgta atcccagcac tttgggaggc 138900 ctcggcaggc ggctcacttg agttcgaaac cagcctggcc gacatggtga aactccgtct 138960 ctactaaaaa taaataaata aagatggttt taatatatgt tttagtttta tgattttagc 139020 atctttctga aatttttctc aaggcaagta aatttgtatc agttggtata ttggtaccca 139080 tctatgaaat aacttattag gaagatatct ctaaaataag atcactttgc ctaaaataaa 139140 ctgatatatt gatgttcaca gaatttttct tttaaccgac ttgataaatg cattattctt 139200 gacgtcaagt gatccacctt cctcagcctc ccaaagtgct gggattacac acatgagcca 139260 ccgcacctgg cattattctt ataaaaggtt aaatttctag ttaagtttaa tgtcctcttt 139320 gttcatgtac cattgcttat tttcttccct tcctactcac agtaatcatt cttatggtat 139380 gcacttttgt ttgcttattt ttatgtaatt gatattacgc tccattctgt acgttgtact 139440 ttcattcaca gtgagttttg gacattccta tgttcatcta tacagactta cttcatttta 139500 actacactgt agtattccgt atgtaatatt tactataact catcactgta gcagagcatc 139560 tcatagtgta tgtattactg ttttgccatt ttggtatcaa tgagtattta agtcatttgc 139620 agtttttccc tcttataccc agtattacag aggatctctt tttatatgct tctttgtacc 139680 aagaggcaga ttaaaaaatt tttttttgaa aaaatttttg aaaaaaaatg aaatgaagtc 139740 tcactatgtt gcccaggctg gtctcaaact cctaggctca agcaatcctt ccatcttggc 139800 ctcccaaagt gctggggtta caggcatgag ccaccatgcc tggcctacat tttaaatttt 139860 gatagctctt acaatttact ttgtaaagta tctgcatcat tttatgttct caccagtctt 139920 taataagaat acttcatact tttggctgga cacagtggct cacgcctgta atcccagcac 139980 tttgggaggc cgaggcgggc agatcaagag atcgagacca ccctggccaa tatggtgaaa 140040 ccetgtctct actaaaaata caaaaattag ctgggcgtgg tggcgcaccc gtagtcccag 140100 ctactcgaga ggctgagaca ggagaatcac ttgaacccgg gaggtggagg ttgcagtgaa 140160 cttagatcac accactgcac tccagcctag caacagagtg agactctgtc tcaaaaaaaa 140220 aaaagaatac ttcagactta attttttttc cagtcttaag tgtttgctaa tgagattgag 14.0280 tttcttttgg tatgtctctt gattgttcag gttttttctt ttatgaattg actgttcatc 140340 tctttttcac attatttctg ttgggtgatt ttattagtga cttgttaaaa ttctgtatat 140400 tttttcagca tgacacttca ttattcaaaa aaaaaaaaag attctctatg tttctcgata 140460 ctaatcattg gttggtaata ccttaaaaat aagaccctta ctgtattttt tgcttttttt 140520 tttttttttt tttttttttt tttgagatag agtcttgctc tgttgcccag gctggagtgc 140580 aatggtatga tctcggctct cagctcactg caactgcaac ctctacctcc ctgtttcaag 140640 caattctcct gccttagcct cccaagtagc tgggattaca ggcatccacc acCacaCCCa 140700 gctaattttt gtatttttag tagagacagg gtttcaccat gttggccagg ctggtctcaa 140760 actactggcc tcaagtgatc cgcctgcctc ggcatcccaa agtactggga ttacaggcat 140820 gagccacagt gcctagccac tttttgcttt ttaactttgt tttatagtac tatagtttta 140880 gtataaacag atgtatgtat acacacaact atggctttat aatatgtttc agtcattgtt 140940 agagcaaggc ctaccttttg ggtgcttctt ttacaaaatt gtcttggcta ttcttgtgcc 141000 ttttttctta tttgtgaatt ttagaattgt gaattacctg ttgactcacc atgttttgta 141060 aactgaggat tttgaatgga attgcactca attaaagatt atcttgcttt ctgtgcagca 141120 atgttttatt tcaaataatc cctactttaa attacttagg atagctataa attgtgtttc 141180 tggctttcta gatttagatg aaacgcttta aattgattgt tttctcctaa atttaaaact 141240 gattgttaga agttaaagtc ttctgttcat tcttatttag gaagatgaca tttggaagag 141300 tcagtgactt ggggcaattc atccgagaat ctgagcctga acctgatgta aggaaatcaa 141360 aaggtttgtg gtgtttttat acttcatatt aagcctttac tcacattagt gattgactgt 141420 aagtcaaaga ccacttaagg tttaaactgt ttattttgta aagtaaccac tgtatctttc 141480 accttgtgtt tatagtcaga agtaagtaca agggcttcct gtagtcacat ctttatgcaa 141540 tctcctctga atcaaaagtt agtgaacttg ctttgccact ccagaaggca catgaatatg 141600 aaaaagcatt gtctattttc ttatttaatg gcaaaatacc cgacctaagt tggacttaat 141660 gtttgagacc gtttatttta ttaaattata ttttttctct tttctttttt ttttttgaga 141720 cagttcttgc tctgtcaccc agaccggagt gcagtggtct gaccgcacct cactgcaacc 141780 tctgcttcct aggttcaagc gattttcctg cctcatcctc ctgagtagct gggactacaa 141840 gtgcgcacca ccacacctgg ctaatttttg tatttttagc agagatgagg tttcaccacg 141900 ttggctaggc tggtctcata ctcctgacct caagcaatcc atccgccttg gcttcccaaa 141960 gtgctgggat tacaagtgtg agccaccatg cctggcctta ttaaattatt tttattaaat 142020 ttcctcaaga ttgatgaaag taatgaaata taaaagtaat gaaatatatg tggaaaatag 142080 actggattaa gaaaatgtgg cacatataca ccatggatac tatgcagcca taaaaaagga 142140 tgagttcatg tcctttgtag ggacatggat gaagctggaa accatcattc tgagcaaact 142200 gtctcaagga tagaaaacca aacaccgcat gctctcactc ataggtggga attgaacaat 142260 gagaacactt ggacacaggg tggggaacat cacacgctgg ggcctgtcgt ggggtggggg 142320 gctgggggag gaatagcatt aggagatata cctaatataa atgacgagtt aatgggtgca 142380 gcacaccaac atggtacatg tatacatatg taacaaagct gcacgttgtg cacatgtacc 142440 ctagaactta aagtataata aatttaaaaa aaataaatat atgtggaaaa tattaatagg 142500 tcaaaattca aattgttcat ttaatcagaa gagtagttta gtcaaatcca agggttagac 142560 aacagaaatc ttttttgtca agtgcattct ttgtgactga tttcattttc ttcctggttt 142620 acacaggaag atttcagaaa caaatgtgga tccgtgacag atggtatcta gaagttttta 142680 gtttggttga attgacagta ttttattgag taaaagatac taatttttgt aagaagaaaa 142740 attcaatttt gataagtatg tttaagatta agagctattg gccaggcgct gtggctcatg 142800 cctgtaatcc tagcactttg ggaagctgga gcaggtgggt cacgaggtca agagattgag 142860 accatcctgg ccaacatggt gaaaccctgt ctctactaaa ttagccaggc gtggtggcac 142920 atgcctgtgc acccgcctcc gggtttaagc gatcctactg cctcaggctc ctgagtagct 142980 gggattacag gcgccatggc taatttttgc atttttagta gagacagggt ttcactacat 143040 tggccaggct ggtctggtct caaactcctg acctcaggtg atctgcccgc cttagcctcc 143100 caaagtgctg ggattacagg catgattcac catgtctggc catttatctt attttctttt 143160 tttttttttt ttttgtttga gacggagtct tgctgtgtcg cccagagctg gagtgcaatg 143220 gtgcgatctc agctcactgc aacctctgcc tcctgggttc aagcaattct cctgcctcag 143280 tcttccaagt agctgggatt acaggcgcgt gccaccacat ctagctaatt tttgtatttt 143340 tagtagagac agggtttcac catgttggcc aggctggtct cggaactcct gacctcgtaa 143400 tctgcccacc tcggcctccc aaagtgctga gattacaagt gtgagccact gtgcccagcc 143460 atcttatttt ctttcttttt ttttgtcggg tgggaggggg acagagtcta gctctgtcgc 143520 caggcttggc tcactgcaac ctctgccccc caggttctag caattattct gcctcagcct 143580 cccaagtagc tgggattata ggcacctgcc accacgcctg gctaattttt tgttattttt 143640 agtagagatg gggttttgct atgttgacca tgctggcctc aagtgatccg cccaccttgg 143700 cctcccaaag tactgggctt acaggcgtga gcttgtattg ggtaaaagaa caatattggg 143760 ggctgcatgg tggttcatac ctgtaatctg agcactttgt gagactgaga tggaaggagt 143820 gttggagccc aggagggtga ggctgcggct gcagtgaatt gtgatcacgc cattgcactt 143880 ccacctaggt aatggagcaa gaccatgtct ctaaaaaaca aaacacaatt tttttaagga 143940 atactgggaa gaggtcagtg gtggttttag aacagaggaa gtgccagatg acctttgtga 144000 ggcattggcc aggaagaact ctacagtgtc tttaggtagc ttctgtccat aaggataatg 144060 gggtctcctc cccagtatta atagaaaatc tctgagctgt ttttttttgt ttgtttgttt 144120 tgtttttttt tcctgagatg gagtctctct ctgtcggcca ggctggagtg ctgtggcgcg 144180 atcttggctc actgcaagct ctgcctccca ggttCaCaCC attCtCCtgC CtCagCCtCC 144240 caagtagctg ggactacagg tgtccaccac cacgcccagc taattttttg ttatttttag 144300 tagagatggg gtttcaccat gtcagccagg atggtctcga tctcctgacc tcgtgatccg 144360 CtCgCCtCtg CCttgCaaag tgCtggagtt acaggcgtga gccaccgtgc ctggcctggt 144420 ttttttgttg ttgttattta tttatttatt tatttatttt ttgagacaga ctctcgctct 144480 gtcgcccggg ctggagtgta gtggcacgat gtcggctcac tgcaagctct gcctgccagg 144540 ttCaagCCat tCtCCtgCCt CagCCtCCtg agtagCaggg aCCaCaggCg CtCgCCa.CCa 144600 cgcccggcta attttttgta tttttagaag agacggggtt tcaccgcatt agccaggatg 144660 gtctcgatct cctgatgtcg tgatccgccc acctcggcct cccaaagtgc tgggattaca 144720 ggtgtgagcc accgtgcctg gcctgatttt tttttttttt taatctggtc tcatacctct 144780 gacagctcat gaagaagtge tcctgcttca tatgtatatg tgttagcata gtgttaacat 144840 agcataggtg ttcggtgttt gcagtttctg tttgttttat atgaattaag gtgtattatg 144900 agcagttgaa gatatatagg aaattttttc ccaaaccact atctctgctc gttctattca 144960 ttcagtctgt ttatgttatt ccttcattca ttcattttat agaacagtgg agtgcctact 145020 gtatgcatct attgttctgg gtcctgggga agaaaacaaa gttcctgctt tcatggaact 145080 tacattatat tggcggagac agtaacagac aaacaaatgt agcctgtgta catgtgttac 145140 atgaaaagca gggtaggggg ctgggagaga gtagtaggga gtgctatttt cgaggtggtt 145200 gtcaggaaag gcctcactga ggaggtggca ttttgagtag acctgagcgc agcgggggcg 145260 taagcccagg cagcatgtgg aggaagagtg ttcttggtga aaggaacaag gatagaggcc 145320 cgaagctaga gagctcagca tgatcaagga acagcaagcc ccgtgtggct ggaatggagt 145380 gagcaaagga atgagcagta gaaggtgagt gagttgggag gtcaccagag accatggcaa 145440 ggacttgaaa gtgtcaggga cacattggaa gttggagcag ggaaatgatg ggatttatgt 145500 tttgtttttg ttttatgttt agtgttttta agggattgct ctatcagcta tttggaaaat 145560 ttagtgtagg gcttcaagaa gagaagcaga gaaacaacat tcttgccata gtcatagtct 145620 aagtaaggga tgatggtggt gtggattagg ctggtagtgg aagaccagtc cagttcgggt 145680 tgtatttgaa ggtagaggca aaaagattat atttctacca gcaagcccat ctatgaagtt 145740 acttgtatta ttaatttaat tgagacatgc ccacataaac taataaatag gaatttctgc 145800 agtttggtta aacacccctg tatatcctgg ttcttctttt agttgtccag atgtctcttt 145860 aagtcaagta ttttttggtg gtgtaggagc ctagagattg aatttattca cccaaaaggc 145920 atttgagtga ttactatgtg ccaggcacta tgctgaatgc caaggatgta aataagaggg 145980 cgtagtctca gtCtgtttta CtCCagCttg gttCCttttt aatgaccctg acttgttaag 146040 catatcagtt atcctacaga atgtttaatc ttctgtactt tcctggttgt gttatttagc 146100 ttatttctct ttccttgaca tttcttgtaa actggaagtt acacctatag tcttgatgat 146160 tcgtgttaca cattttagat tagaacacat catgtgttgt atatggtgtt tttgaaagcc 146220 tctctgtata ttggtctgta cattaaaatg ttgcctgaat ggatacacat aaaatttaac 146280 agtgattaca ttagagatga gaagaaagag gtgcctttta cttttcaata taccttttcc 146340 tctgcttttt gaactttctt gccctatgca tacgttattg cttaatcatc cacctcatct 146400 cttcccctgt ggctttctgt tgcatttgga atgaaatcta gcctctttgc tgttacctgt 146460 ggatgtccct tgctggcctc tatcacctta ctttgaacca ctcctttcat ggactgagct 146520 ctcattggac tatcttttat tcttttgctg aagtttcttc actttgagtg cctctgcagt 146580 tgctatttca tggctgtggc aagccctgcc atggctttca tgcaaggatg gttcctcctt 146640 ctcatctcaa tattatctct tcagagaggg accttcccaa ctccgatgat ctaaaatcct 146700 ttgtatatac cactcactac cacttctttc ttttcttttc cttttatctt tttttttttt 146760 tttttttttt gagatagggt cttgctctgt tgcccaggct ggaatcacga ctcactgcag 146820 cctcatcttc ttgggctcaa atgatcctct cacctcagcc tctcgagtag ctggaactgc 146880 aggcacacac caccatactt ggcttattat tttacttttt gtagagacag ggtttcacca 146940 aggctggtct caagctcctg ccgcaagcaa tccacatctc tcagcctccc aaagtattgg 147000 gattatagga gtgagccact actcctggcc tattttctta ttcactgtct aaaattatct 147060 tgttcattta tttacatact tgtttatagc ttatttctca gctggacatg gtgcctcaca 147120 cctgtaatct caatactttg ggaggctggg ttggagaatt ggttgagccc aggacttcaa 147180 gaccagcctg ggcaacaaag tgagaccctg tctataaaaa attgtttaaa aattagctgg 147240 gCatggtggC aCatgCCtgt ggtCCCagCt acttgggagg cagaggtggg agaatcgctt 147300 gggcccagga ggttgaggcg acggtgagcc atgattgtgc cactgcactc tagcctagtg 147360 acagagtgag accatgtgtc taaaaagtaa ataaaaatag tttctctttc atgactagaa 147420 tattacctct atgtgggcag ggagtttgtc tatactattt ggcactatat ttectgattc 147480 tgaaattatg cctagcacat ggtaagtact ccttaaatat ttattgactg aattatttaa 147540 tacttaagaa tttcatttgg gattatctga gtggtaagat tacggattat atttatgtaa 147600 gaaaaaatca ttttttaaac ttggttgccc tttgccacac tgacatagac actaagtttt 147660 cttagccaga ttacttccga ggatactcac agaggccatt ctcttctcaa tccccaaata 147720 attgatattt cttagcactt tcaagctaat gcaattctta gatgatgtat ctgtgtatat 147780 catatcctca ttctacaaat gtagaaattg aagtctgggc acagtggctc tcacctgtaa 147840 tctcagcagt ttgggaggcc aaggcgagcg gatcactgag gacaagagtt aagaccagcc 147900 tggccaacat ggtaaagcct tgcctctatt aaaaatacaa caattagggc cgggcgtggt 147960 ggctcacgcc tataatceca gcacgttggg aggccaaggc aggcagatca cgaggtcagg 14.8020 agttcgagac catcctggct aacacagtga aaccccatct ctactaaaaa tacaaaaaat 148080 tagccaggca tggtggcacg cgcttgtagt cccagctatc gggaggctga ggcaggtgaa 148140 tcccttgaac ccgggaggcg gaggttgcaa tgagctgaga ttgcaccgct gaactccagc 148200 ctggtcaaca gagggagact ctgtctcaaa aaaaaaaaaa aaaaacaatt agccaggcgt 148260 ggtggcgggt acgagtacct gtaatcccag ctactaggga ggctgaggga ggagaatcac 148320 ttaaacccag gaggtggagt ttgcagcggg ctgataatgc accactacat tccagcctgg 148380 gcaacagagt gagactctgt cttaaaaaaa aaaaaaagaa agaaagaaat tgaggaatgt 148440 ggagattgtg gtctgtgatt tgttaggaat cacacagcag gttagtagca actacagggc 148500 tttggttCag aatacCacCt tgaCaatggt ttgtttaCag ttCggCtCCC CttCCtCtgC 148560 ctttctctcc ttccttattg agggcagctg gaaagaattt tcatcattta ctagcctata 148620 gctttaattt gagttttgaa accttgataa tagagcacag aggaaaagac tgagttttct 148680 ttttttgaga cagtcttgct ctatggccca ggctggagtg cagtgacacc atctcagctg 148740 gttgcaacct CtgCCtCCCa ggttCaagCa attCtgCCtC agcctctcga gtagctgaga 148800 ttacaggcac gtgtcaccac gcccagctaa ttttctgttt ttgtttcgtt ttgttttttt 148860 ctgagatgga gtcttgctct gtcacccagg ctggagtgca gtggtgcgat gttggctcac 148920 tcaaacctct gtctcctggg ttcaagcaat tcttctgcct cagcctcccc agtagctggg 148980 actacaggta cgtgccacca tccctagttc atttttgtat gtttagtaga gatggggttt 149040 cactatgttg accaggctgg tctcgaactc ctgatctcag gtgatctact cgtctcagtt 149100 tcccaaagtg ctgggattat tggcacacgc ctatttttgt atttttagta gagacggggt 149160 ttcaccatgt tggttagact ggtctcaaac ttctgacctc aagtgatttg cccgccccag 149220 cctcccaaag tgctgggatt acaggcgtga gccaccgtgc ccagccaaga ttgagttttg 149280 aaaagagcct tctgagatta tgagaagggc aagcaagata acttaagaag ttacattaaa 149340 atcatctaag agacagtgta acaagaagga attgtaaaat gatgttatga gcacgtgccc 149400 aatgtagtgg caatcccttg tgcttcgata cattggtggg agacaaaact gtacttaaat 149460 tgataaatcc cttacatgtc attttaagga gcttagactg actcccatca tgtagacatc 149520 agagatttct tttttttttt tttttttttt tttttttttt tttgtgacag agttttgctc 149580 ttgttgccga ggctggagtg caatggcgtg atctcggctc accacaacct ccacctccca 149640 ggttcaagca attctcctgc ctcagcctcc cgagtagctg ggattacagc catgcaccac 149700 cacgcctggc taattttgta tttttagtag agacggggtt tctccatgtt gtggctggtc 149760 tcgaactcct gacctcaggt gatcctcccg cctcagccac ccaaagttct gaaattacag 149820 gcgtgagcca ccgcgcccag cccagagatt tctaaacaga gttctaacca gatgcttttc 149880 cctgtcagta gaatgagaat gaattggagg tgggagagac tggcatgagg gacaccagtc 149940 agccagtgga attagctggt aatgttgata ggagaagaaa aagattcaaa gttaggtagt 150000 ggtagcaaga attagaggga aggtcggatt tatgatatgt ccaaggttga attctaaggt 150060 gaaatttggt ggcagatttc atgtgtaaat tgggaaggta gattgagttt ttttaacatg 150120 ggttttctaa catgtcaata gagtgactct gcaggggggc ctgacgagag aacagtgcat 150180 ggggtgattc aacagccagt tgagccttca tgcagagcat ttaacactgt gactctgtag 150240 actctggttg gcagtaaaat ttcattaaac caatatttaa acccttaggt aataataaaa 150300 attgagggaa aaggatccag gttttgtatt ttttatgaat tcagttattg aattaaacag 150360 gaccttgcct caagaaataa tctaccaaca attaacttgt tttaaagcaa agttaggaag 150420 tgagcatgtt caaattatta aataaaaaag taagctgtgt atttcattca tagaaataga 150480 ggctggccta cttcggatga ttctcagcat gtgattacag atgtgggctt atacatccta 150540 gggagttaag gcgtactctg gcttggatag agtagagctc tttgaaactc ttctctcacc 150600 cagctagttt atatagacta gagaactaga atgtagcagc atactctgtc ttagaagccc 150660 ttttatatag gagctggtct ggaaggtttg aaaacataac aaatgtgttg gtgtctccca 150720 atgtattgct agattcttac ccaagagcat tatcctggtt agggtttggt ttggttttgt 150780 tttgtttttt aatgtttgcc acaaactaac actagatgtt agttctttca tcaagtgagg 150840 agagtagaag aaaagtccag aactctgaaa caccttttca aaagtttttc aagccatgat 150900 gtttgcaagt taaatgctct gttatgtaag caatataatc agtttttatt aatgtaacat 150960 tccttagtgt tttggggtat cacacaaaaa agaatatcca tatctggaag caacagcttt 151020 taaataagag cattgtggtg gtggtggtga tagtggtttt tttttttttt tttgagttgg 151080 agtctcgctc tgttgcccag gttggagtgc agtggcacga tctcagctcg cttcaacctc 151140 tgctcccagg ttcaagcaat tcttctgcct cagcctcctg agtagctggg attataggca 151200 cctgctacca tgcctggctg atttttatta ttttagtaga gacaggtttc accatgttgg 151260 ccaggctggt cttgaactct taacctcagg tgaatcaccc acctcggcct cccaaagtgc 151320 tggaattaca ggcatgaacc accatggcca gccaaataag agcattttta atgtaaaatt 151380 atgcatgaaa tgtacattca attttgtctt tgtttactag gatccatgtt ctcacaagct 151440 atgaagaaat gggtgcaagg aaatactgat gaggtaaatc ctacctttag gataaaaaga 151500 tttctgttta taagtgCCa.C CCtCatgtaa gtgaggttta aaattttcct tttctttagg 151560 tcccatgttt aagcagcatg gcacatttat gttctcttac ccagaatgta ccaagaaagg 151620 gtggtccctt cttaacatct aacaattgcc tggtagtagc agtgaaggta tcttcagtca 151680 gaggctagga ccactgaagg atatacatgc attcaagttt ccatcagcca gcaggcatca 151740 gtaatcagtg tgtagatcaa aagctcaaat gtttccttcc ccactggcag ttttacttca 151800 agtagtggag gcttgctttt ttaatagtta attaagtaca ttgagagatg ggaggtgaaa 151860 aaaggaaaat gttttatttt gaccatctaa tatgaaagta gttcggtgtt aggtatccag 151920 tagttgacac tggaagacag ggaatgacat gttaatattc atagccagag ggtggcccag 151980 gttttttcgt acatgggaat gaaattctta tccaaataag tagaaattat gtgcgtaagc 152040 catttgttaa gagcactgag tatgtgcatc tcgatccatc taatgaataa ccattatcac 152100 cagtttaaat tattttcttt aggcccagga agagctagct tggaagattg ctaaaatgat 152160 agtcagtgac attatgcagc aggctcagta tgatcaaccg ttagagaaat ctacaaaggt 152220 aaggatgact tcgttttgtg taaactaaaa agtattattt tccaggtgta aaaataaaaa 152280 agaacataag gggtttcttt gcctttgaag gattaactgc tgtggggatt accttcttat 152340 cataagcaac tagaaaattg acaaactaaa tgaaacaact gtttgcatat attggacaat 152400 gggcaataca gggaaaccat ggaaaccaaa cagagcccag tagtcttgct gaacgaaaga 152460 gttaaatatc aaagttcagg ccaggtgcag tggctcacgc ctgtaatccc agcactttgg 152520 gaggccaagg cgggtgaatc acttgaggtc aggagttcaa gaccagcctg gccaacatgg 152580 tgaaaccctg tcttagccgg gtgtggtggc aggcacctgt aatcccaact atttgggagg 152640 ctgaggcagg agaatcgctt gaaccaggga ggcggaggtt gcagtgagcc gagatcacac 152700 cactgcactc cagcctgggc gacgagcgaa accccatttc aaaaaaaaaa tcaaagttca 152760 gagagctcaa tttgagtaga agttgtagga taaggtagca gaaaagagga agctgcccag 152820 aaagaaagcc gtagagatat ttagagagat tcccatggat ccttggccta ggagtgatct 152880 gtatatgtgt ggggtgaaaa cgcatgtgtc caggtagaga accccccaga aattagtagg 152940 ctgaatgatt gctggaacat agggctaaga aaagttcatg gccagaagga tctggccaga 153000 gtagagagac ttagtaatac acaaggcatt gggtagtgtc ttcacagagg ttatgcctta 153060 ctactgaaga taaattagtc ctagagtaca agcacctgaa ccaagtttca aagcaaattt 153120 ttaaagggtc aaattaccta acaactgcat gccaaaacaa aggcctaacc ctctttacag 153180 taacacaaca aaattcagca cttcacagtg taaagttaga atgtctgacg tccaggctgg 153240 gcgcagtggc tcatgcctgt aatcccagca ctttgggagg ccgaggcagg tagatgacct 153300 gaggtcagga gttcaagacc agcctggcta acatggtgca accccgtctc tattaaaaat 153360 acaaaaactt agccaggcat ggtggccggc acctgtgatc ccggctactt gggaggctga 153420 ggcaggagaa ttgcctgaac ccaggaggtg aaggttgcag tgagccgaga tcgcaccact 153480 gcactctggt ctgggcaaaa agagcaaaac tcaggctcaa aaaaaaaaaa gaatgtctga 153540 cgtcaatcac aaattaccaa gcatgacatg aagttgacct ataaccagga gaaaactcaa 153600 tctatagaaa cagacccaga tgtgagaaag atgatgaatt tagcagacaa agaccatcaa 153660 gtggctattt taaatattaa aaatatgttc aagtggccag gtgcagtggc tcatgcctgt 153720 aatcccagca ctttgggagg ccaaggtggg taggagttca agaccagctt ggccaatatg 153780 gtgaaacccc ttctctacta aaaatacaaa aaaattagct gggcatggtg gcaggtgcct 153840 atagtcccag ctatatggga ggctgaggca caagaatcac ttgaacccgg gaggtggagg 153900 ttgaggttgc agtaagccga gattgtgcca cttgtactcc agcctggaca acagagtgag 153960 actctgtctc aaaaaaaaaa aaaaaaaagt taaagaaaac aagagtataa tgagaaaaat 154020 gcaaaatagt tttaaaagaa ccaaatggaa tttcttaaaa taaaaaatac cagaaatggg 154080 ggccgggcgt ggtagctcac gtctataatc ccagcacttt gtgggggctg aggcaggcag 154140 atcacctgag atcggtagtt caaggccagc ctgaccaaca tggagaaacc tcatctctac 154200 taaaaataca aaattagctg ggcgtggtgg cgcattgcct gtaatcccag ctacttggga 154260 ggctgaggca ggagaattgc ttgaacccgg gaggcagagg ttgcggtgag ctgagattgc 154320 accagtgcac tccagcttgg gccacaagag tgaaactccg tctcaaaaaa aaaacaaaaa 154380 aaaacagtag actcgaagaa ctagctgagt ttttctttac tttaggcagt aagtgtgacc 154440 ttttgcaggt gactacttta gttcctcatg tcctcattag tagatcagag aaattcgaca 154500 ccaaaacccc aaaagaaaaa ccccttctaa tcctcattcc atgattttat gaatgcatga 154560 agtcctaggc ctgcgaagga atactcattc tctttatcct gtgttgatac ctctctgctt 154620 caacctccaa ctcgacattt gcctatagga tgtacttgga cattcagcat aaactacctc 154680 acaccattac tgaattgctt catgtgcaca tgtcccatgc cacaataccg gggaccttgt 154740 cttccgtgat atttgtccgc agtgctgtga ctacaggagg gagtcagtga atgtctgcat 154800 gtgtgtcttt aCCatCCCtC ttgaatatgc tctagggtta attcctagaa gtagaattac 154860 tctattgaaa attggcaata tttttcattc taatatctat tgccaacatg ggaaagcaag 154920 tctggatgcc agtccttgtt atatgcccct tgggtaagtt acgtaacctc tttaagcttc 154980 tgttcactca tattttaaca aggaaaatta caatatttta cctcacaaaa ttgtagtcag 155040 cttctggctg tcttaaactc tggtatatag taaacactaa gtgttggtgt ccatccttaa 155100 tttgtaataa taggtcactt gttagagaaa tgcaccttac CattttCttt tCttttcttt 155160 tttcagttat gactcaaaac ttgagataaa ggaaatctgc ttgtgaaaaa taagagaact 155220 tttttccctt ggttggattc ttcaacacag ccaatgaaaa cagcactata tttctgatct 155280 gtcactgttg tttccaggag agaatgggag acaatcctag acttccacca taatgcagtt 155340 acctgtaggc ataattgatg cacatgatgt tcacacagtg agagtcttaa agatacaaaa 155400 tggtattgtt tacattacta gaaaattatt agttttccaa tggcaataac ccatttatga 155460 gagtgtttta gcctactgga atagacaggg accacatcct ctgggaagca gataagcata 155520 gaactgatac ttgatgcaca ctcgtagtgg taactcatcc ctaatcagca ttgtaaagca 155580 ggtgccagag gtggtttgct ttgtccttcc aaagcaggtg agtcagcccc accgagagcc 155640 aggcagcttt gagtggcagc gtggtgctag cagcttcagc ggaacagggt gagagttaat 155700 tatgcagtct tcttgacagc ggcattaatt tggaaggaaa ctgacaagtc atgggtcaag 155760 tttcagtgac ttcctccttc ctctgatggc agtatatagt tttcacattt taattcctcc 155820 tcctgagatg cactatactt aaaaccattc tctcccctgc taacagaagg gtgtgaatct 155880 ggtttacttt gagcattagg atttgcccct ttggaattct gcactccagt tacttaactt 155940 tcccttcaga atacatgtgg aaagaaagaa agaaatagcg atgactccac ttttgcccct 156000 gtggcacctt gaacaaagca gttcttccca aattatactt tttttttttt taaataaggt 156060 gagcaggatg actggggaga gagaaacatt tgactttgac tgcctccccc attctttgct 156120 gtgagctgga aagtgtgcag ttggtcgtct ttcttctcct ttctttagga tagtaagaga 156180 ctcactcact gcacttctgc tcagttggct tctgcatcgg gatcacacag ccatcagcag 156240 gactgcccag ttggtgagca cactccattg accacgtggc gccagcgctt cctcaatgca 156300 catgattgag aggaaagaaa gttctcttag atgttactgc ttttgctcag actttgcaaa 156360 aaaaaaaata tatatatata tgtataaata tataattatt aatcactttt gtccttgaga 156420 aagtcttgaa tgaacagaga atttattcca ttgcaatatt tgattgtata gaggcacact 156480 gtttcatcga cagaagaagc aaaaaggctt tgtgtaagtt tttggtacta tgtaccacct 156540 ctgttattct tttaaagctg aagtattcat gtacttaaac catattatat ttaattgtgt 156600 ttgattttaa aatatatata tatgaattct atttaaaatt gtgtcaactt tctgctttca 156660 gggcatttat ggctcttctg ttgaaatata ttgatctttc caaatatttt catttgcttt 156720 ctaaaaaccc agaacatgag ccactactgg actttgcctt gtgtttgaag tgtatggcat 156780 aaacccaagg tttttattag tcatctatgc tgtgattaat tcattttgtt cttttaacaa 156840 aatatttcca tccacttcac attgcttcaa tctttaacag aaaagcaata taaaggttat 156900 agaataaaat gtggttttgg gcaactcttg ctgcctctgc atgttttgga ataacaattt 156960 ctacaagact ctaggctgtt taaactagtg ctttcagtta agataaattc taatcatttc 157020 tttgtatata cattttgtgc ttctgagcta gagatgccaa gtagttgtaa actgcttata 157080 aagagaatag cagcaaattt gagactcggc tacttttttc tgccccacct gctttgagac 157140 acagaagcgg agtgtggccc gaaattatta gccagattta atatttgatc taaagtaggt 157200 ccttgtactc attttaaagt tggaatttga ttcctccaac attgagcacc caccatgttc 157260 caggctctgt gcattgtgcc cacaaaataa gattccctgg tggagttttt atgggttcaa 157320 ataatcagtt gaacaccctt catctttatc atgttgttga cattgacaca aattgtttaa 157380 aaagaaaaga tattagagag aaagtggtac ctttgtaact tgatgtgtct tcatcattcg 157440 gtaagatttg atgaaagtaa aaagcaaatg tcagccaaat ccagtgaaca gcaataaaac 157500 agggagtaac tttttataac tttttctact tggatttcaa cattcagtag agcttttcga 157560 aatgtaagta gtttacagta ctggaggttt gactagttca gtaggaattt ggaggggaag 157620 gtcattctga attgtaacaa agtacaaact tctttgctgt tttatttaag tactgagagc 157680 taagcacctg atgaagtgac tgacctctct ccagtgacag tgtttgggta cctgcctgac 157740 ttcaggagtg gggtttatgt ttctacacag tgaccttttc tctcgccctc tcctccctct 157800 tgcccacaca ccagttgatt ggacctgggt tgaactcctg atccagacag gcccaagaca 157860 gttcttaatg ttaagaattt tggggccggg cacggtggct catgcctgta attgcaacac 157920 tttgggaggc cgagacaggc ggatcacttg aggtcagggg ttcgaggcca gcctggccaa 157980 catggtgaaa ccctgtcttt actaaaaata caaaaattag ctgggcatgg tggcgcacgc 158040 ctgtaatccc agctacgtgg gtggctgaga caggggaatc gcttgaacct ggaggcggag 158100 gttgtgcaat gagccgagac cgtgtcactg cattccagcc tgggtgacag agggagactc 158160 tgtctccaaa aataaaaata agaaaaagaa ttttgggcta ggtgcagtgg ctcacgcctg 158220 taattacagc attttggaag gcccaagatg ggcagatcac ttgaggacag gagttcgaga 158280 ccagcctgga caacatggtg aaactccatc tctactaaaa agacaaaagt tagccagatg 158340 tggtgatggg cacctataat cctagctcct cgggaggctg gggcaggaga atcacttgaa 158400 cccaggaagc agagattgca gtgagccaag atcacatctc tgcactccag cctgggcaac 158460 agagcaagac tctgtctcaa aaaaaaaaga atttggccag gcgcagtggt tcacgcctgt 158520 aatcccagca ctttgggagg ccaaggcagg cagatcacga ggtcaggaga tcgagattgt 158580 cctggctaac atggtgaaac cctgtctcta ctaaaaatac aaaacattag ccgggtgtgg 158640 tggtgggcac ctgtagtccc agctactagg gaggctgagg cagaggaagg atgtgaaccc 158700 aggaggcgga gcttgcagta agccaagatc gtgccactgc actacagtct gggcgacaga 158760 gtgagactcc gtctcaaaaa aaaaaagaat tttggccggg tgcggtggca catgcctgta 158820 gtcccagcac tttgggagac caaagtgggc ggattacctg aggtcaggag ttcaagacca 158880 gtccggccaa tatggcgaaa ccctgtctct tactaaaaaa aatacaaaaa ttagccaggt 158940 gtggtggcgg gcacctgggg aggctgaggc agggagaaat gcttgaaccg gggaggcaga 159000 ggttgcagta agccaagatc gtgccactgc actccagagc aagactcttt ctcaaaaaaa 159060 aaaaaaaaag aattttgcat ggggaaggag agatactgtt caccatctgg aatggtgctt 159120 ggatgtggca cttacaaaat caggagccag cactgcatgg acaaacagaa gcatgtgggc 159180 CtgagatagC aggtaCCttg ataaCCCtga agaCatCCtt ggtttCtgCa tCtattCCtg 159240 catccttgca ttggactaca ttaatctgtc agttatcctt ataatgattt ttgatttttt 159300 ttttttgaga tggagtttcg ctcttgttgc ccaggctgga gtgcaatggc acgatctcgg 159360 ctcaccacaa cctccacctc ccaggttcaa gtgattctgc tgcctcagcc tcctgagtaa 159420 ctgggattac aggcatgcgc caccacacct ggctaatttt gtatttttag tagagacggg 159480 gtttctccat gttggtcagg ctggtctcga actcccaacc tcaggtgatc accctgtctc 159540 ggcctcccaa agtgctggga ttacaggcgt aagccatggt acccggtctg ttttttgatt 159600 ttttgaaacc agtctgaagt gagttttttt aattacgtga aaggagtttg gctaaaatac 159660 tgccatactg ccctaatgcc taatgattat gtattctcag catgtctgca aagtactgct 159720 gatttctgga gaataatttt tctttagtaa acttcactta agtcgtcatg tgtattctct 159780 caaaatggta tcctaaccta atggagctaa aagacacccc ttgtttttat aacaagcagt 159840 tactgaggcc caggaagggg agaagtccct ggcttgtgag atgatcacca ttagaactca 159900 ggcctgggcc agtgcctttt catgcttctc agatccttcc aaagaataat gaagattata 159960 accgctttta gcaattgtaa taaacccaga aatagaaagc tttttggtta gagtactggt 160020 agaagtttgg cgggagagat aatttttaca aaatttgtaa atacctgcca attctatata 160080 ctaggcaagg tctctggcct tgtaaaaccc ctcaaggtta caactttggt ggcccacact 160140 aatagttacc cactgaggcc ctctccgggt gaacattgag cactagagga agcccctctg 160200 cttgggcagg actgggcgtg gtgcagagta ggagcggtga tactgtggat tctgggcagg 160260 tggagatggc cagtgatgtc caataaagga cactggaggg agcagtgtga gtaaaggccc 160320 tgagggcatt catgttcagg gagggttgct gcccactggc ttgcttggca cacaggagag 160380 tgggtattcc tgccttagta actttatgta aacaagtatt tcctcagtct gttcctctca 160440 aactgcctgc tctggcacat tcagaatgtc acagaactca cctggatgca ttcagcccct 160500 tgcctaaagg tgacagtgca tCtCCttCCC CaCCCCaCCC CtCataCCaC tgaagcacct 160560 gtcagactgg cccagtctgt gggcaaggag cctagagagg gcttagtttc agcttgaaag 160620 gagctgggat ttaccaagaa gcaaatgaga gacgaggatt gcaacaactg tgccatttcc 160680 ccagcttcag ctgactcctg tatattgact gtgccttcag actcatccgt aagtgacccc 160740 aggctggcct ctcccacatc acagtaagaa ttccacacac catacaactt ggaaagaggc 160800 tccagctgaa ggaagcccca cacttctttc aagtttttct tagtcttctc ttcttggcaa 160860 agagtacctt ttgtttettc taattatgta actattggtt tagtaaatat tcacccattc 160920 agtcaccctg taagtggcag gcactgttta cagggacaca ggaaggaata aaaacttgca 160980 ggcaccttgg agcttgcatt ctattgaaga ggtaatggaa gttgggatag cagctaaact 161040 atgctggtat tggccaggcg cagtggctca cacctgtaat cccagcactt tggaggccaa 161100 ggtgggcaga tcatgaagtc aggagatcga gaccatcctg gctaacatgg tgaaaccccg 161160 tctctactaa aagtaaaaaa aaaaattagc caggtgtggt ggcgggcgcc tgtagtccca 161220 gctacttggg aggctgaggc aggagaatgg tgtgaaccca ggaggcgaag attgcagtga 161280 gccgagatgg caccactgca ctccagcctg ggtgacagag cgagactctg tctcagaaaa 161340 aaaaaatatg ctggtagttt tgattcaaga tggectttgg agcccatgat ttaggtctcg 161400 tacccaccaa ggtctactgg aaaacatcag gctctcctgc tatagaccca tagggagagc '161460 tgcagccgag agggggagct gaagagaagt gccccttctg tgtcctgtca gcctcatcct 161520 tccgcaagga ccagttgctg tgccactcca ttcacttgct gcaagactgg aggtttttcc 161580 tcaggtgttg agcacctggt ttacaagatg tcagcatctt gatgcctgag accatcaagg 161640 caagtctctg aacagggctt accttagagt aaggcttaga agaggccgta aagtcagtct, 161700 cagctccgtg gctctgcaga gctttgggac atgtgaattc ttaaaaacaa gactattgta 161760 cagttactat atgcatgcag tataaaatta taaccttgga aaatcctagc tagctgttga 161820 gctaattcca taaagtaatc agctcctgag ttctgcagtg gtaataataa tcagcataat 161880 gagtaaacac tgtgtgtgcc aggcagcgtc tcatttgatc cttgtgataa tcttgtaagt 161940 actgattttc tcccttcttt aaacaaagtt tttttttttt ttttagagag ggtctcacta 162000 tgttgcccag gctagtcttg aattc 162025 <210> 14 <211> 162025 <212> DNA
<213> Homo Sapien <220>
<221> allele <222> 129600 <223> Nucleotide sequence of chromosome 17 containing the genomic sequence of the allelic variant <400>

gaattcctatttcaaaagaaacaaatgggccaagtatggtggctcatacctgtaatccca60 gcactttgggaggccgaggtgagtgggtcacttgaggtcaggagttccaggccagtctgg120 ccaacatggtgaaacactgtctctactaaaaatacaaaaattagccgggcgtggtggcgg180 gcacctgtaatcccagctactcaggaggctgaggcaggagaattgcttgaacctgggaga240 tggaggttgCagtgagCCgagatCgCgCCaCtgCtCtCCagCCtgggtggcagagtgaga300 ctctgtctcaaaaagaaacaaagaaataaatgaaacaattttgttcacatatatttcaca360 aatttgaaatgttaaaggtattatggtcactgatatcctgtttcattctttatataatca420 ttaagtttgaaatgtatacttgcactactaacacagtagttaatcttagtcctacaagtt480 actgcttttacacaatatattttcgtaatatgtatgcactggtgtttatgtacgtgttta540 tgtttatatctgttaaaattagcagtttccatctttttctattttgtaccatcacatcag600 ttcagaaggattgaeagagcaaaatgatttgatgaagtataaaagtcacatggtgagtgg660 cataaatacaactctgaacaattaggaggctcactattgactggaactaaactgcaagcC720 agaaagacacatatcctatatgtcaagagatgtaccacccaggcagttaaagaagggaag780 tacacatagaaagcacaatggtgaataattaaaaaattggaatttatcagacactggatt840 catttgctcctaaagtcagagtcctctattgtttttttgtttttgtgggtttctttttaa900 atttttttattttttgtagagtcggagtctcactgtgttacccgggctggtctagaactc960 ctggcctcaaacaaacctcctgcctcagcttcccaaagcattgggattacagacatgagc1020 cactgagcccagcccagacgctttagcatttatgaagcttctgaaatagttgtagaaacc1080 gcataagctttccatgtcactttcaaagtttgatggtctctttagtaaaccaaccaagtt1140 attcctcaagggcaaaataacatttctcagtgcaaaactgatgcacttcattaccaaaag1200 gaaaagaccacaactatagaggcgtcattgaaagctgcactcttcagaggccaaaaaaaa1260 aggtacaaacacatactaatggaacattctttagaagagccccaaagttaatgataaaca1320 ttttcatcaaagagaaaagagaacaaggtgttagcaaattcctctatcaaataacactaa1380 acatcaaggaacatcaatggcatgccatgtggaagaggaagtgctagctcatgtacaaac1440 cagtagataatttcaacttgctgccgaatgaaacctctttgcaaggtatgaatcagcact1500 tctcatgtttgttttgctttgttttgttttgtttttagagaCaggCCCttgCt CtgtCa.C1560 acaggctggagtgcagtggcacgatcagagctcactgcaacctgaaactcctgggctcaa1620 gggatcctcctgccttagcctcccaagtagctgggactacaggcccaccatgcccagcta1680 attttttaaattttctatagagatgggatctcactagcacctttcatgtttgatgttcat1740 atacaacgaccaaggtacaatgtggaaaagggtctcagggatctaaagtgaaggaggacc1800 agaaagaaaaggggttgctacatagagtagaagaagttgcacttcatgccagtctacaac1860 actgctgttttcctcagagcagagttgatgatctaaatcaggggtccccaacccccagtt1920 catagcctgttaggaaccgggccacacagcaggaggtgagcaataggcaagcgagcatta1980 ccacctgggcttcacctcccgtcagatcagtgatgtcattagattctcataggaccatga2040 accctattgtgaactgagcatgcaagggatgtaggttttccgctctttatgagactctaa2100 tgccggaagatctgtcactgtcttccatcaccctgagatgggaacatctagttgcaggaa2160 aacaacctcagggctcccattgattctatattacagtgagttgtatcattatttcattct2220 atattacaatgtaataataatagaaataaaggcacaataggccaggcgtggtggctcaca2280 cctgtaatcccagcacttcgggaggccaaggcaggcggatcacgaggtcaggagatcgag2340 accatcctggctaaaacggtgaaaccccgtctactaaaaattcaaaaaaaaattagccgg2400 gtgtggtggtgggcacctgtagtcccagctactcgagaggctgaggcaggagaatggtgt2460 gaacctgggaggcagagcttgaggtaagccgagatcacgccactgcactccagcctgggc2520 gacagagcgatactctgtctcaaaaaaaaaaaaaaaaaaaaaagaaataaagtgaacaat2580 aaatgtaatgtggctgaatcattccaaaacaatccccccaccccagttcacggaaaaatt2640 ctcccacaaaaccagtccctggtgccaaaaaggttggggaccgctaatctaaataatcta2700 atcttcattcaatgctaaaaaatgaataaacttttttttaaatacacggtctcactttgt2760 tgcccaggctggagtacggtggcatgatcacagctcactgtagcctcaatcacccaggcc2820 ccagcgatcctcccacctaaacttcctgagtagctgggactacaggcacgcaccaccatg2880 cccagctaatttttaaattttttatagagatgggggtctcaccatgttgcccagactggt2940 ctcaaaccctgggctcaagtgatcctccctcaaactcctggactcaagtgatcctccttc3000 cttggcctcccaaagtgctgggattacaagcatgagccactgtacccagctggataaaca3060 ttttaagtcgcactacagtcatggacaatcaggcttttcaacatgcagtatggacagtga3120 gtcccagggtctgcttttccatactgaaatacatgtgatactaaggagaaaggtgctcgc3180 aaggatatttaaaatgaagaatatttaaaatgaggaaaaaactgtttcttcatgactttg3240 ataaggctgataaagaccatttctgtgatctcaggtgattcactcaagtagtatatttca3300 gtaatcattatctggaacagcctgaatcttaaccaaaataccatgattttttaatgctgt3360 tatgataccttgatgatatgaccaaactgcaatgtaggcagctaaatctccacgagtttg3420 acttccccgagagttgacagttttcttcacaaattaaagaaatatattttttgatacatg3480 attggcatatttaaaaactacactgaaatgctgcaaaatgatataaagaaacattttcca3540 gaatcaaatgcaatcaaagagtggattaggaatctactcaccattatcaactaaatagaa3600 acacttggactgggtgtggtggctcacatctgtaatctcagcactttgggaggccaaggc3660 aggtggattgcttgaggccaggagctcaagaccagcctgagcaacatagcaaaactctgt3720 ctctacaaaaaaaaaaaaaaattaaccaggcatggtggcagatgcttgtaatcccagcta3780 ctctggaagctgaagtaggaggactgcttgagcccaggagatcaagactgcagtgagccg3840 tggtcatgctgcgccacagcctgagtgacagagagagaccctgtctcaaaaacaaaaaca3900 aacaaaaaacacttaaccttcctgttttttgctgttgttgttgttgtttgtttgttttga3960 gatggagtctcactctgttgcccaggctggagtgcagtggcgtgatcttggctcactgca4020 agCtCtgCCtCCCgggttCaCgCCattCtCCtgCCtCagCCtCCCgagtagCtgggaCta4080 taggcgcccgCCaCCaCgCCCggCtaCttttttgCatttttagtagagatggggtttcac4140 CgtgttagCCaggatggtCttgatCtCCtgaCCtCgtgatCCaCCtgCCtCggCCtCCCa4200 aagtgCtgggattaCaggcatgagCCaCCgCaCCCggCCaaCCtttCtgttttttagttt4260 gatatgcttgttaactcagcagctgaaagaatgctgaaagtggccttcagtaaaaaaatt4320 tcactagaatctctacatccatatttaatctgaatgcatatccagattgatcagttagag4380 caaaaacactcatcatcattcctgatgacctctaattctggtttcggctttctatttcaa4440 tggaaacagaataaggaaagaaatggaagggctctggaaatttgtcctgggctatagata4500 ctatcaaagatCaCCaacaataagatctctcctataaatataaaacaagtataattaatt4560 ttttaattatttttttctcttcagaggattttatttcaagataaaacataacttctaccc4620 ata~ctattgattccaaaggttagaaaaagtgtttttcctcatcttatccttcaaagaggt4680 cacagcaatgcaaacatctataaaatgcctctgcataattgtcagaagctatagtccaga4740 aatcattgaaaatgcttttccattttaagcttaggtgaggtgtcttaggaaacctctatg4800 acaacttactctatttattgggaggtaaactcccagactctCCCagggtCtCCtgtattg4860 atCtCattttttaggCttCCtaatCCCttgaagcacaatcgaaaaagccctggatctctt4920 ttctgcacatatcatcgcggaattcattcggcttccagcaagctgacactccatgataca4980 agcggcctcgCCCttCtCCggacgccagtcCttgCtgCggttagCtaggatgaggggttt5040 gctgggcttcagtgcaggcttctgcgggttcccaagccgcaccaggtggcctcacaggct5100 ggatgtcaccattgcacactgagctcctggcaggctgtaccaattttttaattatttaat5160 atttatttttaaaattatggtgaatattttggtattctgctctaaaataggcccataaat5220 gcacagcagatatctcttggaacccacagctttccactggaagaactaagtatttttctt5280 ttaaagatgctactaagtctctgaaaagtccagatcctctaCCtCtttCCatCCCaaaCt5340 aagacttggaatttatgagagatctagctaacagaaatcccagacacatcattggttctt5400 cccagagtgcagtcctcctaaagaggctcagccctaagcaggcccctgcaccaggagggt5460 gggtctgagacccacatagcacttcccaaggtgcatgctccagagaggcactgaaacagc5520 tgagcacaagcctgcaagcctggagaactctcacagtcagaacggagggggcccagtggg5580 actaacataaagagaaaagggaacacagagaaatggatggcaccaacaaccagcaaagcc5640 ttcatggccaatgaaagcatcagtgacggggccagaaccctcatccccaaagactcttca5700 ctgcctttagtgaaaaacaatggctagagagtgaagttatgatcatgtatagagaggtaa5760 agttacatttttatattctgactctgctaatgtgaaattccctatctgctagactaaaag5820 tttcagacaccctgttcaaatatcccattagttgctagagacttaaaatgaacagaacgc5880 acattgtcaggatgactattaccaaaaaatcaaaagacagcaagtattggtgaggatgta5940 gagaaactggaacttttgtgcactgtttatgagaatgtaaaatggagcagctgctgtgga6000 aaagagtatgcaggttcctcaaagagtaaaaccaagatgtggaaacaactaaatgcccat6060 cagtggatgaaggggtagacaatatgtggtatatacataccatggagtactattcagcct6120 ctaaaaaaaaaaaaggaaattctataacatgcaacagcatggatgaatcttgaggacatt6180 ttgctaatgaaataaggcagtcatagaaagacaaatactgcacgactccacttatatgag6240 ataccaaaaatagacaaattcatagaatcaaagagtacaatggaggttacctggagctgc6300 agggcgggaaacgaggagttactaatcaacgaacataacgttgcagttaagtaagatgaa6360 taagctctcaagatcagctgtacaacactgtacctagagtcaacaataatgtattgtaca6420 cttaaaaatttgttaagggtagattaacaaatgtagtagatccacaaatgtggttaagtg6480 ttcttaccacagtaaaataaaaaaagaatatcaagcccaggagttcgagactagcctggg6540 taacatggtgaaaccctgtctctacagaaaatacaaaaattagccagctgtggaggtgca6600 ctcctagggaggctgaggtgggaggcttgcttgagcccaggaggtcaaggctgcagtgag6660 ccatgattgcaccactgtactccagcccagatgacagagcaagacaccaccccccccaaa6720 aaaagaaaaagaatatcaaacattttaaaagatcagatacgcaagaacaacaacaaaaaa6780 gagatgaacagagcatcgaccctcatctagtgggattcttggtctaactgaaaaacagac6840 attgagagacaaacaatgacagtgatgtgatcacagcaattacacaggtatcccctgggg6900 actgcagaagaaaggaggaatgcctaactttcagaaaatagagaaagcgtcaaacagttg6960 gtgaaagccttccaaaactagagagaactgcacacaccaaatcacagaaagaagaaaagc7020 cgtgggagattctgggacccaccggctatttttgatggctgaacaccctgctgcaggaga7080 gacaggagctggaaagcatggtgggatgaaacctcaaacagctttgcctgcattgcttaa7140 gatgactgggcttgattaactctagtcaatggggacaattcaatcaaagaagaaagatgc7200 tcaaattcacattttagaatgattttttatggcagtatggggaatagattaaaagagagt7260 gaagctggaggcaagaaacttgttaagaggcaactgaaacagtctagatgataaataata7320 aactgacagagtgactagaaaaatcagaacaggctgaatcaacagatacctagatgaaaa7380 taacaggacttgatcaccagttgtatcttggagaggaaggagttgtttccttgctttccc7440 tacgactgggaatacggaaggtttgccgtgtgtattggttatatactggtgtgtagccaa7500 tcactgacaaccatttagcagcttaaaacacaaaggcttatctcccagtttctgtgggcc7560 aggaatctaagataggcttagctggctggttctggctcagagtttctcaagaggttgcaa7620 tcaagatgtcagctggggttgcatcatctgaaggctcaactggggccggagggtccactt7680 ccaaggagttCaCt CaCCtgcctgacaaggcagtgctggttgttggcaggagatctcaat7740 tcattgccaagtgagcctctctatagcattgctggaacatCCtCCCCatCtggcagttgg7800 CttCtCtCagCatgagtgatctgagagagagagcaaggaggaagccacagtgttcttcct7860 actcctactcctaacactatggacctactcctaacactctcacttctgccttattccatt7920 agttagaaagggaactaagctccacctcttgaaataagaagtgtcaaagaatttgtggat7980 atatttaaaaatcatcacaCtgtggaagtggatagggggttcaattaatgctgaacttga8040 aatgcctgagacattcaaatgtccaacaggcaatgaacatacccatagatggtcatgact8100 ttagcaagaatagaggaagatcacagaattaaggaggaattgaaaggtaaaagaagtgga8160 gtcagattccccctgaaaagtgagccatgaaaggaactttaactattgagttagaggtca8220 gagtaggaaatttcggtggaattcttttttaaagaaaggaaccatataagcatgttttga8280 ggtagagggagaataaatcagtagacagggagaggtaaaaaacataaatgataggggata8340 gttgacaaaggtcttggcagaatcccttacccattgacttggggccaagagagggacact8400 tctttgtttgagggataaggaaaataagaaagaatgggtgCtatttagtgtggtcctgtc8460 tctagggcaaacgcataggtaacaaactgtgtgtgttaggaatatagatgtgacctcaca8520 ttgagattctcacctcaaatccattttgttgttacctgtaccttcctaccttctcttttt8580 gctacatgcagactgctgttttgtcttcctggcctgttccaggtttcagcattctggcat8640 atCtgCtaCCCtgttCCCaaaCCtCtCtagagtCCatgCtCCttCCttggatagtgtttg8700 attgggCCaCgtatCtaagaagtgatgCCttCagttaggCCtgagaaCCtcctctatgga8760 aatCtCCatCagtgaccctgacagacttggtatcttggagatgtcactgctcccagcctg8820 tggtctaggagaatctcagcctgggcctctagtagtatggataaggcgttaaggtatctt8880 tgaaccagagtctgtcatattcctcaatgtgggacagataaaacagtggtagtgctggtg8940 tttctgagctagaactctggtttttggtctagattctttgatgtatgacctttcagaggt9000 attaaaatttgttctaatacaatgttcaatacaaatgtagttccttttctgttaggacct9060 caacaaaacatgaccaactgtagatgaacattaaactatgacaattcatggaaatgaata9120 cagtaatacctgcggttcccccattttagcagtcactatggtgacatttggcacaaatgg9180 CtatttaagggtgcttttgttaaaaCCtaCCatCttaCtaggcacatgatattgaaacta9240 atgaaataatggagaaacttcttaaaaacttttaatgaataaagtgatgaagtgataata9300 ttttagctgctatttataaagtgactattacaggtcaaacattcttctagggtttttttg9360 ttgaagttgtcacatttaatccttaataacccactatgagtcaggtattcttctctcccc9420 tttggacagttggggaaatgggggtcagagaggttaggtaatttgctcagggccacacaa9480 cctgcatgtagaaaatctgagatttgtacaggaacgtatcaaactctgaagtccatgctt9540 ctattttcccatgctgcctttctaataaaaggtaactaatgctactggatgctgccccca9600 aagtgagtcactttcaccccaccctacttgattttctccataaaactaatcacatcctga9660 caacttatttattgctgatctcccccactagattataaactcaataaaagcaagatcctt9720 gtctgctgaatatcagtacctaaaacgctgtctagcacagagcaagtaattaatatttgt9780 tgaatgaacaaataaaggaaaaaaattcaaaggaagaaaaagccctaaaacagatgttta9840 cctaaacatacattttaaaagaaagcatataacaaattcaggacagaatttaaatttgat9900 tttttaaagaaataaccaagtgctagctgggcacagtggctcacacctgtaatcctagca9960 ctctgggaggccgaggcaggcagatcacttgaggtcaagagttcaagaccagcctggcca10020 acatggtgaaacctgtctctactaaaaatacagaaattatccaggcatggtggcaggtcc10080 ctgtaaccccagctactcaggaggctgagtcaggagaattgcttgaacccaggaggcaga10140 ggttgcagtgggccaagattgcaccactgcactccagcctgagtaacaaagcaagactct10200 gtctgaaggagaaggaaagaaagaaggaaagaaggaaagaaggaaagaaggaaagaagga10260 aagaaagaaagaaagaaagaaagaaagaaagaaagaaagaaagaaagaaagaaagaaaga10320 aagaaagaaaaagaaagaaagaaagaaagaaccaagtgcttatttgggacctactatgct10380 atgtttttccatgcacgctattttcagtaaagcagttagcaaacttgcaagatcataaca10440 acaaatatatgcttctataactctaaaattgtgctttaagaagttcctctttaccagctc10500 atgtatgcattagttttctaagagttactagtaactttttccctggagaatatccacagc10560 cagtttatttaaccaaaggaggatgcttactaacatgaagttatcaaatgtgagcctaag10620 ttgggccagttcatgttaatatactccagaacaaaaaccatcctactgtcctctgacaat10680 tttacctgaaaattcattttccacattaccaaggagccagggtaggagaatatagaaaga10740 ccacccaagaatccttacttctttcagcaaaatcaattcaaagtaggtaactaaacacat10800 gccctaacaatgaatagcagattgtgctcagaagaatgatctacaacatcttactgtgaa10860 ggaactactgaaatattccaataagacttctctccaaaatgattttattgaatttgcatt10920 ttaaaaaatattttaagcctaaattttaaaaggtttgatattggtacatgaatagacaaa10980 cagacatggactagaccaagaattaggttcaaacatatacaggaatttaatatacgataa11040 atctagtattccaaaggaaccaacaaatggtgttcagacagcaggataggcatcaggaaa11100 aacacagttgggcaccctaccttactcctaacaccaggagtaactgaaggagcaccaaat11160 atttatttattttaattatagttttaagttctagggtacgtgtgcacaacatgcaggttt11220 attacataggtatacatgtgccatgttggtgaggagcaccaaatatttaaaagaaaaaaa11280 ttggccaggggcggtggctcaCaCCtgtaatcccagcactttgggaggccaaggtgggca11340 gatcacctgaggtcgggagttcgagaccagCCtgagCaaCatggagaaaccccatCtCta11400 ctaaaaatacaaaattagccaggcatggtggcacatgcctgtaatcccagctacttggga11460 ggctgaggcaggagaatagctttaatctgggaggcacaggttgcggtgagctgagatatt11520 gcactccagcctgggcaacaagagcaaaacttcaactcaaaaaaattaataaataaataa11580 aaataaagaaagaaaagaaaaaaatgaaaatagtataattagcagaagaaaacaccgtag11640 aatcctcggactcttaggatggggaatgcctataatataaaaaccctgaagttataaaag11700 agaaaatcacctacatacaaaccaaatctttctacatgcctaaaacatagcacaaacaca11760 gctaaataatcatagctgaatgaactgggaaaacaaaacttgactcatatCcagacagag11820 ttaattttcCtacacataaagagtacctatataaacccaacaaaaaaaccaccactaacc11880 caaaataaaaatgtgacaggtaatgaacaggtagttcacagagaatacaaatggctcttc11940 ggcacataagatgctcagactgacttttacttatttattttttgagagacagggtctcac12000 gatgttgcccaggttaggctcaaactcctgggctcaaatgatagtaccaggactacaggt12060 gtgccccaccgcacctggctcctcaaccacctgtattaacaggaaatgcaaaataaaact12120 ttcaaatctattttacctattagaatggcaaaaatttgaaaaacttcaaacatcatcatg12180 ttggtgagaatgtgaggagactggcactctcattttttgctgatagcatatatatactga12240 tggcttctatggaaagcaatctggcagcgtctatcaaatgtacaagtgcatatatccttt12300 gacaaagcaattccactctaggaatgtgttctatatggttgtgcttcctggggctgggaa12360 ctgggagctaagggacaggggcagaagataatcttcttttccctccttccccgttddaca12420 tgttgaattttatatactgtaatatattatttttcacaaaagataatttttaagcgatat12480 gtctgggaatttttttttttCttttctgagacagggtctcactctgtcatccaggctgga12540 atgCCatggtatgatCtCagCtgaCtgCagCCtCgaCCtCCtgggttCaagCaatCCtCC12600 cacctcagcctcctgagtagctgggactacaggcacgtgccatcatgctaatttttgtat12660 ataCagggtCtCa.CtatgttgcccaggctaatgtcaaactCCtaggCtCaagCaatCCaC12720 ccacctcaggctccaaagtgctgggattacaggcgtgagccaccgcgcctggccctggga12780 attcttacaaaagaaaaaatatctactctccccttctattaaagtcaaaacagagaagga12840 aattcaacctataatgaaagtagagaagggcctcaaccctgagcaacaaacacaaaggct12900 atttctgagacaggaatttgctgaacaaaatcgagggaagatgacaagaatcaagactca12960 cttctcggctgggcgcagtggctcacacctgtaatcccagcactttgggaggccgaggcg13020 gacagatcacgaggtcaggagattgagaccatactggctaacacagtgaaacccagtctc13080 tactaaaaatacaaaaaattagccgggcgtggtggcaggtgcctgtagtcccagctactt13140 gggaagctgaggcaggagaatggcgtgaacccaggaagcggagcttgcagtgagccgaga13200 tCaCgCCaCtgCaCtCCagCCtgggtgaCagagcaagactctgtctcaaaaaaaaaaaaa13260 aagactcatttctctagatcttgagccgtattcaaatttatctcagcttagtgagaggtt13320 aaagcaaggaatatccttccctgtgggccctgctccttactgaaggaaggtaacggatga13380 gtcaaggacaccaatggagaaaagcactaacaccattatctgatgaacattacgtgaaga13440 agggtaagaagtgaagtggaattgctgaagaagtcagtgaaagcggacattcatttgggg13500 aaatggaatataggaaatccataaaagtgattaaaaagatgttagaggctgaggcggggg13560 gaccacagggtcaggagatcgagaccatcctggctaacacggtgaaaccccatctctact13620 aaaaatacaaaaaattagccaggcgtggtggcaggcacctgtagtcccaactactcggga13680 gactgaggcaggagaatggcatgaacctgggagacggagcttgcagtgagccgagatcac13740 gccactgcactccagcctgggtgacagagtgagactccatctcaaaaaaaaaagttagat13800 acgagagataaagatccaacagacacacaactgctaattctgaacagaacaaaacaaatg13860 gcacaggaaaagaaaatttaagatataacaccggaaaactttcctgaaattgagtaactg13920 aatctatagcttgaaagggtttagcatatgccaagaaaaatcagtagagtccaaccagca13980 caagacacatctagcaaggctggtgattctaccaacacagagaaagaagtgggtgaccca14040 taatgcggaaaaaggcagaccatctgcagtcttctccagaacactggagtctgaagacaa14100 _57_ aagaatgctgcctactgagccagaagggagagaaagtgacccaacacatctttaccaagt14160 tagaatgtcacgcattatttaaaggctgcaaaagccatgaaagacatgaaagaacacaag14220 catttacaacatgaaagaacacaagcattctcatactcaagaatccttaagaaaaatgta14280 gtcctaatccagcccactgaaagttaaatgtacttaatgtgctcattaatgggaacttca14340 tagcttcaaatcagtctggtcccatctaccaacatctctcgcccggctttcctgcaatag14400 tcagcacctttccctcctcccagtcttgtcCCCtggagtCtgCtCtCagCatagcagagt14460 gaccacatcaacacccaagtCagagCCCtCCagtgCgCa.Ctggtctacaaagcccttccc14520 aCCCCCC3CCCCaCgtgCCCtccggatccttgtgacgtgtctcctgcataccctagcagc14580 cctggcctcctCaCtgCCCCtcctgtacatcaggaaggcgactccttgagtcttggctct14640 ggccgcctcctccacctgcagtgagttaactcccttacctactctaggtcattgctcaaa14700 tgtcagcatctcaatggggccctccctgactaccctatttaaattctacataCtcCCCtt14760 gaccccatggaCCtCaCtCaCCCtattCCaCttttattCttaCaatttagCacttgttct14820 CttCtaaCgtattCtaagaCttaCtCatttattaCattgtttgCCaCCCCCtCtagtaCa14880 taaactccagaggggcagggatttctgtctatttattcatttctttatccctaggacata14940 gaacagggcatagttcagagtattcaatgttatcaatgaatgaactagcagtagtaccag15000 ttccagttaggcacagaattaaatctaaatagaattaaatctcatggtctgggttaacta15060 tggatagaaaattagatataattttaagaagcctagaaagaaaaaattaataatgtaaaa15120 ataatattaatttgataataataacaaaaactctgccaggcactgtggctcaaatctgca15180 atcccagctactcaggaggctgaggtggaaggatcacttgagaccagagttcaagactca15240 gcctaggcaacacggcaagaaactgtctctaaaaaaattaaaacttaaatttttaaaaaa15300 gaattctcaaagcgtcacaaaaactggagattaaggtacaggaagtgtgaagtaatatta15360 ctatgctaatggttttttttttttttagaaaggtataaccaaaagatttctttctcaagt15420 cgataaactgagaaagataagcatatcttccaattaacagagggggaggaaaagccagat15480 acaacaaaataagatataaattagtttccagttgaaaacaagagtaggagttattttgca15540 tcaCCtCaCCtgtgaCCtCCCCCagCCCaaaaaaCaCtaCtgataaaCagggtagaaaag15600 catcatctcagataaagcaggaaaaactgccacagtctcaaaccacaaactataagcaca15660 CaCCtggCCaaCCCtgCCaagtCtgggCtCagtaggaggaaCgtgCtgagagctaggatg15720 taccaacttagacattctgtgggatacagatgtccctggaagggtcacaccatctcaaag15780 gcacctgtaatgcccactgattacagccaccatatgtgagagagaaactcagggcactta15840 gagagtataacaagaaccttatgtcatctgagatgaggaatcctcagccctgcaaattaa15900 ccaactctttagaacaactggcaaaacataaatatccacaacttttgtttcagtaattcc15960 actcttagatatcaatccaaagtacatgagacagcagatacacacacaaaatggtattta16020 ctgcagcattgtttataatagcaaaaaacaagaaataatccatatgtctcaataggatac16080 tgggtacatgagggtatgtacccatcattcaaccatcaaaaagagtgatatggatgtcca16140 cagatggacataaaaagctgtgtgttacgtgaaaacaaactcaagcagcagcaggatggg16200 cttatgatagtcagtatgagctaatttctggaaaaaaaaatctagtgtgtgcacagaaaa16260 catctgaaagaacagaaacaaaactatcagcagaatattgagatgttttactaagttgta16320 tatctatactgcttgtaatttttaccccaagcaagaattactttttggaaaaagaaaatt16380 caggaaataaagcatttctttaaacttcatgtttaaacaaatggtgatggaataaaagag16440 ttcttattcatcataaacacacacagcacacatgcacgcatgtgcgtgagcacacccttt16500 acttgataaataceatgttgaatattttagtctttccttttaggttctatcccttcactc16560 aaaatgcggttataaataaatgtacttttcatgtgccttctgcctaaacccactttaata16620 taactttacagtcccattatcattatagtctcaaagctagactcagcctgaaactaccct16680 ttcatttggaacccttattaaaatgccacatacagctccttcaaataaaaacaaacccta16740 ggacctgacactaggcttcctttgttgctactcataatggccaagttctgtgcttataat16800 acatcttctttcattttattgctacatatccaagggttttatatgtttttCttattatat16860 cttaattcaaaacaccatcacgctcttttccagatgaaaataaggaaaagaaattgagca16920 actgactgacttaaaggtcataaaactatatagtagcagagtcagcaaaagaagaaacac16980 acatctcccaagtagaggctgaaaaccagtaccattcacctccagggtgagctatataca17040 gattacaaagtcaccttctctaaatgttcaaactgaatcccatacccatactttaccact17100 acctcgtaagaacagcctcagatcttgttatagccttttttttagcatgctgaagccaat17160 aaaatgcttcccattcagcaagagaaacaagttctgaaacactgaataatctgcccaggg17220 cctatgaacatttccactgtgagaaatgttctccactgtgtggagaagatCCttactctt172$0 ctccacacaggcagaacattagaaaaattcttggattctatgatgcacagcttaggagtc17340 tgtttagcacaatttaagtccaaatagttattaaatcctcctctgttccagaaacagtgc17400 taaatactgtgaatataaaaattgaaaagatactctcctggctcccaagaaagtcagcca17460 gatagaggagacacaggcacacaaatcactgtcacatgaagctctacctccctaacttca17520 aacgagggcctaagtcaccaagaatacagtagcagttgtgactacgagtaactactataa17580 ttcaatactttatcttcccttagaaaactcttctcccttggaaatttatttgcatttcta17640 aataccattccttactaaaaggaagcagggctccttggggaaatagctgattctaggtgt17700 ggactatgaaatgaaaatggtgagtctgggacatcccatgttgcccagaaatcaaggaac17760 tgcccaaagattaacagagtcatgttaaatggacctaagagtgaaccagaaggagctcac17820 tttgccccgcgtggaacaatttcaagaaaaacatgacagtaatgaattataaaacatgaa17880 ttaaaatacatattggtactaaaaagagaacaaaaggatgtggctttggataaagctctt17940 cttcatggaagaataccagctaataaatgtaaaggaaatgagagaattagaaaaattatc18000 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tgtcaggggaacctggacttccactcccacccaggagtgatgaggccctccctgctgggg18960 tcatgtcagaggaggcctagtggagattcagtgacttaaccttttcccagagataatgag19020 gCCa.CCtttCCtCCCtCttCCCCCatggtgacagtgaaagcactgtggcaagcagtaggc19080 actcctacccctcctagccagggaggtatcagggaggccaagtagggaaccagaataccc19140 acaaccacccagcagcaacaggggtcccccaccccattgggtgtcaatggaagcagagcg19200 gaaagcctggatatttacccccatctagaagtaacaagctgatgtcccccttcttctact19260 acaatggtgttcaaaacaggtttaaataaggtctagagtctgataacgtaatacccaaat19320 cgttgaagttttcattgaggatcatttataccaagagtcaggaagatcccaaactgaaag19380 agagaaaagacaattgacagacactagcactaagagagcacagatattagaactacctga19440 aaggatgttaaagcacatatcataagcctcaacaggctgggcgcggtggctcacgcctgt19500 aaccccagcactttgggaggccgaggcaggtggatcacaagatcaggagatcgagaccat19560 cctggctaacacggtgaaaccccgtctctactaaaaatacaaaaaaaaatagcaaggcat19620 ggtggtgggcacctgtagtcccagctactcgggagcctgaggcaggagaatggcatgaac19680 ctgggaagaggagcagtgagccgagatcgcaccaccgcactccagcctgggcaacagagc19740 aagacttcgtcccaaaaaaaaaaaaaaaaaaaaaaaaagcctcaacaaacaactacaaac19800 gtgcttgaaacaaatgaaaaaaaaatcttggcaaagaaataaaagatatatattttggcc19860 aggtgcagtggctcacagcctgtaatccctgcactttgggaggctgaggcaggcggatca19920 cctgaggtcaggagtttgagaccagcctgaccaacatggagaaaccccgtctctactaaa19980 aatacaaaattagccagtcatggtggcacatgcctgtaatcctagctactcaggaggccg20040 aggcaggagaatcgcttgaactcaggaggtggaggttgcggtgagccgagatcccgccat20100 tgcacattgcactccagcctgggcaacaagagcaaaactccatctcaaaaaaatagatac20160 atattttaatggaaattttagaattgaaaaatacagtaaccaaattgaatggaaagacaa20220 catagaatggagggggcagacaaaataatcagtgaacttcaacagaaaataatagaaatt20280 acccaatatgaagaacagaaagaaaatagactggccaaaaaataaagaagaaaaaagagg20340 agcagcaggaggaatgatggaaaaagagaaaggaaggaaggaagggaaggagggagggaa20400 ggagtgagggagaaagtctcaaagacctctgagactaaaataaaagatctaacacttgtc20460 atcagggtccaggaaagagacaaagatggcacagctggaaacgtattcaaaaaataatag20520 ctgaaaacttcccaaatttggcaagagacataaacctatagattcgaaatgctgaacccc20580 aaataaaaagcccaataaaatccacaccaaaatacatcatagtcaaacttctgaaaagac20640 gaaaagagaaaacgtcttgaaagcagtgagtgaaacaacacttcatgtataagggaaaaa20700 caattcaagtaacagatttcttacagaaattaaggaagccagaaggaaatgacacaatgg20760 ttttcaagtgctgaaagaaaagaagtgtcaacacaaaattctagattcagtaaaaatatc20820 cttcaagaatcaatgggaaatcaagacagtctcagataaagcaaaataagagaatatgtt20880 gccagcagatctcccctaaaggaatggcaaaaggaagatcatgcaacagaccaaaaaatg20940 atgaaagaaggaatccagaaacatcaagaagaaagaaataacatagtaagcaaaaataca21000 tgtaattacaataaaatttctatctcctcttaagacttctaaattatattgatggttgaa21060 gcaaaaattataaccctgtctgaagtgcttctactaaatgtatgcagagaattataaatg21120 gggaaagtataggtttctatacctcattgaagtggtaaaatgacaacactgtgaaaagtt21180 acatacacacacacacgtaagtatatataaatatatgtgtgtatatgtgtgtgtatatat21240 atatatacatataatgtaatacagcaaccactaacaacactatacaaagagataataacc21300 aaaaacaatttagataaattgaaatggaattctaaaaaatattcaaatactctacaggaa21360 gacaagacaaaaagagaaaaaaagaggaggacaaactaaattttttaaaaacataaataa21420 aatggtagacttaagccctaacttatcaataattacataaatgtaaatgatctaattata21480 tcaattaaaagacagagatagcagagttaatttaaaaacatagctataagaaacctgctt21540 tgggctgagtgcagtgactcacacttgtaatcccagcacttcgggaggccaaggcgggtg21600 gatcacctgaggtcaggagttccagaccagcctggacaacatggtaataccccatctcta21660 ctaaaaatacaaaaaaattagccaggcatggtggcacacgcctgtagtcccaactactca21720 ggaggctgcgacacaagaactgcttgaacccgggcagcagaggtagcagtgggccaagat21780 tgcgccactccagcctgaacgacagagtgagactccacctcagttgaaaaacaaaaaaga21840 aacctgctttaaatataccaacatatgttggttgaaattaaaagaataaaatatatcatg21900 aaaacattaatcaaaagaaaggagtggctatattaataacataaaatagacttcagagaa21960 aagaaaatttcaagagacaggaataaaaggatcaagaaaagatcctgaaagaaaagcagg22020 caaatcaatcattctgcttggagattcaacaccctctcttaacaactgatagaacaacta22080 gacaaaaaaatcagcatggagttgagaagaacttaacaccactgaacaacaggatctaat22140 agacatttacggaacactctacccaacaatagcaaaataaacattcttttcaagtattca22200 ctgaacatatccttagaccctaccctgggccataaaacaaagctcactagtgattgccga22260 aggcttggatggacagtggaagagctgcatggggagggagaaggtgacagttaaagagtg22320 taggatttctttttgggataatgaaaatgttccaaaattgattgtggtgatgttggcgca22380 actctacaaatataaaaaaggccattgaattgtacgttttaagtgggtgaaacatatggt22440 atgtggattatatctaacgctttttaaaaacttaacacatttcaaagaatagaagtcata22500 cagagtgtgctctactggaatcaaactagaaagaggtaactggaggataacgagaaaagc22560 ctccaaatacttgaaaactggacagcacatttctaaaatcatccgtgggtcaaagatatt22620 catttctgatattcatttttattgtttaatgtatttttaaaaatttcttaagggaaataa22680 actgactaaaaatgaatatggctgggtgcggtggctcacgcctgtgatcccagcactttg22740 ggaggccgaggctggtggatcacaagatcaggagttcgagaccagcctggccaagatggt,22800 gaaaccccgtctcaactaaaaaactacaaaaagtagccaagcgcagtggcgggagcctgt22860 ggtcccagctacttgggaggctgaggtaggagaatcgcttgaacacaggcagcagaggtt22920 gcagtgagccaagattgtgccactgcacgccagcctgggcgacagagactgcctcaaaaa22980 aaaaaaaaaaaaaaagaatatcaaaatttgtgggacatagttaaagcaatgctgagaggg23040 aaatttataacactaaatgtttacattagaaaagagaaaaagtttcaaatcaatagtctc23100 cactcccatctcaagaacacagaagatgaagagcaaaataaacccaaagcaagcaaaaga23160 aagaaaatataaaaataaatcagtaaaattgaaaacagaaacacaataaagaaaatcagt23220 gaaacaaagtactgattcttcgaaagattaataaaattgacaaacctctagcaaggctaa23280 caaacaaaaaagaaagaagacacggattaccagttattagaatgaaagcataattagaaa23340 caactctacacattataaatttgacaatgtagatgaaatggactaattactgaaaaaaca23400 caaattaccacaactcacccaatatgaaatagataattgggatagcctgataactactga23460 gaaaattgaatttgtaattttaacactcttaaaacagaaacattaaacttaatattttat23520 aaatattagataaggtaattatacccttccttaacaaataaaaacgacaaattattttgc23580 agctaaagagatgtatgtactgtgaaaaatatcttcagaaaaatagaactttgtttgaag23640 aataaggatttaaaaaatgtttttaactctcaagaagcaaatatctgggcccagatggtt23700 tcactgaagaattctaccaaatgtttaatgaagaattaccaccaactctacatagcatct23760 ttgagaaaactgaagagaagggaacatctcccagttcattttatgaagtgggtgttactc23820 tgatactagaactgtataaggacagctactcttgacacactgcctatgggtagctctgct23880 ctgcaggaacagtcagaaaaaaaaaaaaaagaagcactggacaagggcagtataaaaaaa23940 gaaaactgggccaggtgcagtggctcacacctgtaatctcagcactttgggaggctgacg24000 ctggtggatcacctgaggtcaggagtttgagactagcctggccaacatggtaaaaccctg24060 tctctactaaaatacaaaaattagccaggcagggtggtggggaaaataaaaaggaaaaaa24120 aaacaaaaataaactgcagaccaatatccttcatgagtatagacacaaaactccttaaac24180 tccttaacaaaatattagcaagtagaagcaatatataaaaataattatacaccatgatca24240 agtgggacttattccagaaacgcaagtctggttcaacatttgaaaacaaggtaacccact24300 atatgaacgtactaaagaggaaaactacataatcacatcaatcaatgcagaaaaaagcat24360 ttgccaaaatCCaatatCCattcatgatactctaataagaaaaataagaataaaggggaa24420 attccttgacttgataaagcttacaaaagactacaaaagcttacagctaacctatactta24480 atggtgaaaaactaaatgctttcccctacgatcaggaacaaagcaaggatgttcactctc24540 attgctcttatttaacatagccctgaagttctaacttgtgcaaaacgataagaaagggaa24600 atgaaagacctgcagattggcaaagaagaaataaaactgttcctgtttgcagatgacatg24660 attgtctcatagaaaatgtaaagcaactaggggtaggggggcagtggagacacgctggtc24720 aaaggataccaaatttcagttaggaggagtaagttcaagatacctattgcacaacatggt24780 aactatacttaatatattgtattcttgaaaatactaaaagagtgggtgttaagcgttctc24840 accacaaaaatgataactatgtgaagtaatgcatacgttaattagcacaacgtatattac24900 tccaaaacatcatgttgtacatgataaatacacacaattttatctgtcagtttaaaaaca24960 catgattttggccaggcacagtggctcatacctgtaatcccagcattttaggaggctgag25020 gcgagcagaaaacttgaggtcgggagtttgagaccagaatggtcaacatagtgaaatccc25080 gtctccactaataatacaaaaattagcaggatgtggtggcgtgcacctgtagacccagct25140 acttgggaggctgaggcacgagaattgcttgaacaagggaggcagaggttgcagtgagct25200 gggtgccactgcattccagcctggtgacagagtgagactccatctcaaaaaaaataaaat25260 aaagcatgacttttcttaaatgcaaagcagccaagcgcagtggctcatgcctgtaatccc25320 accactttgggaggccgaggcaggcagatcacaaggtcaggagtttgagaccagcctgac25380 caacatggtgaaaccccatctctactaaaaaatatataaattagccaggcatgtgtagtc25440 tcagctactcaggaggctgaggcaggagaatcacttgaacccggaggcagaggttgcagt25500 gttgagccaccgcactccagcctgggtgagagaacgagactccgtctcaaaaaaaaaaag25560 caaaataacctaattttaaaaacactaaaactactaagtgaattcagtaagtctttagga25620 ttcaggatatatgatgaacatacaaaaatcaattgagctggacaaaggaggattgtttta25680 ggtcagtagtttgaggctgtaatgcacaatgattgtgcctgtgaatagctgctgtgctcc25740 agcctgagcagcataatgagaccacatctctatttaaaaaaaaaaaaattgtatctctat25800 gtactagcaataagcacatgggtactaaaattaaaaacataataaatactgtttttaatt25860 gcctgaaaaaaatgaaatacttacatataaatctaacaaaatgtgcaggacttgtgtgct25920 gaaaactacaaaacgctgataaaagaaatcaaagaagacttaaatagcgtgaaatatacc25980 atgcttataggttggaaaacttaatatagtaaagatgccaattttatccaaattattaca26040 caggataacattattactaccaaaatcccagaaaaattttacatagatatagacaagatc26100 atacaaaaatgtatacggaaatatgcaaaggaactagagtagctaaaacaaatttgaaaa26160 agaaaaataaagtgggaagaatcagtctatccagtttcaagacttacatagctacagtaa26220 tcaagactgtgatattgacagagggacagctatagatcaatgcaaccaaatagagaacta26280 agaaagaagcacacacaaatatgcccaaatgatttctgacaaaggtgttaaaacacttca26340 acgggggaagatatgtctctcattaaagggtgtagagtcattgcacatctataggcaaaa26400 agatgaacctgaacctcacaccctacagaaaaattaactcaaaatgactcaaggactaaa26460 cataagatatacatctataaaacatttagaaaaaggccacgcacggtggctcacgctcgt26520 aatcccagcactttgggaggccaaggcaggtggatcacctaaggtcaggagtttgagacc26580 agccggatcaacatggagaagccccatctctactaaaaatacaaaattagctggacgtgg26640 tggcacatgcctgtaatcccagctacttgggaggctgaggcatgagaatcgcttgaaccc26700 ggggggcagaggttgcggtgagccaagatcacaccattgcactccagcctgggcaacaag26760 agcaaaactccaactcaaaaaaaaaaaaaaaaaggaaaaatagaaaatctttgggatgta26820 aggcgaggtaaagaattcttacacttgatgccaaactaagatctataaggccagtcgtgg26880 tggetcatgcctgtaattccagcactttggtcaactagatgaaaggtatatgggaattca26940 ctgtattattctttcaacttttctgtaggtttgacatttttttagtaaaaaattggggga27000 aagacctgacgcagtggctcacacctgtaatCCCagCdCtttgggaggCCggggcaggtg27060 gatcacacggtcaggagttcgagaccagcctggccaacatggtgaaaccccgtctctacc27120 aaaaatataaaaaattagccgggtgtcatggtgcatgcctgtaatcccagctactgagga27180 ggctgaggcaggagaatcacttgaacctgggaggtggaagttgcagtgagccgagattgt27240 gccactgcactccagccttgggtgacagagcgagactccgtctcaaaagaaaaaaaaaaa27300 aaagaatatcaaacgcttactttagaaactatttaaaggagccagaatttaattgtatta27360 gtatttagagcaatttttatgctccatggcattgttaaatagagcaaccagctaacaatt27420 agtggagttcaacagctgttaaatttgctaactgtttaggaagagagccctatcaatatc27480 actgtcatttgaggctgacaataagcacacccaaagctgtacctccttgaggagcaacat27540 aaggggtttaaccctgttagggtgttaatggtttggatatggtttgtttggccccaccga27600 gtctcatgttgaaatttgttccccagtactggaggtggggccttattggaaggtgtctga27660 gtcatgggggtggcatatccctcctgaatggtttggtgccattcttgcaggaatgagtga27720 gttcttactcttagttcccacaacaactggttattaaaaacagcctggcactttccccca27780 tCtCtCgCttCCtCtCtCaCcatgtgatctCa.CtggttCCCCttCCCtttatgcaatgag27840 tggaagcagcctgaagccctcgccagaagcagatagtgatgccatgcttcttgtacagcc27900 tacaaaaccatgagcccaataaaccttttttctttataaattatccagcctcaggtattc27960 ctttatagcaagacaaatgaaccaagacagggggaaatcaacttcattaaaataa_tetat28020 gcagtcactaaacaaataagaacaagaggctccagaagtgggaagccaatacccagagtt28080 cctacaatacagtatctgaaaagtccagtttCCaaCCaaaaaatatatatatacaggccg28140 gacatggtagcttatgtctgtaatcccagcactttgggatgctgaggcgggcagatcacc28200 ctaggtcaggagttcgagaccagcctggccaatatggcaaaaccccgtctctactaaaaa28260 taeaaaaattagccaggcatggtggtggatgcctgtaatcccagctactcgggaggctga28320 ggcagggaatcacttgaacccaggaggcagaggttgcagtgagccgagatcacgccactg28380 aactccagcctgggcaacaaagtgagactccacctcaaaaaaaaaaaaaatatacatata28440 tatatgtgtgtgtgtgtgtgtgcgcgcgtgtgtgtatatacacatacacatatatacata28500 tatacagacacacatatatatatgaagcatgaaaagaaacaaggaagtatgaaccatact28560 ttctgtggttatgataggatggggtatcacgggggaagtagacaagggaaactgcaagtg28620 agagcaaacagttatcagatttaacagaaaaagactttggagtaaccattataaatatgt28680 ccacagaattaaagaaaagcgtgattaaaaaaggaaaggaaagtatcataacaatattac28740 tccaaatagagaatatcaataaaggcatagaaattataaaatataatacaatggaaattc28800 cggagttgaaaggtagaataactaaaatttaaaattcactagagaaggttcaacactata28860 tttgaactggcagaagaaaaatttagtgagacaaatatacttcaatagacattattcaaa28920 tgaaaaataaaaagaaaaaagaatgaagaaaaataaacagaatctcagcaaaatgtggca28980 caccattaatcacattaacatatgcatactgagagtaccggaagcagatgagaaagagga29040 agaaaaaatattcaaatgatggccagtaacttcctagatttttgttttaaagcaataacc29100 tatacaatcaagaaactcaatgaattccaagtaggataaatacaaaaagaaccacaaaca29160 gatacaccatggtaaaaatgctgtaagtcaaaaacagagaaaatattgaaagcagctaga29220 ggaaaacttataagagaacctcacttacaaaagaacatcacttataaaagaaccacaata29280 atagaaacagttgacctctcatcagaaacaatgaatgataacatatttgaagtgctcaaa29340 gaaaaaaaataaagattcctatatacgacaaagctgtctttcaaaaatatacatccaaaa29400 ggattgaaaccagggtcttgaagagttatttgtacatccatgttcatagcagcattattc29460 acaatagccaaaaggtagaagcaacccaagggtccatcgacaaataaataaaatgtggta29520 tatgtatacacaatggaatttattcagtattaaaaaggaatgaaattctgacacatgcta29580 caacatggctaaaccttgagaacactatgctaagtgaaataagccagccacaaaaggaca29640 aataccatattacttcacttgtatgaaatacctagggtagtcaaattcagagatagaaag29700 taaaacagtggttgccaagggctgagggagggagtaacgtggagttattgttgaatgggt29760 acagaatttcagttttgcaagataaaaagagttctggagacagatggtggtgagggtggt29820 acaacaatacaaatatactttatactactgaacagtatacttaaaaatgattaacatggt29880 gaaaccccgtctctactaaaaatacaaaaaaattagctgggtgtggtggcgggcacctgt29940 aatcccagctacttgggaggctgaggcagcagaattgcttgaaaccagaaggcggaggtt30000 gcagtgagctgagattgcgccaccgcactctagcctgggcaataagagcaaaactccgtc30060 tcaaaaaataaaaaataaaaaaaatttaaaaatgattaagcaggaggccaggcacggtgg30120 ctcacacctataatgccagcactttgggaggccgaggcaggcgatcacttgagacca'gga30180 gtttgagaccagcctggccaacatggcaaaaccctgtctctgctaaaaatacaaaaatta30240 gccaggcatggtggcatatacttataatcccagctactggtgagactgagacacgagaat30300 tgcttgaacccaggaggcagagattgcagtgagtcgagatcgcgccactgaattccagcc30360 tgggcgacagagcaagattctgtctcgaaaaaacaaaaacaaaaacaaaaagcaaaacca30420 aaaaataattaagcaggaaacgagattgctgctgaggaggagaaagatgtgcaggaccaa30480 ggctcatgagagcacaaaacttttcaaaaaatgtttaatgattaaaatggtaaattttat30540 atgtatcttaccacaaaaaaaagggctggggggcaggaaatgaaggtgaaataaagacat30600 cccagagaaacaaaagtagagaatttgttgccttagaagaaacaccacaggaagttcttc30660 aggctgaaaacaagtgaccccagagggtaatctgaattctcacagaaaattgaagcatag30720 cagtaaaggttattctgtaactatgacactaacaatgcatattttttcctttcttctctg30780 aaatgatttaaaaagcaattgcataaaatattatatataaagcctattgttgaacctata30840 acatatatagaaatatacttgtaatatatttgcaaataactgcacaaaagagagttggaa30900 caaagctgttactaggctaaagaaattactacagatagtaaagtaatataacagggaact30960 taaaaataaaattttaaaaaatttaaaaataataattacaacaataatatggttgggttt31020 gtaatattaatagacataatacaaaaataccacaaaaagggaagaagacaatagaactac31080 ataggaataacattttggtatctaactagaattaaattataaatatgaagtatattctgg31140 taagttaagacacacatgttaaaccctagatactaaaaagtaactcacataaatacagta31200 aaaaaataaataaaataattaaaatgtttgtattagtttcctcagggtacagtaacaaac31260 taccacaaattgagtggcttaacacaacttaaatgtattttctcccagttctggaggcta31320 aacacctgcaatcaaggtgagta_cagggccatgctccctgtgaaggctctaggaaagaat31380 ccteccttgtctcttccagcttccagtggttctcagtaaccctaagtgctccttggcttg31440 tagctatatcattcctagcaaccagaaagaagaaaataataaagattatggcaaaaaata31500 atgaaatcaaaaggagaaaaatggaaaaaaataaataaaaccaaaagctagttctttgaa31560 aagatcaaccaagttaacaaaccttttaactagactgacaaaaaggaggtaagactcaaa31620 ttactagaatcagaaataaaagaggggacattactaatgagggattagaaaagaatacta31680 cgaacaaatgtgtgccaacaaattagaaaacttagatgaaatggacaggttcctaggaca31740 acatcaactaccaaaatttactcaagaagaaagagacaatttgaatgagctataacaagg31800 gaagagactgaattgacaaccaagaaactatccacaaagaaaatcccaggcecagaagat31860 ttcactgtgaaattctttcaaacttataaatataaattaacatcagttcttcaeaaactc31920 ctccaaaaaaaagaacagatctctatttacaggcgatacgatctttagaaaatcctaagg31980 gaactactaagaCactatgataactgataaacaagttcagcaaggctgcaggatagaaaa32040 ccaatatacaaaaatctattatatttctatacacttgcagtgaacaacccaaaaatgaga32100 ttaagaaaataattcaatttacaataacatcaaaaagaataaaaacactcaaaaataaat32160 ttattcaagtaagtgcaaaacttatactctagaagctacaaaacactgttaaaagaaatt32220 aaaggtttacataaatgaaaaactatcccatgttcatggatcaaaagacttattactggc32280 aatgctctccaaattgatctataaattcaacaaaatccttatcaaaatcccagatgaggc32340 tgggggtggcggttcatgcctgtaatcccagcactttgggaggctgaggcacgcagatta32400 cctgaggtcgggagctcgagatcagcctgaccaacatggagaaaccctatctcttctaaa32460 aatacaaaattagtcaggcgtggtggcacatgcctataatcccagctactcgggaagctg32520 aggcaggagaatcgcttgaacccaggaggcagaggttgcagtgagccaagatcgtgccat32580 tgcactccagcctgggcaacaagagcaaaattccatctcaaaaaaaaaaaaaaaaaaatc32640 ccagatgacttcactgttgaaattgaaaagattattctaaaattcacatggaattgcaag32700 accttgagaatagccaaaacaaacttgaaaaacacgaacaaaatataggatgactcactt32760 gccaattgcaaatgttacgacacagcaacagtaatcaagactgtgtggtactggcaaaag32820 acacatacatacatacatatcaatggaatataattgagagtacagaaacaagcctaaaca32880 tctatggtaagtgcttttctatttttttctttttttttttcttttttgtagagatagaat32940 ctcaccatgttgcccaggctggtcttcaacttctgggctcaagcaatcctcccactgtgg33000 cctcccaaagtgctgggataactggcatgagccaccacatccagcccagatgattttcaa33060 aaaagtcaacaagaccattcttttcaacaaataggtctgggatgatcagatagtcacatg33120 aaaaaaaaaatgaagttggaccctccatcacactaaagtgctgcgattataggcatcagc33180 caccacatccagcccaaatgattttcaaaaaggtcaacaagaccattcttttcaacaaat33240 aggtctgggataatcagatagtcacatgaaaaaaaaaatgaagttggaccctccatcaca33300 ccatatgcaaaaattaattcaaaaatgaattgatgacttaaacgtaagagttacgactgt33360 aaaactcttagaaggaaacatacgggtaaatcttaaagacgttaggtttgacaaagaatt33420 cttagacatgacaccaaaagcatgaccaactaaggtaaaatagggtaaattgtacctacc33480 aaaatgaaaaacctttgtgctggaaaggacaccatcaagaaatggaaagccaaaatagcc33540 aaggcaatattaagcaaaaagaacaaagctggaggcatcatactacctgacttcaaagca33600 acagtaacca aaacagcatg gtactagtag aaaaacagac acatagacca atggaacaga 33660 ataaagaacc caaaaataaa tccacatatt tatagtcaac tgatttttga caatgacacc 33720 ccttcaataa atgatactag gaaaactgga tatcgatatg cagaagaata aaactagacc 33780 cctatctctc accatataga aaaatcaact cagactgaat taaagacttg aatgtaagac 33840 ccaaaactat aaaactactg gtagaaaaca taaggaaaaa cgcttcagga cattggtcca 33900 ggcaaagatc ttatggctaa aacctcaaaa acacaggcaa caaaaacaaa aatggaaaaa 33960 tagcacttta ttaaactaaa aagctcctgc acagcaaagg aaacaacaga atgaaaagac 34020 aacctgtaga atgggagaaa atatttgcaa actatccatc catcaaggga ctagtatcca 34080 gaacacacaa gtgactaaaa caactcaaca gcaaaaaagc aaataatctg gtttttatat 34140 gggcaaaaga tctgaataaa cattctcaaa ggaagacata caaatgtcac tatcattctg 34200 ccagtaccac actgtcttga ttacttgtta gtgtataaat ttttaaattg ggaagtgtga 34260 gtcatcctac actttgttct tgtttttcaa gtttgttttg gctattctgg gagccttgca 34320 agtataaaat agccaacaag tatgaaaaaa tgctcaccat cactaatcat cagagaaata 34380 aaaatcaaga ccactatgag atatcctctc actccagtta gaatggctac tatcaaaaag 34440 acaaaatata atggatgctg gcaaagattt ggagaaaggg gaactcctat acactgtggg 34500 tagggatgca aattggtaat ggccattatg gaaaataata ctgaggtttt tcaaaaaact 34560 gaaaatagaa ctaccatatg atccagcaac cctactactg ggtatttatc caaaggaaag 34620 aagtcagtat actgaagaaa tatatgcact ctcatgttaa ttgcaacact gttcacaaca 34680 gccaagacag ggaataaatc taaatgtgca tcaacagatg aatggataaa gaaaatgtgg 34740 catatacact caatagaata ctattcagcc attaaagaag aatgaaatcc tgtcatccca 34800 gcaacatgga tgaacctgga ggacattata tttaatgaaa taagtaaagc acaaaaagat 34860 aaacagtaca tgttctcact cagacatggg tgctaaaaag aaaatggggt cacagaatta 34920 gaaggggagg cttgggaaaa gttaatggat aaaaatttac agctatgtaa gaagaataag 34980 ttttagtgtt ctatagaact gtagggcgag tatagttacc aataacttat tgtacatgtt 35040 caaaaagcta gaagagattt tggatgttcc cagcacaaag gaatgataaa tgtttgtgat 35100 gatggatatc ctaattaccc tgattcaatc attacacatt gcatacatgt atcaaattat 35160 cactctgtac ctcataaata tgtataatta ttacgtcaac aaaaaaagga aaaaaaagaa 35220 aattaagaca acccacataa tggaagaaat aaaatatctg caaattatat atatctgata 35280 aatatttaat atttataata tataaagaac tcctacaact caagaacaac aacaaaacaa 35340 cccaattcaa aaatgggtaa aagccttgaa tatacactta tctaaagact atatacaatt 35400 ggccaataaa gacacgaaaa gatgctcaac atcactagtc atcagggaaa tataaatcaa 35460 aaccacaatg tagaatgtag acaccacttc atatgcacta ggatggctag aataaaaagg 35520 taataacaaa tgttggtaag gatgtgaaaa aatcagaaac ctcattcgct gctgttggga 35580 atgtaaagtg atgcagccac tttggaaaac agtctggcag ctcctcaaat tattaaatac 35640 agagttaccg tatgacccag gaatattcct cctgggtcta taaccaaaaa aatgaaaaca 35700 tatatccaca taaaaacttg tacatgggca tttatagcaa cattattcat aacagcaaag 35760 gtggtaagaa cccatatgcc catcatctga tgaacaggta aataacatgc ggtattatcc 35820 atacactaga atattatctg cccatacaag gagtgacatc Cagctacatg ctacaaggat 35880 gaatctcgga aaccttatgc taagtgaaag aagccagtca caaatgacca cagattatga 35940 ttccatgcat cggaaatgac cagaataggg aaatctatag agacagaaag tagattagtg 36000 gttgggtggg gctgggagga caggtagtac actactttcc cagaactact ggaacaaagt 36060 accacaaact ggggagctta aacatagaaa ttgatttcct cacagttctg gagactagga 36120 ctctgagatc aaggtgtcag cagagctggt tctttctgag ggccctgagg caaggctctg 36180 tCCCaggCCt CtCtCCttgg ctggcaggtg gccatcttct CCCtgCgtCt tCaCatCatC 36240 ttttCtCtgt gtgtgCCCat gtCCaaattt tgattggCtC attCtgggtC atggccaatt 36300 gctatgcaca aagtgaagtc tacttccaaa agaagggaag agggaacact gactaggcta 36360 aacttatagt cattttaatg tccgcttttc ctatgagatt gtgaacacac agaagtaggg 36420 tttttatcta cattgtgcaa agtttaataa gaaaaataga attcaagaga agcagttcaa 36480 tagcaggaat ttaatatggg aactaattac aaggtttagg gcaggactaa aaagccagtt 36540 gggatggtga gccaacccag agattagcaa cagtgggacc ccatCtaCCt accacccatg 366OO
aagctggaag gataaaggag gggctattat cagagtccac aagccagtgt cagagtcctt 36660 ggctggagct gggaccaccc tagagacact gtgcaaagca gaaaacaagg gggaaaaacc 36720 ctgacttctc CCttCCtCCC aCCtttcaat CtCCCaCtag tgcttcctac tagccatact 36780 tggccagaga cagtgacaag gaacactgca aaatgaagtt tgtaggaatc atctccctct 36840 gagacagaga aatatggaag ggtagaaaat gaatcagagg ataaagagaa aaaaccctga 36900 gtactatctt atttatcttt gtatctccag tgcctaatct gtctctcaaa aaaggaaagc 36960 aattgagaga aactgaaaac tccaattgaa atgaaagaat ggagaattac tggactagaa 37020 gagaagagaa aaatttattc cgcatagagt aaacaagaat ggattcacaa aggacgtgat 37080 gaatgaaaag ctataatcag caaagatttg ccagagaaat taaaaagtgg taaactcagc 37140 cacgctgtac aacctgaagg cacaatgcat gaaaacgttt caagaaatga caagatttga 37200 agtcaaattc taagtgcttt tccagaatct ctcaagacga ttatatagct accccatttt 37260 attaaataaa atggaaactt actaaacttt ccccttgtat taaactaaca tatgtcctaa 37320 tagcaaacga ttctggaatt cctagagtaa aatatatttc gtcaaagtgt attgctcttt 37380 taatattctg ctgacctcct tttgctattt aggatatttg tatacacatc acacgtaaat 37440 ttggtctata gtttacatet acgggcttat actgttcttt ttttcatttt tttaaaattt 37500 ccaacccccagtatccatatactgctctctatcagggttattttaactttgtaaaatcag37560 ctgagatgctttccatgttttttttttttattttctgccacatttgaatagcataggagt37620 taccaccatcaaccttggattatttaagcattcacgattccacgtgtggattttttattc37680 agagtctttcttgtcattcctgctatcagcacagaacccaatctcagctttccagctata37740 ctctcaccccatggaatttgcagatgaagttcaaaaggacctttgcattatcctgcctcg37800 ccctcttcccccttcatttagacatcaccttcttctagaacgtcttacctgacatgccct37860 gctcccaacccctgctgcccaattgtgtgctctcccgtgtCCtggCCtgCCatCCt 37920 Cttt agtaattgcctgctccctcatctgtctccccacccagacattaagctgaatagactggat37980 ttgtgtcttgtccatcactataatctcagcacctagtacctagtaggtacttaccatgta38040 ttcattagcaaaatgttatgtataaccttgcaccttaaaaacaagagaaggaagacaaaa38100 ttaagtcttaagactatggtttagaacatggatcagaaactacagtctgcagcccaaatc38160 cagaccaaatgaagagaccatgttcatttacatacaacctatagcagctttcacactaca38220 ggagcagagctaagtagttccaagggaacacacggccctgcaaagcctaaaatatttact38280 ctatagctcttcacagaaaaagttttcagatccctcgtttagaactcttgttcatatgca38340 atttcactaaaccatagttttttgggtttgtttggttttttttggcaaaaaggaatgagc38400 cgatccagaaaaggttgaaaagaatgaatcattactgctgaaagaatgtgcacacagtcc38460 gtcagtattctgctgccatgctgacacccatccaatagtgtcatgagatgcagcagctac38520 tactgtgttctcaatgccgagtccacccactccataaccatgtccaagcaatcttgggaa38580 catcatcaccatgcttgtttatccttaaggtattgcctcacatacagcagtggctggtca38640 taaagtcaaatgacactagtggccaggaggtcaagagaatgagtgaggacaggtgggtag38700 gcagcccaggccctagcaacagcaggagctcacccctcagtcactctagccaggactgaa38760 atacttttcaccctttcaagagagactaggaatctggatttttatgtgaaatatcttgat38820 tactaaatgttgtcaacagacatgtcaaaaggtaaaactaagtaagttcatggggcagat38880 tgactattcaggttatagaattaaggattcttatccaacacagataccaaccaaaaagct38940 gacgtataacatattaggagaaactatgtgcactgtcgaaacatcaacaaggggctaatg39000 tctaaaatagtctatattggattccagttgaaacatggggaaaggacatgaacaggcaac39060 ttatgtcaatggaaactcaaaaagataacaagcatatataaaagcattctcaaattcagt39120 agtaaacagacagatgcaaataaaaagagggaaactgctgccgggcacagtggctcacac39180 ctgtaatcccagcactttgggaggccgaggcgggcggatcatgaagtcaggagatcgaga39240 ccatcctggctaacatggtgaaaccccgtctctaetgaaaacacaaaaaattagccaggc39300 gtagtggtgggcaccagtagtcccagctactcaggaggttgaggcaggagaatggcatga39360 acccaggaggcggagattgcagtgagccgagaccatgccactgcactccagcctgggcga39420 ctgagtgaaactccatctcaaaaaatataataataattataattataataataataaata39480 gtaaataaataaaaagagagagactgctaaagtctagaaagttgaatgatgccaagcgca39540 tgcaaagatcagggccttgggatggccgggtgcagtggctcacgcctgtaatcccaccac39600 tttgggaggCCaaggCgggCggatCatgaggtCaagagatCaagaCCatCCtggCCgaCa39660 cagtgaaacccggtctctactaaaagtacaaaaaaatatatatatatatatatattatta39720 tattatatatatatatatcagagccttgggaC.tccttgtgtgctgctggggaaggtagtg39780 gtgcagccacccttgacagcaatctggcagtacttggttatattaagtataggcacacac39840 cacgaccaggcagtcctactcctgggtctaaatcccaaagaattctcacacaagtccata39900 aggagacatgtacgaggctcattcagcattactgggagtgggaatcaacctgggtgtcca39960 tctacaggagacgagatggacaaaatgtggtggatattaagaccagaatcaccaagtaac40020 agagatgggtggtgagtgacaatcctaagatacagaataaaggctagaacatgatgccat40080 tcatgtaaattaaaaatagatgCaCaCaaagcagtatacgcgtgacccttgaatagcaca40140 ggtttgaactgCCtgtgtCCaCttaCatgtggattttcttCCaCttCtgCtaCCCCCaag40200 aCagCaagaCCaaCCCCtCttCttCCt CCCCCtCagCCtaCtCaaCatgaagatgac40260 CCt aaggatgaagacttttatgataatccaattccaaggaactaatgaaaagtatattttctc40320 ttccttatgattttctttatctctagcttacattattctaagaatatggtacataataca40380 catcacacgcaaaataaatgttaattgactgtttatattatgggtaaggcttccactcaa40440 cagtaggctgtcagtagttaagttttgggagtcaaaagttatacacagattttcaactgt40500 gcaggcaatcagttcccctgaccccctcattgttcacgggtcaactgtatatacacaaaa40560 gtattatatgaacctcattagaatagctgtctatagggagaagagaatgagagtgggata40620 aaacggaatgaacaaataaaccaacaaatgcattaacaagcaaaacaacagaggggcttg40680 catgggccagtgatgataaagggctaagaatgagaatataattaattcaattcctcacac40740 ctgaggtctaaaaccaaggaaagggagggccaggcgtggaggctcacgcctgtaatccca40800 gcactttgggaggctgaggcgggcggatcacaagattaggagtttgagatcagcctggcc40860 aacacagtgaaagcccatctctacaaaaaatacaagaattacccaggtgtggtggcacat40920 gcctgtagttagctactctggaggctgaggcaggagaatcacttgaacccaggaggcgga40980 ggttgcagggagccgagatcacaccattgcactccagcctgggtgacagagtaagactct41040 gtctcaaaaaaataaaaaaaataaaaaaacagagaaagggaggaaactagatccaggctg41100 actagatacagcctttagagttagaaaagatgatttgacaatctaagcccacactcagat41160 tgaatgaaattgaaaagcctttcaaactaaaacatttaattacaccatctgctgcagaca41220 gaactcagacaactcaaacaggtaatgtcagcgtggtgttttatatcaccaccctcaaca41280 cagaataaaaatcagctgcatgtgaagcagtgactagaatgaagaaaaggctgcttctta41340 cttccttctagtggttctttccgaaaacattaataggcaccagctctatgcatgtcaccc41400 tgcagggaga catggggtat ataactatga cttactgttc attcctcaag gaattcccaa 41460 tcttgtggaa gattatacac aatgaggcaa caaaaactat ccaataaaac cacggaaaag 41520 aagccagtga caaagaagcc agtgatgaaa ggccctgtga gcagagctga tggccatttg 41580 gggaagaaag accaacatgg atgggggtga tcagggtggc tccgtgggaa agctggaaga 41640 gaagtggcag atctctgagc tggatgatgg gccactacca tctgtatatg gctaattaaa 41700 gaccatgtgt ggatttttta ttcagctctt tcgtgtcatt cctgctatca gcacagaacc 41760 caatctcaac tttccagcta tattgagcta aacttctcac ctcatggaat ttgcagataa 41820 agttcaaaag gatccttgcc ttttcaaaat aattttgaat ggttgagtag tccctctgtg 41880 ctctctcact gacaccctct caaggctgct gagcacgtgc catgctatgg ctttctccaa 41940 catcaggaaa tgttctccac tcagtttcac cttaatacaa atgtgttctc tcttcagaga 42000 aggcaaaaaa attcatgacc atctgactgg gagaagtcat ttctaggtaa agtgtccatc 42060 tttttctgag gaacacagga ggaaaatctt acagaaaaga gttaacacag caggcctaag 42120 actgcttttt aaaataaata aataaataaa taaataaata aataaataaa taaataaata 42180 aataaatgaa tgatagggtc ttctgtattg gccaggctag tctcaaattc ctggcttcaa 42240 gagatcctcc caccttggtc tcccacagtg ttgggattat agacatgagc cattgtgctt 42300 ggcccaagac tgttattctt aaaaagtctc ataaaaagca tggttaatcc ttggctggca 42360 cctgggaact tagatttcag aagggttccc accatccaac ctggaaagag ggactcactg 42420 tgcctaaatt attgtgtggt ttatgctgaa ctcctgcttt tcttcaggta gcgtggaatg 42480 tggtatgtgc tgggcaaagg gggcctgcat gaccagcccc caataaaaac cctgggtgtt 42540 gggtctctag tgagtttccc tggtagacag CatttcaCat gcgttgtcac agctccttcc 42600 tcggggagtt aagcacatac atcctgtgtg actgcactgg gagaggatgc ttggaagctt 42660 gtgcctggct tcctttggac ttggccccat gcacctttcc ctttgctgat tgtgctttgt 42720 atcctttcac tgtaataaat tacagccgtg agtacaccac atgctgagtc ttccaagtga 42780 accaccagat ctgagcatgg tcctgggggc ccccaacaca gaaataaatt ataaaagacc 42840 aaggactggg catggtggcc catgccggta atctcagcgc tttgggaggc cgaggcagga 42900 ggaCCagtta agCCCaaaag ttCaaagtta CagtgaCCta tgaCtgCgCC aatgCaCtCt 42960 aacctgggag acagagcaag accctgtccc caaaacaata aactaaacac atacttctgc 43020 cttccaagtg tcttaaaatt caatggaatg gtagaaacat ttttaaaaca ctaaatcaaa 43080 agaaacctgg aaaacaagag tgccgatggc caactaaaat gtctaggaaa tttctgaaaa 43140 gtaaaaagta ctcagaacca gattacctga gcaaaccata gcccaataca agcttgggag 43200 gaggctgtta tgcagaagga aatggtaaca ggtttccagg aacagacttg taacagcaga 43260 tagaacagca gaggtagaac ctgacaaggt gattacctgg ggaactgcag tctgaatgac 43320 caggactgtt ggacccttcc cctcacatgg aatacacacg ccactcagca gcacaccaca 43380 gctcttcaac aatcacagga ggcacgctac gcctagtaag acaggaaaaa aggaattctc 43440 aaacttcgaa gatgaacaca taaagaatca ccaagttttt attcagtatg atgaaacagg 43500 gacactgaat caacagaaca caaacccaag caaagataat tactagagca catagaagaa 43560 attattagat attcttggga agacctaagg ggacattata aagagcaagc agttggtatg 43620 tgacgatctt tgtgatatac caagaaataa aaacacagga tgaagaccag atagagaata 43680 atgctactat ttgtgcaaaa aaggagaaat ggagaatctg attcatattt gcttgtattt 43740 gcatgaagaa actttggaag gtacataagt aactaacaac aatggttacc tacttgtaag 43800 gcgagagaag taagaggaca ggaatggtgg gaacaccttt tgtgtccgga attggtgggt 43860 tcttggtctg acttggagaa tgaagccgtg gaccctcgcg gtgagcgtaa cagttcttaa 43920 aggcggtgtg tctggagttt gttccttctg atgtttggat gtgttcggag tttcttcctt 43980 ctggtgggtt cgtagtctcg ctgactcagg agtgaagctg cagaccttcg cggcgagtgt 44040 tacagctctt aagggggcgc atctagagtt gttcgttcct cctggtgagt tcgtggtctc 44100 gctagcttca ggagtgaagc tgcagacctt cgaggtgtgt gttgcagctc atatagacag 44160 tgcagaccca aagagtgagc agtaataaga acgcattcca aacatcaaaa ggacaaacct 44220 tcagcagcgc ggaatgcgac cgcagcacgt taCCaCtctt ggctcgggca gcctgctttt 44280 attctcttat ctggccacac ccatatcctg ctgattggtc cattttacag agagccgact 44340 gctccatttt acagagaacc gattggtcca tttttcagag agctgattgg tccattttga 44400 cagagtgctg attggtgcgt ttacaatccc tgagctagac acagggtgct gactggtgta 44460 tttacaatcc cttagctaga cataaaggtt ctcaagtccc caccagactc aggagcccag 44520 ctggcttcac ccagtggatc cggcatcagt gccacaggtg gagctgcctg ccagtcccgc 44580 gccctgcgcc cgcactcctc agccctctgg tggtcgatgg gactgggcgc cgtggagcag 44640 ggggtggtgc tgtcagggag gctcgggccg cacaggagcc caggaggtgg gggtggctca 44700 ggcatggcgg gccgcaggtc atgagcgctg ccccgcaggg aggcagctaa ggcccagcga 44760 gaaatcgggc acagcagctg ctggcccagg tgctaagccc ctcactgcct ggggccgttg 44820 gggccggctg gccggccgct cccagtgcgg ggcccgccaa gCCCaCgCCC aCCgggaaCt 44880 cacgctggcc cgcaagcacc gcgtacagcc ccggttcccg CCCgCgCCtC tCCCtCCaCa 44940 cctccctgca aagctgaggg agctggctcc agccttggcc agcccagaaa ggggctccca 45000 cagtgcagcg gtgggctgaa gggctcctca agcgcggcca gagtgggcac taaggctgag 45060 gaggcaccga gagcgagcga ggactgccag cacgctgtca cctctcactt tcatttatgc 45120 ctttttaata cagtctggtt ttgaacactg attatcttac ctattttttt tttttttttt 45180 tgagatggag tcgctctctg tcgcccagac tggagtgcag tggtgccatc ctggctcact 45240 gcaagctccg cctcccgggt tcacaccatt ctcctgcctc aacctcctga gtagctggga 45300 ctacaggcaatcgccaccacgcccagctaattttttattttattttttttttagtagaag45360 cggagtttcaccatgttagccagatggtctcaatctcctgacctcgtgatccatccgcct45420 cggcctcccaaagtgctgggattacagacgtgagccactgcgccctgcctatcttaccta45480 tttcaaaagttaaactttaagaagtagaaacccgtggccaggcgtggtggctcacgcctg45540 taaccccagcactttgggaggccgaggcgggcggatcacgaggtcaggagatcgagatca45600 tcctggttaacacagtgaaaccccgtcgctactaaaaatacaaaaaattagccgggcgtg45660 gtggtgggcaccggcagtcctcgctactggggaggctgaggcaggagaatggcgtgaacc45720 tgggaggcagagcttgcagtgagccgagatagtgccattgccttccagcctgggcgacag45780 agcgagactccacctcaaaaaaaaaaaaaaaaaatagagacccggaaagttaaaaatatg45840 ataatcaatatttaaaaacactcaagagatgggctaaagagttgacggaacaaatctaaa45900 tattagattggtgacctgcaaaaccagcccaaggaacatcccagaatgcagcccataaag45960 ataaagagagcatttccgctgggcacagtggtatggcaggggaattgcctgagtccaaga46020 gttgcaggtcacattgaaccacaccattgcactccaggcctgggcaacacagcaatactc46080 tgtctcaaaaaaaaaaaaaattaaattaaaaaagacagaatatttgagagaaaaaaatgc46140 ttatttcaagaaacatgaaagataaatcaagatattctaattcccaagtaagaataattc46200 cagaagcagaaaatagaatagaggcaaggaaacactcaaaacttctccagtgccatagaa46260 atgtgtattaatctttagaatgaaacggactaccaaatgctgagcaggaagaacaaaaga46320 gatccactcttaagccagtgtggtgcccaagcgcagtggctcatgcctgtaatcccagca46380 ctttgggaggccgaggcaggtggatcacctgaggtcaggagtttgagatcagtcaggcca46440 acatggtgaaaccctgtctgtactaaaaatacaaacattagctgggtatggtggtgcaca46500 tctgtaatcccaactacttgggaggctaaggcaggagaatcacttgaaaccaggaggtgg46560 aggttgtagtgagccgagatcatgccacactcccagcctgggtgacagagcaagattcca46620 tctcaaaaaaaaaatccactcctagacaaataatagttaaattttagaacaccaaggaga46680 aagaaaaaaaattgtaaagcttcagagaaaataaacattaactacaaagaaacgagagtc46740 agacgcgtgcacttcttcctagataccagcagataaagcaatatctccaaaattcagaag46800 gttttaacgtagaatcctatacccagtcaagaatattcacatggaaaagtgaaataaaaa46860 acattgtttaaacatgcaagggttcagaaagtttaccattcacagaatccctgaaaacaa46920 aaccaaataatcacttaaggactcattaagaaaacaaatgaaataaaagcaccaatgatg46980 agtaaataatcagaaaaatttacagtttacctaaataactgtttatgcataatgtatgaa47040 aacccaaaaatttaatatgggacagaattaaaatcatgataagattcttttttgctttac47100 tcatggagagttcacataaacagattatcttttaatagcaagagaaaaaaatgtttagat47160 atgtgtgaaaaactaagggtaccaaaacagtgcaaattcatttatcatcaggaaaatcca47220 aattaaaaccacagtatccaccagaataactaaaaggtaaaagacagaaattaccaagag47280 ttggcaagaatgtggagcaaccacatatacttctggggtaaataagttggtgcaaccggt47340 actgaaaactgtttgctagtatctactaaaaccgagcacatgcacagactacaaccaagc47400 agttccactcccagatacacactcaacagaaatgcacacactcactcaacaaaagacgtg47460 tactagagtgttcatgtacttactattcataatagtccaaaaatgcaaacaaccaactgc47520 caatcaaagtcaaatgtatatctatattagggatatatacaatggcatatacacagcaat4.7580 gagaatgaaatgaaccagctcggcacagtggttcatgcctgtaatctcagcactttgggc47640 gggtaaggcaggcagatcacttgaggtcagaaatttgagactagcctggccaacacggtt47700 aaaacctgtccccactaaaaacacaaaaattagccgggcatagtggttgcaggcctgtaa47760 ttccagctactcgggaggctgggttgggagaatcgtttgaacccgaaagccggaggtcgc47820 agtgagcggagatcgtgccactgcactccagcctggacgatagagcaagactccgtctca47880 aaaaaggaaatcaaaaatataaaataagatgacaggaataatccgcaaaagatcagtaat47940 caaaataaatataaatgggctaaagctacctattaaaagacaaagatttcacacccataa48000 ggatagctactatcaaaaaaagagagagaataacagatgttagcaaggatgtatggaaac48060 tgaaattctcacgcattgctggtgagaatataaaatggttcagcctctgcggaaaacact48120 atgctgggtcatcaaaaaattaaaaatagaagtactacttgatccaacaattctacttct48180 gggtatatacccaaataactgaaagcagggtcttgaagagatatttgtacacccatgatc48240 atggcagcattattcataatagctatgatgtggaaccaacataaatatcctttgataaat48300 atatggataagcaaaatgtggtgtatacattcaatggaatattaattagcaataaaaatg48360 aagaaaattctgacacatgctacaacatggatgaaccttgagggcattacattaaatgaa48420 ataagccagttataaaaagacaaatactatatgaggtactatattagatactcatgcaag48480 gtacctaaaataggcaaattcatagagacaaaaagcagaatggtggttgccaggggctgc48540 ggtaatggatacagagcttcaattttgtaagatgaaaaaattctggagattggttgcata48600 acaatgtgcacacacttaacactggggaactgtaaacttaaaagtagtaaatggtaaaaa48660 taaaaataataaataataaattttatgttattttaccacaatatttattaaaagacaaag48720 attaactaattaaacaaaatccagccataagctaatggtaagagtaacaattaaagaaga48780 cacagaaaattgaaaatcagtgactagaaaaagatattccatataaatgctaacaaaaag48840 caagtacagcaatataaagagaatgaacaaaaaaaaaattaaataagatggctcgtttat48900 tcccaaaaggtacaattcaccaagaagatacaagaattgtgaacctttaagcacataaaa48960 cagcttcaaaaatacaacatttaaagaaaaatatatattaaacatagaaatagtacaaaa49020 acccctacaagaatcataatgggagtcttcaatacaactctccatatcaacaggtcaaac49080 agagaaaaaaaataagttaaggatgcagaaaacctgaattaccatcaataaacttgagat49140 taatatagaactgtatacccaatatactaagagttcagggaacagtcgtgactgacagtg49200 gactgcaaat taatctgttc ttaatctttg tttttctttc agcactgtgg cagaatagag 49260 atcctaaaaa ccttccagct acaaaacatc tttttaaaaa tataaaaaaa tacaaaaata 49320 actctgaaat caatagaaga cacatggtga aaccaaaatt ctagaataca gggagaataa 49380 aggcattttc agatattaca aaaacagaaa attgatcatt gctgaagtaa tttctaaaga 49440 atgtacttga gggagaagaa aaatgttcca aagaaaagta tctgtgatac aagaaggaat 49500 ggaaagtgaa gaaatggtaa acaggtagat aaagctaata aatgttgacc tagaaaataa 49560 caaaaacaat agcaataatg tctcgttgga agggttgaag taaaaataca attaaggcca 49620 aatgtgaggt aagtggaatg aaagaattag aagtccttgc cttgttcaca ggactgatta 49680 aataaatgag ccaggttttc cattcaaaca gttaaaactt gaacaaaata aactcaaatt 49740 aagtagaaag ataaaaaaca gaaattaatg tcatagaaaa ataaaaaatc aatagaatta 49800 atcaataaat cctggttaat aaaagctggt tctttgaaag gattaataaa ataatcatta 49860 agcaagtctg atcaaaaaaa aagagaaaag gtaccaaaaa aagtactgta tcagaaagag 49920 aacatacaga tacatacaga tatgtaagag tctgttttct tacaccagaa tactatatac 49980 aacattatgc tagcatatat taaatttcaa taatgttaat gattttctag gaaaacagaa 50040 aatattaaat ttactttgaa gaaacagaaa aactgagaaa aataaatgat catgaaaaaa 50100 atgaaaaggt aattaaatac tgatattaac tgcctaaaca acaccagcag cagcccaggc 50160 agtctgcagt caagttctgc caaacttgag ggaacagata attcttctat tccagagcat 50220 agaaaatgat ggaaagtttc ccaatttaat cagagaggac agcctgatcc ttgttatgaa 50280 cacagataaa aatggggtaa actatatgcc aaactcagat accaaaaccc taaataagat 50340 gctagcttat tgatgtgaac aatccaaaag tgcattttaa attagcccag ggttttagag 50400 aaagaaaatc tagcaatgtg accaccactt atgttaacaa ttttaagacg aaaatctaca 50460 tgatcatatc aatgcatgct acacaaaagc atttgggcaa aaaacccaac acccaccctt 50520 gactttttaa actcttagta attaggcata aacagaaatg tacttaatgt gatagaatac 50580 actcggtgaa gatacagagg gaatgctccc taaaaccaag cccaagacaa agattcctat 50640 ttaacctcaa tagtcaacac tgcagcgaga gtaatctatg gaagacaagg aaaaaagtaa 50700 aaacatgaga gacatctgtt gtttaacaga caataagatc acctacttgg aagaggcaaa 50760 cgaatcaagc gaaaaactat taaaactgag acaggcttta gtatggaggc tcagcttcag 50820 ctgtagtttg ggctaccaaa ttcaactcgc ttgcttggag agttaatcct gcaaagctaa 50880 tttctgttga ggtattagga ttgacaagcc tgtgCtCCtC CCtCCtCCCC CatCttCaaC 50940 actgaaataa cacggtgttt ggaactggat aacagaatct tccaaaaaca aaaattgtcc 51000 tgaagggctg acttgtgccc ttactcaaaa aacactttat ctgctgcctg cagctcctac 51060 agttgctggt ggataagcct gccaaccagc tcggcgtaat tcttcctgca gagggcaagg 51120 aagagcactt tcacaggaaa atttttttcc gaactgtatg ccgcttatta cataaactta 51180 cgtgctggca aatggagctc cagcaaaata agatattcag agtcaaactt ccttaggaaa 51240 aaaaaaaaaa aaaagcaagc acataacact aatttccttg catgggcact ggggaaggag 51300 gtcgttactt CCgCaCgCCC gcaggtccgc accaccggga aacccacggg caccgcgcgc 51360 tgcccccggg ccttccaggt gcactgcgcc gcggcgcccc agctgacccg ggatgcgcag 51420 ccctagccct tcccctgtca ccccggccag gaaggggcgg gagcgcggcg gacgccgagg 51480 gcgaagggct tctcggtcct ctgcaccacg cagcaccccc aaggcacaac agggagggtg 51540 cgggaggctc ccgagaccca ggagccgggg ccgggcgtgc ccgcgcacct gtcccactgc 51600 ggcgagggct ggggtcgcct ccagggccgc agctgtcggg agccacctgg ctctcagtcc 51660 cgggtccctg cgacaaccct cgggcccgga ggggaggagg cggccacctg ccgctgccac 51720 CtgCggCa.CC ggtCCC2CCg CtCCgggCCg ggCaggaCag gCCaggaCgt CCCt.CCtggg 51780 ctggggacag gacacgcgac gaggggaccg gggcccccgc ggcgaagacg cagcacgcct 51840 tCCCagaaag gCagtCCCgt gCCCCCaCga CggaCtgCCg gaCCCCCgCg CtCgCCCgCC 51900 catcccttca gaccacgcgg ctgaggcgca aagagccggc cggcgggcgg gctggcggcg 51960 cggctagtac tC2CCggCCC CgCtggCtCa gCgCCgCCgC aaCCCCCagC ggccacggct 52020 ccgggcgctc actgatgctc aggagaggga cccgcgctcc gCCggCgCCt CCagCCatCg 52080 ccgccagggg gcgagcgcga gccgcgcggg gctcgctggg agatgtagta cccggaccgc 52140 CgCCtgCgCC gtCCtCCttC agCCggCggC CgggggCCCC CtCCCtCCCa gCtCtCagtg 52200 tCtCatCtCC CtatCtgCtC atCCtCtggt cgcacataat cgatgtttgg gcgtcccaag 52260 ccagatgtgg accccatttc cgcactctac actggaggtt ttctaagggt ggtgcccgga 52320 ccagcagctt cagcctcatc tgggaacttg agaaaatgca gattctccgt cccacccagc 52380 ctattcggtt tttcctgcac taaaaccatg aaggtggggc ccagcagtcc acattctcgc 52440 aagcccgtca agtgattctg aggcgccctc cagtttgaga gctatgctca cggcctcacc 52500 tccgccccgc aaggagcccg gtcttgcctg tggcgctagc cgcacacgga cacctcatcc 52560 tgcggggccc gcccccccgc tgcaccctca ccgcccaacg cctcctccgg gatgcagcgg 52620 aggcgcctgg aagtcggcaa ggtcaacatc cccctcagca tcttccctac cctcacggct 52680 cctcctccag gggtgcctca tggccagggg ttagaaagag ccactgtgtt tcttgacatg 52740 gaagtggcct aagaccttaa tgaaaactgc aggagtggaa tgacagaacc tttggtcata 52800 cttgagggcg tgaagctcaa atgaggagga aggaaaggat ccagggagaa taaccaaccc 52860 tggcaagttg tggcgcccag gtagaggggc gagcctaggc tagcggttct cgaccagggc 52920 cggtgttgcc cctcctcgcc gccccgcgta catttgggga ggtctggaga catttttggt 52980 tgtcatgatg cgggagttgc tactgttgcc taagtgggta gacacgaggg tgctcctcaa 53040 catcctacct gaaggacagg actgccccac aaggaagaat gatccggccc caaataagaa 53100 accctgggct ggtcagcaac aacccctttg ttctgagaag agaggaggaa agaataaaag 53160 aagtggggtg aagttttggt ttggtagagg aaacttgaag acattttcac tggaaaggaa 53220 gagaggaaga ggagggagat gtctgtaagg acgagcaaac cgggtgacag ctgatttcct 53280 catattgaag taatgagtcc tagttataat aaattcctaa taaaaaccca gtttatccct 53340 gcaataaact tgtctttttt ttttaaatat actgcttgat tctgtttgct aatattttat 53400 ttacaggctt tgcattgata tgcaaaaatg agatgggcaa taattttctt tttgaatgtc 53460 taatgttgtt tggtttcaga atcaatgtta tgctcacatc ataaaaaatt tggaaccgag 53520 gcaggaggag tgcttgaggc cagaagttcg agaccagtct aggaaacaca gtgagacccc 53580 cccatctcta caaaaaaaaa aaaagaaaaa aaaatgggca tgtttgcttt ttccttttac 53640 tctgaacaat ttaaggagca ttaaaattat ctattctttg aggtttgatc atttcccagt 53700 taaaaatgtt cctcccagcc tgatgctttc tttggggagg gtaaatcttt taaggctaga 53760 aaagtttctt ctgtggcaat tttattattt acattttaaa aattattcta gagttaattt 53820 tgataaagca tgtatttctt aaaacaaatt atcctttttt tccagatgtt caagtgtatt 53880 tgcataaagt tgaggaaagt agtcttttgt gaatctttta acttctccca aatatcttat 53940 tttgtgtatt tttgcttctt tattttgtta acttttaaaa gtgtattttt ttttcaaaga 54000 atcagctctt aggtttatgt ttttggttat actggagctt ttttcttctt ctttttaaaa 54060 tattttttct cctttatttt ttagacgtat tttgatctaa cgtaatcgga agaaggtaaa 54120 ttagaatctt ttgttactat tgtgttttta tttctcctta tttctctgaa gtcctgcttt 54180 ataaatagta ccatgttatt tgtgcataaa tattcatttg tcttatattc ttgggaattt 54240 tcccacttca tcataaaatg accttccttg tctcatttaa tgtgttcaaa ctttgccctg 54300 aatttaactt tgtctgatat tttaccatcc tgctgaattt tgtttgttac cccaaacaac 54360 ctttgctgtt ttcgtctttt ctgaaccctt tattttaggt aatcccttga attagagcac 54420 taagttttgc tttgtgatta aatctgaaaa tctttatctt gccatagatg agttgagccc 54480 tattcatgtg acagctatat tatgctgttt CatagCCCtt ttggtCCttt tttCaCtCtt 54540 gcattgcata ttttgtgttt attgtgtttt gtgtttcttc tgataatttg gaaggtttgt 54600 atttttattc agggagttgc cttataatca tactccgcaa tacacatcgt cctcagtttc 54660 ttcagactgt ctgttaactc cctattctga ataaaaatga cattgtaatt tccctctttt 54720 ttctttaccc cttttcttct cctcacctaa tgtaaatgat tttatccttc tttagtattt 54780 gcttttttaa ttaactacat ttataaatat ctttatcact tgatttttaa atcagctttg 54840 aatgagatat ttggattcct agatataaaa gatgttaatt ataccatttc cacgttagta 54900 ggtttataaa atcatacatt ctgctgtgta accataatcc cacgtttgtt ttagttccac 54960 tcctacagtt aaaagattca gaagtattat taacagttat tttgccatag ttttttcccc 55020 aacccatttt gtggtaagtt atgatcctgc tttagtttct taagaataat ttatagagca 55080 gagtgtggtg gctcacgttt gtaatcccag cactttggga gacaagaggt agaaggatcg 55140 cttgaagcca gcagttcaag accaccctga gcaacatagt gagaccttgt ctctacaaaa 55200 aattttaaaa tttagccaga cgtagtggcg tgtgcctata gtcccagcta ctcaggaggc 55260 tgaggcaaga ggattgctag agcccagaag tttgaggctg cagtgacctc tgattgtgcc 55320 actgcacccc agtctgggca agaaagtgag aacctatctc tttaaaataa caataataac 55380 ttatgaaaat tatattccct gagtttttca tgtttaaaaa tatttgttgc ctttatcctg 55440 taaaagtttg agtataaatt cttgggttat actttattta ttgaagaatg tataagtatt 55500 gtcttctaga attgagtgtt gctgtaatga aaccagaagt cagcctggtt tatttttcct 55560 Cagaaatgag gtaattgCCg gCCggaCaCC gtggctcatg cctgtaatcc caacactttg 55620 ggaggccgag acaggtggat cacgaggtca ggagattgag accatcctgg ctaacatggt 55680 gaaaccccgg ctctactaaa agtacaaaaa gttagctggg catggtggtg gacgcctgta 55740 atCCCagCta CCCgggaggC tgaggCagga gaatggcgtg aacctgggag gaggagcttg 55800 CagagagCtg agatCgCgCC aCtgCaCtCC agCCtgggCg acagagtgag actccgtctc 55860 aaaaaaacaa aaaaaaaaca aagaagtgaa gtaattgcca tgatgctcca agaattatct 55920 ctttgtctat gaaatccaga aatctcactg ttatacattt tggaattatt attctgggcc 55980 aatatttcct gggacacaat agattgactc tatagattta attttttttt tttttttgag 56040 acagagtctc actgcaatct cagcttactg caacctctgc ctcacgggtt caagcaattc 56100 tcctgcctca gcctcccaag tagctgggac tacaggcgcg tggcaccatg cctggctaat 56160 ttttgtcttt ttagtagaga cagggtttca ccatgttggc caggctggtc ttgaacgcct 56220 aacctcaagt gatccacctg cctcagcctc ccaaagtgct gggattacag gcgtgagcca 56280 ccatgcccag cctcaattcc tctttctatc tggtaatttt tctgaagttg aaaacatttg 56340 ttctaatacg ttatttcagt gttcttctaa gatgtgtaaa gcaccctatt cccaggtcag 56400 cccccatctt gctagtgagc tcggctggtt cttcacaaga gctctggttt tctcctgctt 56460 aatctcaagt acctctgtca gcctccacct ggtttatgat ttggagtttt ttggtttttg 56520 ttttttgttt ttgacagagt cttactctgt cacccaggct ggagagcagt ggcataatct 56580 cagctcactg caacctctgt ctcccaggtt tgagcgattc tcctgcctca gcctactgag 56640 tagctgggat tacaggcgcg tgccaccaca cccggctaat ttttgtattt ttagtagaga 56700 tggggtttca ccatgttggc cagggtggtc ttgaactcct gacctcaggt aatccacctg 56760 cctcagcctc ccaaagtgct gagattacag gcgtgagcca ccgcgcctgg catggtttgg 56820 agttttaatc tgtagtttta ataaagatag tgcttatgtt tgtgtttctt atatttcttg 56880 gtactcttgg gtaatttgta agatccccat atctacacaa gaagtccatt ttcaattctt 56940 ttcttcagac tgtttatttt attttatttt attttatttt tatgtttgag atggagtctc 57000 gctgtgtcacttctggaggctggagtgcagtggcgcgatctcaggtcactgcaacctccg57060 tctcccgggttcaagcaattctcctgcctcagcctcccgagtagctgggattacaggcac57120 ctgccactttttaatttttttagagacagagtctcgctttgttgaccaggctggagtgcg57180 gtggtgcaatcatggctgactataacctccaaatcctgggctcaagtgatcctcctgcct57240 cagcctcctgagtagctgggactacaggcacatgccaccatgcccagttaattttaattt57300 ttttgtagagaCagggtCtCCatatgttgCCCaggCtggCCtCCtaCtCCtggcctcaag57360 taatcctcctacctcagcctcccaaattactaggattataagcatgagccaccatgccca57420 gccttgttctactactttaatttcatatgttaggtgaccatgtaattgatcatccaaacc57480 aggatactgtaagaatgaaagaggctgacagtagtatgatgctgggactagcattgtgca57540 ctgagattatttctgggaaagcaggagatacggtcaccctacttatagtgtgcttgtctt57600 tggattgttgaatttggagtttctatttgcaggcttatttcaactgggcagccttgatcc57660 gccctgcccagcaatgctaccgttctctccaccgggtctctgggaccccttcagtcacta57720 tacttagctcagttccccaccctcccactccctaaaagcgtaaccaggaatcctgcctca57780 ggtctactgccgtcttccgtgggctgtttcagttcctattacccagagtcaaactcccag57840 cattccctacctgattccagacttggagtccagagctttaacctcttcaggccaactccc57900 cactttgcatttctgtccctatatcttagtccatggagatacatttcatgtctttgagtc57960 tacttacaaagtaaattttgctgttttttaattttttttttgagatggagtcttgccctg58020 tcacccaggctgtggtgcaatgacgccatctcggctcactgcaacctccgcctcctgggt58080 tcaagcgattCatCtgCCtCagCCtCCCaagtagctgtgattacagacaggcaccaccac58140 gcccagctaattttttttatcttttagtagagacagggtttcaccatgttggccaggctg58200 gtcttgaattCCtgaCCtCgtgatCtgCCCatCtCggCCtcccaaagtgctgagattaca58260 ggcgtgagccactgtgcccagccaattttgctttttttatatttcattgctatatgttta58320 gaggataagtttacagtgctatatgcattcccaaatattagaccaaaaaaatctccaaaa58380 aattagaaagaaaatccaaaaaatctcaaaaaataccaaaaagcaacaatctcacagacc58440 atactcactgacccccaataaaataaaattagaaattaaccacaacttaacaaaataaag58500 tactcaagtcagagaggaaagaggaaataaacatcaaaattacaaagtctaggcggtggc58560 tcacgcctgtaatcccagcactttgggaggccaaggcgggcagatcacaaggtcaggaat58620 tCgagaCCagCCtggCCaatatggtgaaaccccgtttccactaaaaatacaaaaattagc58680 caggcatagtgatgtgtgcctgtaatccagccacttgggaggctgaggcaggagaatcac58740 tgaacccagggagacgaagattgcagtgagccaaaatcgtgccactgcacttcggcctgg58800 gtgacaaagcgagactccatctcaaaaaaaaaaaaattacaaactctttagatagaaatt58860 ttggtgtttttttttgagaCggagtCtCaCtCtgtCC~CagaggCtggagtgCagtgggaC5892~

tatgtcagctcaccgcaacctCCatCtCCtggattcaagcaattctcctgtCtCagCCtC58980 ccaagtagctaggattacaggcgcccaccaccagacccagctagtttttatatttttagt59040 agagatggtgtttcaccatgttggccaggctggtctcaaactcctgacctcaagtgatcc59100 aCCtgCttCagCCtCCCaaagtgCtCagattaCaggCgtgagCCaCCgCaCCCCaCCtag59160 atagaaatttcaacatgaggccgggcacaatggctcacgcctgtaatctcagcacttcag59220 gaggctgaggcgtgggaggatcacttgggcccaggagttcagg2ccagcatgggtgacag59280 agacagaccctgtctctatttatttgaaaaaaaaaaaaaaaaagagagagagaaagaaat59340 ttcaacatgaaaagtatctctcaaacccttcgagatgttggcaaaaagcgactcaaagga59400 aaatgtattactgtgtgtgaatttgcttgaaaataagaaagaggccgggtgtggtggcta59460 acacctgtaatcccaacactctgggagtccgaatcaagtggatcatgaggtcaggagatc59520 gagaccatcctggctaacatggtgaaaccctgtctctactaaaaatacaaaaaattagct59580 aggCgCggtggCtCatgCCtgtaatCCCagcactttgggaggctgaggcaggtggatcac59640 ctgaggtcaggggtttgagaccagcctggcctacatggtgaaacctcgtctcttctacaa59700 ataCaaaaattagCtgggCgtggtggtgggtgCCtgtaatCCCagCtaCtcagaggctga59760 ggcaggagaatcgcttgaacccgggaggcggaggttgcggtgagccgagatcgcaccact59820 acactccagcctgggcaacagcctgggtgacacagtgagactccatctcaaaaaatacaa59880 aaaattagctgggtgtggtggcctgcgcctgtagtcccagctacccgggaggctgaggca59940 ggagaatggagtgaacctgggaggaggagcttgcagtgagccgagatcccaccactgcac60000 tccagcctgggcgacagagcaagactcttgtctcaaaaaaaagaaaaaaaaaggaaaaaa60060 gaaccctgataataaagaaaccaaatgttcaactctcaaagctcggacactttaaagaaa60120 taattaataaaggcagaagttaaagggaggatgataaagcaattttttttgttggttttt60180 ttgagatggagtcttgctctgtcacccaggctggagtgcagtgatgcgatcttggctcac60240 tgcaacctctgcctcccgggttcaagcaattctcctgcctcagcctcctgagtagctggt60300 actacaggtgcgcgccacctggcccagctaatttttgtatttttattagagacggggttt60360 caccatatttgttaggctggtctcaaactcctgatctcaggtaatctgcccacctcggcc60420 tctcaaagtgctgggattacaggcaggcgccaccgcgcctggcctaaagcaaaatattgg60480 ttctgtgcaaaaggtcaataaaaagagcaaacgtttacaaactggagccagcacccattc60540 agctcagtgtgtctggagaaaaaacaatctcgcttcagaattcatgattacgcagccctt60600 tttgcttcctaaaaatcctactatgttgctgttgaccattctctctctttctctctctct60660 tgctttctctccagaaaagctattcagacattctcctctttcctcaaacctccaacactt60720 CCtCCtCCatccttagcctcagctgctgacctcacttctaatcattgagaaaccaggaga60780 agcatttaagagtgaacctccgcctccccgcacgggcaaaaccacccacccacagaattg60840 tgccccaattctgcgtcctctcctctcaccatggatggacggtccaggctccgagccaaa60900 gccaggcctcccctggagctctggatccaccacctgcagcttctcaggcagggccccagc60960 agctcccctgCtCCCttgtaCCatCaatCCCtCCCCtCaCtgggtcactcccaacaatat61020 atatatttagtgatgtttctcccatgtggtaaaatcacttagCCtCtCtCCtCCCCCagC61080 tactatcctatttgtttctttccattctctgcaaaacttctcaaagcattgtgtctatgt61140 gctgactccatttatcttctcccgttctctgctgagtccttcccacagactctcacccca61200 gttactccatgaaatgacctctgcactgccacatccaatggtgaatgttcagttcttaat61260 tttattcagtctttcagcagcatttgacctggccgatcactccctcttcttaaaaatact61320 tttctcagccaggcgtgatggctcacacctgtaatcccaacactttgggaggccaaggcg61380 ggaggatcatgagagcccaggagttcaagatcagcctgggcaacatggcaaga~cctatc61440 tctacaaaaactaaaaagtagccagtgtgatggcatgcacctgtagtcccatctacttag61500 gaggctgaggcagtaggatgacttgagcctgggaaatcaaggctgcagtgagccatgatt61560 gcaccactgcactccagcctgagtgacagcgagaccctgtctcaaaaagacaaaatagga61620 aacttttctcagcatattcctctgattctcctgctgcttctgtctgcacagattcagtct61680 CCtttgCCggttCttCCtCatcctcctgatctcttgaccttgaagtgccccagagtacag61740 tctttttttttttttttgagacgcagtctcgtctgtcacccaagctggagtgcaatggcg61800 aggtctcagctcatgcaacctctgcctcctgggttcaagcgattctcctgcctcagcctc61860 ccaagtagccaggactacaggcacatgccaccatgcccagcaaattgttgtatttttagt61920 agagacagggttttactatattggccacgctggtctcaaactcctgaactcgtgaaccac61980 ccgcctcggcctcccaaagtgctgagattacaggcatgagccaccacacccggcccagag62040 taCagtCtttagaCggCCtCtCtaCCtataCttgCtCCCCtCataaaCtCCtCCtgCCtC62100 atggctttaaataccatcggtagactgatgactcccatatttctcttttttttttggaga62160 cggagtctcgctcagtcccccaggctggagtgcagtggcgcgatctcggctcactgcaag62220 ctccacctgccaagttcacaccattctcctacctcagcctctccagtagctgggactaca62280 ggcacccgccaccacgcctggctaatttttttgtatttttagtagagatggggtttcacc62340 atgttagccaggatggtctcgatctcctgacctcgtgatccgcccatctcggcctcccaa62400 agtgctgggattataggtgtgagccaccgtgcccagccgatgactcccatatttctatct62460 cttgctgtgtgggagttctcctcagaactccatactcataaatccaactctcataaatag62520 tatctcaaatgggcaatatgctcaaaagtcaattcctacttttctccctaaacttgcttt62580 cctgcagtctccaccatcttaatgtccaatctaacattaggaggcaaaaactttgaagtc62640 attcttgactcttctctattacacaccctatccaatctttctgcagatccagtcgacccc62700 CaaatCCagttagCtCtCatCatCtCCCCtgttaCCCCCtggtCCaggCCatCttCCtCt6276~

CtCaCCtgaatCaCtgCagCattCtCCtCaCtggtCtCtttggttCtgttttCaCtCCaC62820 cttagcatagtctccacagagcagtcagagggatccttttaaagtgtaattcccatcctg62880 tccctgctctgctcaaaaccctgtcgtgattcccgttttaatctgtcagattaaaagcca62940 gagtctttccagtgacctacatgatctgcctattatcacctcccacttctttccccttgc63000 tCaCtCCaCtCCagCCCtgCagCtgtCCtttCtgtttCCtgaaCagCCCagattttgCtt63060 ctttagaacctttgtatttgctgtcccctctgtctggaatgtttttccaggaagtcacct63120 ggctctctcctgcacttccttcctgaccaccatgtttaaaaatcactcaaacacacttca63180 ggccggacatggtggctcacgcctgtaatcccagcactttgggaggccaaggtgggtgga63240 tcacctgaggtcaggagttcgagaccagcctggccaacatggtgaaacttcgtctctact63300 acaaatacaaatagtagccaggtgtagtggcacacacctgtaatctcagctactcaggag63360 gctgaggcaggagaatcgcttgaacccagaaggcagaggaggtgcagtgagccaagatca63420 cgccacaacaccccagcctgggtgacagageaagaccccatctcaaaaaaaaaaaaagaa63480 aaaaaaatcacacaaacacacttctcttcatattccttttccaagttttatttttctcca63540 gaatactttacattgttttaatggaagttctccgtttccccccaactagaatggatactt63600 cctgcaggtaggCaCtCtagtCCtCCCatCCaagtaCtaaCCaggCtCaaCCCtgCttag63660 cttctgagagcaggggagatcaggcctgttcagggtggtatggcccaggaattttgattc63720 tgttttattcattgctgttctgttgattctcttttgttcctcctcctagtgctgagaaca63780 CtaCttgtaCataataagCattcaataaatatttgttgaatgaatgacttgttgaatgaa63840 ttaatctcagaaatgcaggactggttctacattagaaaatttttcaaggtcattctctgt63900 tgtcgtaacacattaagagaggaaaattttgtactctaaatcatttgataaaatacatac63960 tgatttctgttttcaaaaactcttagtggctgggcgaggtggctcacatctataatccca64020 gcattttgggaggacgaggtgggcggatcacttgaggtcaggagtttgagaccagcctgg64080 ccatcatggtgaaaccctatctctactgaaaatagaaaaattagccgggtgtggtggcgc64140 atgcctgtagtcccagctacctgggaggctgaggcaggagaatggcttgaacccgggagg64200 cggaggttgcagtgagccaagatcatgccattgcactccagcctgggtaacagagtgaga64260 ctccatctcaaaagaaaactcttagtgagtttaggaatccaaggaagaccctcaaactaa64320 atagataatctagctaccagaagccttcagtaaaccttaacactccatggtgaaacatta64380 gaaacattcctactaaaagacaggctaagaatgcctgcaatcttcacggctagtccaaga64440 agtcaaaaagaagaaatgagcgctgatttaaaaaaataaacaaacaaaaaactaccgatg64500 cagaggctggcagcaaggactgaaggactgtacagtacttgcctggagcaggcggatggc64560 cacacccctgcgaagcctgctcagctggctgggggacgctccagtgtgtgagtggcagga64620 tgcagggtacttcctctgccagggagttgcactggggagatCCtCCCCCaCtCa.CaCttt64680 ggcagctggggctttggaatgtgacttagcttctgtcaaagggtcaatccaccctttgat64740 atatgatgcaaaggcgaacatatgatgcaaaggtgagagaacagcccaaattaggacttt64800 taccacagctgtggaggtggacagcgacagtggtgggccctggccagacttttcatgctc64860 aaaggtggtggttgttcttcctacttcttgtccctccagggcttcctttgcctgtgtgct64920 gaacctgcttcttttaattttttttaacttttttaaatttttaattgttttaattaaaac64980 aaattttgaaaactgtctgaacctgcttttgaaccctgctatgatttgaatgtttgtccc65040 ctgccaaactgattttgaaacttaatctccaaagtggcaatattgagatggggctttaag65100 cagtgactggatcatgagagctctgacctcatgagtggattaatggattaatgagttgtc65160 atgggagtggcatcagtggctttataagaggaagaattaagacctgagctagcatggtcg65220 ccccttcaccatttgatatcttacactgcctaggggctctgcagagagtccccaccaaca65280 agaaggctctcaccagatacagctcctcaaccttgtacttctcagcctctgtaactgtaa65340 gaaataaatgccttttctttatgaattacccagtttcagatattctgttataaacaatag65400 aaaacgaactaaggcaaactctcatgattctactgccatgccattccaataaactccctt65460 tatgcttaagagagccagagttggccaggcgtggtgactcacgcctgtaattccagcact65520 ttgggaggccgaggcaggtggatcacaaggtcaggagatcgagaccatcctggctaacac65580 ggtgaaaccccgtctctactaaaaatacaaaaaaattagctgggcgtggtagtgggtgcc65640 tgtagtcccagctactcgggaggctgaagcaggaggagaatggcgtggacccaggaggcg65700 gagcttgcagtgagtcgagatcgtgccactgcactccagcctgggtgacagaatgagact65760 ccgtctcaaaaaaaaagagagccagagtttatttctgttgcttgcaaccaagaaatctgg65820 ctggtgcactgaagtttccataaataatagcaatttaaagactctttccaagccaggcaa65880 tgcctagccttgtgtagtccttgtggtaatacattcattcattcatttgttcaaccaact65940 gtgctccagagactaagaatacaaaaatgggggccgggtgtggtggctcacacctataat66000 CCtagCaCtttgggaggCCgaggcaggtagatcacctgaggtcaggagttcgagaccaac66060 ctggccaaaatggtgaaacccctactctactaaaaatacaaaaaattagctgggggtggt66120 ggcggacacctgtaatcccagctactcgtgagactgaggcaggagaatcacttgaacccg66180 ggaggcagaggttgcagtgagccgagatcgcaccactgcactccagcctgggcaacaaga66240 gcgaaactccacctcgaaaaaaaaaaaaaaaaaaaaagagggccggggctgggcgcagtg66300 gctcacgcctgtaatcccagcactctgggaggccaaggcaggagaattacgaggtcagca66360 gatcgagaccagcctgaccaacatggtgaaaccccatctctactaaaaatacaaaaatta66420 tccgggcgtggtggcgCacacctctagtcccagctacttgggaggctgaggcaggagaat66480 cgcttgaacccgggaggcagaggttgcagtgagccgaaatcatgccactgcactccagcc66540 tgggtgacagagtgagactccgtctcaaaaaaaaaataaaaaaaaaaaaagaattcaaaa66600 attgtagagttatagtgtgcttctagtttagttgagaggacatctgtccttcaaggaagg66660 ctagaatctataccctgagtccttactgaaatcaatccagcagtcaaaacatgggaccaa66720 cgatcacagcagtaagataggaagagcacctttgtacatttagctcatgttgagataagc66780 cactgacagagctgaaggaagctcacagttctgggttccatcctttggcatttaaaaaga66840 aaagtgctaagaaaattcggttggtcacggtggctcacgcctgtaatcccaacactttga66900 gaggccaaggcaggcagatcacgaggtcaggagttcgaaaccagcctggccaacatggtg66960 aaaccccgtctctactaaaaacagaaaaattagccgggcatggtggcgcatgcctataat67020 cccagctactcaggaggctgaggcaggagaattgcttgaacccgggagggggaggttgca67080 gcgagtgagagcaggccactgcactccagcctgggagacagagcaagactctgtctcaaa67140 aaaaaaaaagaaaaaaagaaagaaaggaaaaaaagaaagaaaaaaaaagaaaaaagaaaa67200 ttcaggccaggccaggcctggtggctcacacctgtaatcccaacactttgggaggctgaa67260 gcgagacggtgccttagcccaggagtttgagaccagcctgagcaacatagcgagaccctg67320 tctctataaaaaaaaatttttttttggccagacgcagtggctcacgcctgtaatcccagc67380 actttgggaggccgaggcaggtggatcacgaggtcaggagatggagaccatcctggctaa67440 cacggtgaaaccccatctctactaaaaaatacaaaaaattaaccgggcgtggtggcgggc67500 gcctgtagtcccagctactcgggaggctgaggcaggagaatggcgtgaacccgggaggcg67560 gagCttgCagtgagCCgagattgCgCCaCtgCc3.CtCCagaCtgggagagagtgagactcc67620 gtctcaaaaaaaaaaaaaaaaaaaaaaaattaattgtcaggtgtgctggcatgcagctgt67680 agtcctagctactcgggaggctgaggtaagaagatcgcttgagcccaggagttcaaggct67740 gcagtaatagtgcctctcactctaccctgggtgacaatgagaccctctctcaaaaagaaa67800 gaaaaaagggaaagaagaaaagaaagaaagaaagagaagaaaggaaggaagaaagaaaga67860 aaaagaaaaggaaggaaggaagaagaaaaaaaaagaaagaaagaaaagagagagaagttc67920 aaagaccaaagggtcaggatcccaaaatagtttttatgttttatttatttatttacttat67980 ttatttttgagacagtatggctctgtcgcccaggctggagtgcagtgatgcgattgcggc68040 tcactgcagcctccaaactgggctcaggtggccctcccacctcagcctcccgagtagctg68100 ggaccacaggcgcgtgccaccatgcccagctaattttttaattctttgtagagatgaggt68160 ctctatatgctgcccaggctggtctcgagctcctgggcttaagccatccacccgcctggg68220 cctcccaaagtgctgggattacagaagtgagccaccgcgcctaatcgggtggtttgtttg68280 tttattgacggggtctcgctgctgcccaggctggagtgccagtggctgttcacaggtgca68340 gtcctggagcattgcatcagctcttgggctctagcgatcctccagagtagctgcagctgg68400 gattccaggcgcgccaccgcgcggggctcagaatgggtttttatattgagggttatgctg68460 ccacctagaggatatatgtagtaccgaactgtgtgcgcagggaggctgaggttgcagtga68520 gccaagatgatgccagggcactccagcgtgggtgacagagcaagatttcatctcaaaaaa68580 aaaaaaaaaaaaaaaaaaaaaagaattgaaagtaaggtcttgaagagatatttgtgcctg68640 tatggtcatagcagtattaactttgacccactagctaaaacacaaaagcaacatgtgtct68700 gtcagcaggt gaacggataa acaaaatgtg gtatatatgt acaattgaat attattcagc 68760 ctttaaaaag gaataaaagg ctggatgcgg gggctcacgc ctgtaatcct aacactttgg 68820 gagactgagg tgggtggatc acccgaggtt aggagtttga gaacagcctg gccaacatgg 68880 tgaaacttca tctctactaa aaatactaaa attagccggg catggtggca cttgtctgta 68940 atccaagcta ctggggaggc taaggcagga gaattgcttg aactcaggag ccggaggttg 69000 cagtgagcta agatggcacc actgcactcc agcctgggca acagagtgag actccatctc 69060 aaaacaaaca aacaaaaaat tattatttcc aaagaaacaa gaccctgggt ccatttccca 69120 gcccacacct gatgttgact cacaacacac agcctggttt gctatgagcc tgcttcattt 69180 aattgtcacc ttaacttcac atcaccctca agtcctggaa taactctttg ctgacctttg 69240 tgtgctgagc catctccatg tcgctcaacg tgcagtccct ctcactgcac tgagtcaata 69300 gccagacgtg gtctgactgc agggtcatcc ttggtggctt aggctgactc gggcatagca 69360 gggtgctctg agacctcacc gcatataggc tttgccccca ataaactcta tataatattc 69420 atattatgtg gtctgggtgt gtgtagcttt gcactgtctt ctcgtgacag tgccctcaac 69480 ctctttccca ggatttcctc ctctacctcc tcaagtccca ctgctctgca aagaccaaaa 69540 gctgcagagt CCCagCtCCC tCCtttacaC cccacgacgc agcctcctct ctcagaaccc 69600 tttaaacaga gtcttttact gcagatccca agaacagcca cacccctctc tcccacccac 69660 tccagacaca cccaggtaat tatagcaccc agggtaacta tgtagatgga gtccctggaa 69720 catgtggata gtgccccctg ggagtatgca aaagcaacat tgctggcacc tgcagagaac 69780 agggtgacat ccaggaatca gagcatgggc ctctgggagg tagggatgtg gccaggcagg 69840 ctgccaaaaa ttggtagagc aaggccacag gatctttctg accttccttc caaacagagg 69900 ctcctgtact ggtgatccct gtgttgattg accactccct tcctgggggt cgtggtctct 69960 gtcccagttg cccggacttc tgtgagtgtc ctactgaggt ccttttcatg agaagcatgc 70020 tgtccttcca cctgctggga gcaagagtga caacttcaat actataatag cagtggcata 70080 cagagaagaa gaaagatgaa gtggcaagaa aaacaggctt ccaagcagga gtttttctat 70140 aaaaacaaaa acgtttacaa gcaaactttt tataaagggc tagatagtaa atattttagg 70200 ctttgagagc cacatagact tgtttgcagg gactcaatgt cgctattgta gtttgaaagc 70260 agccatcagg gttatgtaaa tgagtgagtc tgattttgtt tcagcaaaat tttatttacc 70320 aaaacagaca atgagtgggc tggatttggc ccatgatcct tagtttgcca actcctgctt 70380 tgggctcacc cagatctgat tttgaattCt ggCtCtgCta CtggttagCt gCaggagCtt 70440 ggaaggctct ctgagcctgt ttcctcatct gtaaaattaa agcaataatt tctaacactc 70500 aagagtgtta cctcacgcct gtaatcccag cactttggag gctgaggcag gcggatcacc 70560 tgaggtcaga agttcaagac cagcgtggcc aacgtggcaa aaccctgtct ctactaaaaa 70620 atacaaaaag tagccgggca tggtggcgcg catctgtaat cccagctact tgggaggctg 70680 aggcagggat actgctagaa cctgggaggt ggagcgtgca gtgagtggag atcacacctc 70740 cacactccag cctggccgac agagcgagac tccatctcaa aaaaaaaaaa aaaaagagtg 70800 ttagaaggtt ttgagataat gaataaaaga tgccttgtgt atactaagta ttcaacaact 70860 gatagctgca ttggtctaat tataacagtt tagaagcgat tgagtcaaca aatgctggat 70920 ttgtcaggga ggacttccta tcaggaggta gatcttgggc tgagtcctga agcaaagata 70980 ggcattggat agaggagttg agagaacacc ctaggactgt tattattatt attcgacacg 71040 gagtctcttg ctctgtcacc caggctggag tgcagtggcg cgatctcggc tcactgcaac 71100 ctctgcctcc caggttcaag cgattctcet gcctcctaag tagctgagac tacaggtgtg 71160 tgccaccaca cccggctaat ttttatattt ttagtagaga cagagtttca ccatgttggc 71220 catgctggtc tcgaactcct gacttcaggt gatccacccg cctcagcctc ccaaagtgct 71280 ggaataacag atgtgagcca ccgcacccag cccagaacca tttttcaatc cttggctctg 71340 CCttttatta gCtgCaagat CtCaggCaat ttatttaaCC tCtCCaaaga CtCattttCt 71400 cattcacaaa atgaggcaaa taataatatc tactatccca ggttgtcatg agaattaaat 71460 gcaacatgac atttaatgaa atgagaagtc ccttggacat taactggcta aagtatgtgc 71520 tcgacaagga tatcatttta ggtggatact tagcatctca gaactgatgc tcacaatgga 71580 atatcattga aacgcattaa aattcatttt aaatgattgt aggtagtgag gcaattgaaa 71640 gaagaagaca agaggactga ttataatgct tcaggctcac tagtctcctt ttaggaggga 71700 aaaacaattt caagttaaat tttaggctct agatttttac ccctgctgct cattagaatc 71760 acccagattg atgaaatcag agcccatctg aggctgtgtt tttcatctcc agaatgagag 71820 ctgttgtggg gattaagttt ttgaaaaagt acatctaaca ggtgatcgaa aatgatagtg 71880 atattattgc agtgatggtc attattgttg ttattattat actgaaagag gcttcagttt 71940 tctgatccat aaagtgaggg aattgcatga gaccattgct aagattcctt ctagctctgt 72000 ttttttgttt ttgtttttta gacagagtct ctgtcgccca ggctggagtg caatggcatg 72060 atcttggctc actgcaacct ccgcctcccg ggttcaaatg atCCtCCtgt CtCagCCtCC 72120 gaagtagctg ggactacagg cacacaccac catgcccagc taacttttat atttttaata 72180 gaggtggggt ttcaccatat tggtcaggct ggtctcaaac tcctgacctc aggtgatcca 72240 cccgcctcgg cctcccaaca tgctgggatt acaggcatga gccactgtgc ccaacccctt 72300 ctagctttct tgatcactga ttctagggtt ctctgctgaa atatatttga gacatcctgg 72360 ataaaagatc atgcaagagc tcccaatatg gtattaataa ttgattctgg aggcttagct 72420 actcctgatg gattagacat gactcaactg cctctcttat gtgtacaaca caacaacaca 72480 accaagaaag gttattctgg cattccattt attcagttta tttacagccc ttacttccag 72540 cagcacgtta aagatatggc cagggccggg tgcagtggct caagtctgta atcccaggac 72600 _72_ tttgggaggccaaggtgggcggatcacaaggtcaggagtttgagaatctggcaattcttc72660 agacttagaagcaaccagctcgataacacagtcttgtgtgggctctccctCtgtCCCtCC72720 CtCgCttCCCtCatttCtCatCCCtgCCCCtgagactgtgCaCCttCacatagccctgcc72780 atgagaccttcatctcaggctttgctttctggggtaactgaggctaaacactgagtggcc72840 ctaaaagaggattgggatttggaagttagattattcaccagagaacagactttgctgatg72900 atcaggcccaggttgtaattgttgaaaaaaagagaggatgcatagtcttatctcatctcc72960 tagtcaaagtcaacaccatgataaataagagtcaaatcctgagatgtgaattggggacat73020 ttgagtggttaaccctgagaagcttgcaccttcagacccctcaatacccctgctccccag73080 agaaggctggacattgacctcagcacaggcaggagccctgcaagatgccatttgtcctac73140 taaagatggacccctccactctgtttctaggtaaataaccaaagtcaagtctccacacag73200 cctgagcaagaaagtcagagcctgctacaggagaaaataccacactggccaaaggattca73260 ctagccctggccactgtgtgtgggaggaaccagggaatcatgtgtgggagtcaatgttga73320 agctgttggactgggggtggggtggaatataagcctggccctggggagtttttcccgttt73380 gagggcctttacccacaactcaagatccagtgctatagcaggagatcccagagctagtcc73440 taacagatggtcaggattgaacttggcctagagtaaaatgaggaggatagtgccagaact73500 ttctcaacatactattgaggaagaggtcagaaggcttaaggaggtagtgtaactggaaag73560 gggtcctgatccagaccccaggagagggttcttggaccttgcataagaaagagttcgaga73620 cgagtccacccagtaaagtgaaagcaattttattaaagaagaaacagaaaaatggctact73680 ccatagagcagcgacatgggctgcttaactgagtgttcttatgattatttcttgattcta73740 tgctaaacaaagggtggattatttgtgaggtttccaggaaaggggcagggatttcccaga73800 aCtgatggatCCCCCCa.CttttagaCCatatagagtaaCttCCtgaCgttgccatggcgt73860 ttgtaaactgtcatggccctggagggaatgtcttttagcatgttaatgtattataatgtg73920 tataatgagcagtgaggacggccagaggtcgctttcatcaccatcttggttttggtgggt73980 tttggccggcttctttatcacatcctgttttatgagcagggtctttatgacctataactt74040 ctcctgccgacctcctatctcctcctgtgactaagaatgcagcctagcaggtctcagcct74100 cattttaccatggagtcgctctgattccaatgcctctgacagcaggaatgttggaattga74160 attactatgcaagacctgagaagccattggaggacacagccttcattaggacactggcat74220 ctgtgacaggctgggtggtggtaattgtctgttggccagtgtggactgtgggagatgcta74280 ctactgtaagatatgacaaggtttctcttcaaacaggctgatccgcttcttattctctaa74340 ttCCaagtaCCaCCCCCCgCCtttCttCtCttttCCttCtttCtgattttaCtaCatgC74400 C

CCaggCatgCtaCggCCCCagCtCaCattCCtttCCttatttaaaaatggaCtggggCtg74460 ggcgcggtggctcatgcctgtaatcccagcactttgggaggccgaggcgggcggatcatg74520 aggtcaggagatcgagaccatcctggctaacacggtgaaaccccgtctctactaaaaatg74580 caaaaacattagccaggcgtggttgcaggtgcctgcagtcccagcggctcaggaggctga74640 ggcaggagaatggcgtgaacctgggaggtggaggttgcaatgagccgagattgtgccact74700 gCaCtCCagCCtgggtgaCagagcgagactccgtctcaaaaaaaaaaaaaaaaaaaaaaa74760 tagctgggcatggtggcgcgtgcctgtaataccagctactctggaggctgaggcaagaga74820 atcgcttgaacccagtaggcggaagttgcagtgagccgagatcttgacactgcactccag74880 cctggtgacagagtgagactctgtctcaaaaaaaaaaaaaagaaaaaaaaagacagaaag74940 aaagagcacagacagagtcacaggtatttgcagtaggaagctgtcaggttagagtgcacg75000 gaaatagaaagtatattttacacttacagcacatcttcgtttgattagecacatttaaaa75060 tactgaatagcaacgtgtggctatttagtattcactaaaatcttggacagtgcaagtcta75120 aagaatccttgatccgtccggcatggtggctCa.CgCCtttaatcccagcactttgggagg75180 ccaaggtggaaggatcacttaaggtcaggagttcgagaccagcctggccaacatggtgaa75240 acctcgtctctactaataatacaaaaaaaattagccgggcatggtggtgcatgcctgtaa75300 tcccaggtacttgggaggctgaggcaggagaatagcttgaatccaggaggcgctgcagtg75360 agccgagatcatgccatgccactactgcactccagcctgggcaacagagtgagactgtct75420 caaaaaaaaaaaaaaaattgttgggcgtggtggctcacgcctgtaatcccagcactttgg75480 gaggctgaggggggtggatcacctgggttctggagttcgagaccagcctggccaacatgg75540 tgaaaccccatctctactaaaaatacaaaaattagctgggcgtggtggtgggcacctgaa75600 atctcagctactcaggaggctgaggcaggagaatttcttgaacccaggaggcagaggttg75660 cagtgagccaagatcgcgcctctgcactccatcctgggtggcagagcaagactatgtctc75720 aaaaaaaaaaaaaaaaatacttgattgtctggacattctgcagaacatcatatggagaca75780 ctatgttgacgacatcatgctgattgtaagcaagaaatggcaagtgttccagaaacacag75840 tcaagacacatacatgccagaaggtgagatataaactctactaagattc-agtggcctgcc75900 acactggtgacatttttaaacctgctagatgtttgtgtagaaaaggatttaaCCttgCCC75960 aaagaggggtctggcctttgtccccagctactggacataatctctttaaactcttgaaat76020 atcattcctgatagaagtatttttgttttgactaggggccttgggccagccagatagcaa76080 caatgtgatctgggttgggggctttggatcaggtggcatcagtgtgacctcctgagtggc76140 tagagactagaatcaaccacatgggcagacaacccagcttacatgatggaattccaataa76200 agactttggacacaagggcttgggtaagctttcctggttggcaatgctctatactgggaa76260 acccattctgactccatagggagaggacaactggatattctcatttggtacctccctggg76320 ctttgccctatgCatttttCCCttgtCtgattattattattattatgagatggaatctcg76380 ctctgtcacccaggctggagtgcagtggaatgatctcaactcactgcaacctctgcctcc76440 ccggttcaagcgattttcctgtctcggcctcccgagtagctgggactacagatgcatacc76500 accacacccg gctaattttt ttgtattttt agtagagacg gggtttcacg ttagccagga 76560 tggtctcgat ctcctgacct catgttccgc ctgcctcggc ctctcaaagt gctaggaata 76620 catgtgtgag ccaccgcgcc cagccccctt ggctgattat taaagtgtat ccttgagctg 76680 tagtaaatta taaccgtgaa tataacagct tttagtgagt tttgtgagca cttctagcaa 76740 attatcaaac ctaaggatag ccttggggac ccctgaactt gcagttggtg tcagaaataa 76800 gggtgctcat gtgtgtacca tgccctctaa ttttgtagtt aattaacttt cacaacttta 76860 ttattaccgc ttacactcaa tgtttattca catttatcca cataccactt attctagtgc 76920 cttgcatcaa agactttcta tctcatgtac tttattctgc ttgaagtaaa tcctttagga 76980 tattcttttt tttttttaaa ctttgcacat acatactttt attttttatt tatttttaat 77040 tttgttattt ttgtgggtac gtagtagata tatgtattta tggagtacat gagatgtttt 77100 gatacaggca tgcaatgtga aataagcaca tcatggagaa tggggtatcc atcctctcaa 77160 gcaatttatc cttcaagtta caaacaatcc aattacactc tttaagttat tttaaaatgt 77220 acatttaatt ttgtattgac tagagtcact ctgttgtgct atcaaatata attttttttt 77280 tttttgagac agagtctcac tcagtggccc agactgaaag tgcagtggca caagctcggc 77340 tCaCttcaat CtCtgCCtCC CtggttCaag CgaatCtCCt gCCtCagCCt CCCa.CatagC 77400 tgggattaca ggcacacacc accatgccca gctaattttt atattttttt agtagagacg 77460 ggttttcgcc atgttggcca ggctggtctt gaactcctgg cctcaaatga tctgaccacc 77520 tcagcctccc aaagtgctag gattacaggc atgagccacc acacctggcc aaaatagaat 77580 attctttagt gaggtctgct ggtgacaatt tttttctttt ttttgagact gagtctcgct. 77640 gttgtcagct tgggctggag tgcaatagca cgatctcagc tcactgcaac ctccacctcc 77700 cggattccag caattctcct gcctcagcct cccaagtagc tgagagatta caggcaccca 77760 ccaccacacg cggctaattt ttgtattttt agtagaaatg ggggttcacc gtgttggcca 77820 ggctggtctc gaactcctga cctcaggtga tccacccacc ttggcctccc aaagtgctgg 77880 gattacaagc atgagccacc acgcacagcc aattttttcc gtttttgtct gaaatcttat 77940 tttgtgtcat ctttgaaata tatttttgat ggatataaaa ttgttggttg atagttatta 78000 tcattattat tattattttg agacagggtc tcactctgtt gcctatgctg gggtgtagta 78060 atgtgatCtC ggttCa.CtgC agaCttgaCC tCCtagggCt CaggtgatCt tCCCaCCtCa 78120 gcctccctag tagctgggac tacagatgca tgccaccata cccaactaat ttttctattt 78180 tttgtagaga tgaggctttg ccacatttcc caggctggtc tctaactcct gagctctagc 78240 aatCCaCCCa CCttggCCtt aCaaagtgCt gggCCatgaC tagCCagCag ttaCttttta 78300 tagcatattg aatatttaat atgaatcttc tggcatccac tgtaactgtt taaaaaatCa 78360 gctgtttact tggcactctt tttttttttt ttttttttga gacagagtct tgccctgtcg 78420 cccaggctgg agtgcagtgg cgtgatcttg gctcactgca agctctgcct cccgggttca 78480 CgCCattCtC CtgCCtCagC Ct CCggagta gctgggacta aaggcgcccg ccaccacgcc 78540 cggctgattt ttttgtattt ttcgtagagt tggggtttca ccgtgttagc caggatggtc 78600 tcgatctcct gacctcgtga tctgtccgcc tcggcctccc aaagtgctgg gattataggc 78660 gtgagccacc gcgcccagcc tctttttttt ttttttttag acggagtctt actctgtcat 78720 ctaggctggt gtacagtggc gtgatctcag ctcagtgcaa cctccacctc ctgcctcagc 78780 ctgccaaata gctgggatta caggtgcgta ccatcacgcc cggctaattt ttgtattttc 78840 agtagagatg gggtttcacc atgttagaca ggctggtctc gaactcctgg cctcaagtga 78900 tCtgCCtgCC CCagCCtCCC aaagattaCa ggCatgagCC aCCgCaCCCg gCCaagtagC 78960 actcctttga aggtaatctg CttCCCCtaC ccctagcaat ttttaacaat ttttCttCat 79020 ttttatttcc tgaagttttg ttattaataa tctgtgtgca gatttctttg tatttctttt 79080 gtttgcagtt catagtgatt cttgaattag tgtgttggtt tctgttatca ccacaggaaa 79140 attgtcagcc gttagCtttt CaaatatttC CttgCtaaat tCtCtCttCt CCCCtttCgg 79200 tacaattgat ttgattaaaa ctaaaaccag ggccgggtgc agtgactcat gcctgtaatc 79260 ccaacacttt gagaggctga ggcaggtgga tcacctaagc tcaggagttc aagaccagcc 79320 tggccaatat ggtgaaaccc cgtctctact aaaaatacaa aaattaccag gcatggtggc 79380 acacatttgt agtcaggagg ctgaggcagg agaattgctt gaatccagga ggtggaggtt 79440 gcagtgagct gagatcccac cactgcagtc tggcctgggc gacagagtga gatgagaatc 79500 tgtctcgaaa aaaaaagtta tgaatgtttg ataaactata tttgttagaa tgtttgttgt 79560 agaatactat tcattgattt ttaaacaatg ttagattaaa ccattcactg gatttgtgat 79620 aattaactta ctgattttac ctcactgatt tgttgtaatt aatacaactg gtataaaaag 79680 actgtgacga ggccgggcat ggtggctccc gcctataatc ccagcacttt gggaggctga 79740 ggcaggcgga tcacctgagg tcaggagttc aagaccagcc tgaccaacat ggtgaaaccc 79800 catctttact aaaaatacaa aattagccgg tcgtggtggt gcatgcctgt aatcccagct 79860 cttcgggagg ctgtggcagg agaatcactt gaacccggga ggtggaggtt gcagtgagcc 79920 gatatcgcgc cattgcactc cagcctgggc aacaagagcg aaactccgtc taaaaaaaaa 79980 aaagaaaaaa aacacataaa acaaaacaac actgtgacgg ttcccaaaaa ttaggagcat 80040 aattaaagga actcctgata aaaattaatt ttatcttaca tgtaaactaa aatgacttta 80100 tgaagttaat tcagaaatac aatgcagggt attagtttgc cacagctgcg tattcagcct 80160 aatgtaatat tcttgttatt tttaaattct tcttttaact ttactcatat gtggatcatc 80220 aaatttcaaa agattaaatg acaatactct tagcagcaag cttccctaag catataaaca 80280 ttttaatggg tgatgattca gaaggtaccc gaagaatatg tactgccaga tatcattcac 80340 ccccatatac ctgcccgaca gacatcccat tttgggaccc tggataaatg tgtgggtgga 80400 gagaaagataggagaaagtggtataagcaaatggctttggagtctgattgacagcgattg80460 aaatcctgtctctacctcttaacagcctcatgatcctacataagttaccccgatcctcag80520 ggccacatctgtaaattgggggttgcgatggcagccatctcacagggtctcttttcgggg80580 aagggcaggaattatggattaagtgagctagtaattgtaaagcacttaatacaaggaggg80640 cgcataataagtacttcataaataatgacggccattatcatgactgaggtgtatgcagct80700 gtcggggattacggcgacttcagaatttctggtgggcagggctcaaaggcagcaaatcac80760 actggaagtcgaggtgaggcactgcttctgcacagactgcttagctggagagaatgagga80820 aggcttagaggagatttagaggaacttagagtcctccgcctccaactctgtgggatctgc80880 tcccgtgccagagacattcaggggatttctCgCaCtCtCCCCtCCCCtaCgtccctcccg80940 ccccatccaactaaccacacaacacatacaaaatagcccctgcgaggttctgcacgctgg81000 aagggaacaggagaagggcgctgcgctttcttgctgatgccctgtacttgggcccctggt81060 agacacagccacttgtcccctcagcctgcagagaaatcccacgtagaccgcgcccgggtc81120 cttggcttcagccaatctccctttggtgggggtgggatgcacgatccaaggttttattgg81180 ctacagacagcggggtgtggtccgccaagaacacagattggctcccgagggcatctcgga81240 tccctggtggggcgccgctcagcctcccggtgcaggcccggccgaggccaggaggaagcg81300 gccagaccgcgtccattcggcgccagctcactccggacgtccggagcctctgccagcgct81360 gcttccgtccagtgcgcctggacgcgctgtccttaactggagaaaggcttcaccttgaaa81420 tccaggcttcatccctagttagcgtgtgaccttgagcagttgactttatttttcagtgcc81480 tagttttccagataccaggactgactccaaggactattactcatctggagggtttagcac81540 agtaccgtcgcatagtaaatttccatgtcagttttggttacctttcatgcacttgcaaac81600 atgccatgctctgaaacgaaataggcacatcttttttttttttttttttaaggagtcttc81660 ctctcgcccaggctggagtgcagtggcgcgatcttggctcactgcaacctccacctcccg81720 tgttcgagattctcctgcctcagcctcctgattagctgggactacaggcatgccacgacg81780 cccagttaatttttgtatttttagtagagacggggtttcgccatcttggccaggctggtc81840 taactcctgacctcaggtgatctgactgcctcagcctctcaaagtgttgggattacaggc81900 ataagccactgcatctggccagaaatgaaataagtaaatcttttaacctgctctaacaat81960 atagtgaaaagaccatattattattagagcaggttaagggatttgcctatttcgggttct82020 agttatagtcttaaacttggacattcttgtagaaagtaaaaagtttcctcttcaaagttc82080 cccttcttgttaaagaatacatcataagtgttagaagtaatagtttattttaaagactaa82140 ctttcttcaagcctccttgctttgtgctaataactctttgttaagccctatcctatgtaa82200 ctgttggacatgctcacaggcacgttccagttcacagcctatgccccttccttatttgga82260 aatgttattgcttccttaaacctttcggtaagcaacttcctctccttcttcgttcttcct82320 tgcacttacctatttagaaagttttaggctattagcaaatcggctatcagtttaagagtg82380 tgaggtcccgctccagccaatggatgcaggacatagcagtgaggacgacccaaatgcgta82440 agggataaatatgtttgcttttcctttgttcaggtgtgctCtCgaCatCgttCCatCtgC82500 gattgagCaCCCtttCtgCagaaagtaaagattgccttgctggagatcttttgtctccgt82560 gctgacttttcttcgtggcaccgattatctatttctaacaattttggtatttctaacatt82620 ctgaacaatcttgggctagttgtctcttctgggcctgtttccccatccgtcacatgataa82680 acttcattggtttaaaaaccccagcgaacatttattgagttactattaccttcctgccct82740 ccccaaccccaaccccagggagcagttacaacctcagccgctgagcgcactcgccgggtg828OO

ttaagaagcaccaaagacagggaggcttgattgattttgctttgggagtagagggtcaga82860 agattcacaggaaaatggcatttgagcaaggatgattcactggagctagcttttaaatac82920 tggCgaggCttttatgttgCagtCCCttaCaaagttgagCattCgCagggaetgcactcc82980 gaaataagCCCgCttCCCCttttCattCgCtaatgatCCagggagCtgCtggttCCgCat83040 gcggcaggttgtgccttttcctaatcagggttctgcatcgcctcgaacccgcaggccgtg83100 gcgggttctcctgaggaagcagggactggggtgcagggtgaagctgctcgtgccggccag83160 cgcctgtgagcaaaactcaaacggaggagcaggaggggtcgagctggagcgtggcagggt83220 tgaccctgccttttagaagggcacaatttgaagggtaCCCaggggCCggaagCCggggaC83280 CtaaggCCCgCCCCgttCCagCtgCtgggagggCtCCCgCCCCagggagttagttttgCa83340 gagactgggtCtgCagCgCtccaccgggggCCggCgaCagaCgCCa.CaaaaCagCtgCag83400 gaacggtggctcgctccaggcacccagggcccgggaaagaggcgcgggtagcacgcgcgg83460 gtcacgtgggcgatgcgggcgtgcgcccctgcacccgcgggagggggatggggaaaaggg83520 gcggggccggcgcttgacctcccgtgaagcctagcgcggggaaggaccggaactccgggc83580 gggcggcttgttgataatatggcggctggagctgcctgggcatcccgaggaggcggtggg83640 gcccactcccggaagaagggtcccttttcgcgctagtgcagcggcccctctggacccgga83700 agtccgggccggttgctgaatgaggggagccgggccctccccgcgccagtCCCCCCgCaC83760 cctccgtcccgacccgggccccgccatgtccttcttccggcggaaaggtagctgaggggg83820 cgccggcggggagtcaggccgggcctcaggggcggcggtggggcaggtgggcctgcgagg83880 gctttccccaaggcggcagcaaggccttcagcgagcctcgacctcggcgcagatgccccc83940 tgagtgccttgctctgctccgggactcttctgggagggagaaggtggccttcttgcgcga84000 ggtcagaggagtattgtcgcgctggttcagaagcgattgctaaagcccatagaagttcct84060 gcctgtttggttaagaacagttcttaggtgggggttagtttttttgtgtttctttgagga84120 ccgtggatcaagatcaaggaaatctctttagaaccttattatggaagtctgaagtttcca84180 aatgttgagggttttatgtctaaaagcaacacgtgaaaaaattgttttcttcacccagtg84240 ctgtcttccaatttcctctttggggggaggggtagttactgctgttactaaaataaaatt84300 _75_ acttattgctaaagttccccaacaggaagaccactacttttgatgactttggcaagtttg84360 ctaactactggaaccctaacttacaaacgaactacttacatttttgatttccagttgtat84420 tacctgcccaatgtttacgtagaaacagcttaattttgattctgggtaacgttgttgcac84480 ttcattaaaaatacatatccgaagtgagcaagtatgggtctgtggacagcagtgattttt84540 cctgtcaattcctgttgcttcagataaaatgtaccagacagaggccgggcgcggtggctc84600 acgcctgtaatcccagcactttgggaggcttggcgggtggatcacctgagatcgggagtt84660 caagaccagcctgaccaacatggagaaaccccgtgtctactaaaaatacaaaattagcca84720 gggtggtggcgcatgcctgtaatgccagctacttgggaggctgaagcaggagaatcgctt84780 gaacctgggaggcggaggttgcggtgagccgagatagcaccattgcactccagcctgggc84840 aaaaagagcgaaactccgtctcaaaaaaaaagtaccagacagaaatgggttttgttttct84900 ttttttgttttgagacggagtttcgctcttgttgcccaggctcgagtgcaatggcgcgat84960 CtCagtCtCggCtCaCtgCaaCCtCtgtCtcccaggtttaatcgattctcctgcctcagc85020 ctcccaagtagctgggattacccatgccccaccatgcccggctaatttttgtatttttag85080 tagaaacggggcttcaccatgttaggctggtcttgaacccctgacctcaagtgggcctcc85140 cacctcggcctcccaaagtgccaggattacaggcatgagccaccgcggccagccagaaat85200 gggttttggaaaaagcactaaacaaaatcgaacttggtttcatatgacagctctgctgct85260 aactgtaacaggggcagaccagttaacctacttttctgtcttctgtcagctgagaattag85320 atgattcccaaaggcccattgaactctgaatgactttaaatacttcttcttaagtgggta85380 cacggttttggtaactgatgccaggtgatgaatgcatgaaagtgcttaatgaatgaaacc85440 ggtaaaatagtaggaggaagctttattggtaaggcaggggtatacctaatagctctctaa85500 tttattggtattgaagtggttaacttttgtttttttaaggggggaaaacattctaagaat85560 aatgaggcaaactgcatattgcacaagagactgttgtctctattcaacaaataccttttg85620 agtgtccagagtctgccaggtgctgtgctaggCCCtCdCgattgagtagtgaaccagaga85680 atgtccctgcacccatggagcttattgtctactggggtagacagataataaataagcaaa85740 caaatcttctCt CttCtCCCtttcgctccatgtaagtgtgtgtgtataggtgtatactta85800 caagttgagtaaagtgttatgaaagattaagaggagaaatgcattttggttagatgttag85860 aggactcagcaggtgaccttgaaacttagagctgaaggatcagtaggaggtaactagaga85920 ggccagggaatcgcatgttcaaaggccaggaggcaagaaagagcatggtgcccttcaaga85980 gaggaaagaaggctactgtgactggagcatagatgtaggcaagtgttgggtgattgagag86040 ctctacgggccatggttaggttttattcctaatgccgagatgccaaacatggtggttcat86100 atctgtaatcccagtattttaggaggccgaggcaggaatatagcttgaacccaggagttc86160 aagaccagectgagcaacatgagacctgtacaaaacatttaaaaaattgctgggtatgat86220 ggtgcacacctgtggtcccagctactcaggaggctgaggcagaaggatcacttgagccta86280 ggaggtggaggctacaatgagccatatttgagtcactacactccagcctggatgacaaag86340 tgagaccatgtgtcaaacaaaatacagaaagaatattaatttaaaattttgaaagaggag86400 tgatctgaacttatatcttaaaaagatcattctagggcatggtggctcatgcctgtaatc86460 aagggctttgggaggctgagacaggaggatcacctgaggccagttcgagatcaacctgta86520 cagcatagagagactccatctctacaaaaagaaaaaataaatagctgggtgttgtgagtt86580 attcaggaggctgaagcagaaagatcacttgagcccaggagtttgaggctgcagtaagct86640 atgatcccaccactgcaacacagtgagatcttgtctcaaaaaaaaaaaaaaatcattcta86700 ggtgctttttggaggctggatgtggtaagagtagaagctggagatggtcctgttagggat86760 tcgattcagactttaaataccatcaatgcattgagtcccaaatttacatcactacgttgg86820 atccttgcccctgaatccagactggtatatccaactttaggttcagtttgtatctctacc86880 tgaccaatatagaggtgtccagtcttttggcttccctaggccacattggaagaagaattg86940 tcttgagccacacatagagtacactaacgctaacaatagcagatgagctaaaaaaaaatc87000 gcaaaacttataatgttttaagaaagtttacgaatttgtgttgggcacattcagagccat87060 cctgggccgcgggatggacaagcttaatccagtagataccttcaacttacaatatctaaa87120 attttatgccagatttagtcattttaaacctgctcatcagtttttctcaagaagtagtat87180 tttggctttttttcttttcttttttttgagatggagtttcgctcttatcgttcaagctgg87240 agtgcagtggCggatCttggCtCaCtgCaaCCtCCgCCCCCtgggttCaagtgattCt 87300 CC

tgcctcagcctcgcaagtagctggaattacaggcatgcgccaccatgaccagctaatttt87360 tggagacagggtttcaccatgttggtcaggctggttttgtactcctgacctcaggtgatc87420 tgcctgcctcggcctcccaaaggctgggattacaggcatgagccaccgctCCCggCtgCa87480 tttttggatttttagttgctcagcccaaaactttagtacatctttgaacctcttctttcc87540 tcctactctatatctgatccatcagcaaatctgttaggtctacctcacacatatcgaaat87600 cctaccacgtctcaccatctgtgacaattaacaccctggtctaggcagtcatctctgtta87660 agattgagtggttaaggatgtcctctaaggagatgacattcaaatcttagcttaaatgtc87720 aagagggagctggttttataaagattgaggaggcagcattattttgccataggcttccat87780 ttggtttccattccattcttgatacttatggtatatattcaaaacaaatgcacagaaaca87840 gacccaggtatattgggaatttcggatatagagttcctagttgggaaaagatagactgat87900 ctgtaaatgatgctagttatccatcatctggcaaaaaataatttcctgcctcctctcata87960 tatctcagatcaacagactttttctgttaagggccaaatcataaatattttaggctttcc88020 agaccatatggtttctgtcacactctcctttatccttgaagccatagacaatatgtaaac88080 aaatgggcatggctgtgctacgataaaactttacttacaaaaactggtagtgggccagtt88140 taggcatggccagcactttgggaggctaaggcagatggatcacttggggtcaggagtttg88200 agaccagcct ggccaacatg gtgaaaccct gtctctacta aaaatacaaa aaatagctgg 88260 gcatggtggt gggtgtctat aattccagct actctggagg ctaagacaca agaatcactt 88320 gaacccagga ggcagaggtt gcagtgagct gagatagcac cactgcactc cagccagggt 88380 gacggagtct taaagcaaaa caaaacaaaa ggtagtgggt tgtatttggc ccatgggctg 88440 tagtttgcca atccctgatg cagaaacaaa ttccaggtaa ataagagcct ggaatgttaa 88500 aaaaacaaaa cttgaagtca tgtagaagaa caggtagggg gaacaatect gatctcagga 88560 taggaaggga tattgcttaa aataagacac aggaaaatat aatccatgtt gtgtaaattt 88620 gactacgtta aaacttaaaa ctttcgccaa gcgcggtggc tcacgcctgt aataccagta 88680 ctttgggagg ccgaggtgag cagatcacca ggtcaggaga ttgagaccat cctggctaac 88740 acggtgaaac cccgtctcta ctaaaaatac aaaacattag ccgggcgtgg tggcgggcgc 88800 ctgtagtccc agctacttgg gaggctgagg caggagaatg gcctgaaccc gggaggcgaa 88860 gcttgcagtg agctgagatc gcgccactgc actccagcct gggcgacaga gtgagattcc 88920 gtctcaaaaa aacaaaacaa aacaaagcaa aaaacctaaa actttcatac aataaagtat 88980 acctaagata cttctagaag agaagattta catccaggac gtgtatggaa tttctgcaag 89040 taataagtaa aagacaaggg acatgaagag gcagttcaca aaagaggaag ccaaaatgac 89100 caataaacat gaaaggatgt ttaacctcaa aggaaacaag gaaatgaatt aaaaacatca 89160 aatgccattt caaaactagt aagttggcaa aattaaaaat accaaggatg agaatatgaa 89220 gcatggctat atgagtgcat ggaatggtac agtcactttc attaaaaatg cacataattt 89280 gttttttatt tatttttttg agacagtcta tgtcgcccag gctagaatgc agtggcatga 89340 tCtCggCtCa CCaCaatCtC tgcctcctgg gttcaagcaa ttctcctgcc tcagcctcct 89400 gagtagctgg gattacaggc acatgccaca acgcccggtt aagttttgta tttttagtag 89460 agacagggtt ttgccatgtt ggccaggctg gtctcgaact cctgacctca ggtgagctgc 89520 ttcccaaagt gctgggatta gaggcgtgag ccaatgctcc tggctgaaaa aaatgcacat 89580 aatttgttac ctagcaattc catgtctaga ggcttatcct agagaaattc ttgcttatat 89640 gcataggaag acgtgtacta gaatgttcac tagttgaatg tttaagtgaa aattaggaaa 89700 taaagtaaat gttcattaac aggaaaatga gtaaaggtat atttataaaa caattaagta 89760 gctaaaatga ataaactaga gctgcgtgaa tgaactagaa ctggttcaat agtcatgtca 89820 gattattgaa tgaatacagg tcagatatgt atagagtgtc atttgtgtaa ttaatttttt 89880 tttttttttt gagatggagt ctcactctgt tgcccaggct ggagtgcagt ggcgtgatct 89940 cagctcactg caacctcCac ctcctgggtt aaagtgattc tcctgcctca gcctcccgag 90000 tagttgggat tacaggcatg caccaccatg cccagctcat tttcCtattt ttagtggcca 90060 CagggtttCa CCatgttggC CaggCtggtC ttgaaCtCCt gaCCtCaagt gttCCaCCCa 90120 acttggcctc ccaaagtgct aggattacag gcgtgagcca ccgtgctcag ccatttgcgt 90180 gatttttaaa gatgtgcaga ataatgccat taaaaaaaat acacatacat gtatatatat 90240 acacgtttgg ctgggtgtgg tggctcacac ctgtaatccc agcactttgg gaggctgagg 90300 caggaggatc acttgagccc aggtgtacaa gactagcctg ggcgagatag caagacccca 90360 tcteaacaac agaaaggata attaggtatg gtggcatgag aggatcactt gagcceagga 90420 gttcgagtgt tatcaggcca etgcaetcta gcctggacaa caaagcaaga ccgtgtctca 90480 aaaaaataaa aataaaaagt atttgtatgt ggtcatagtc aaaaaacgta catggaagga 90540 aaatgtcttt atttatttat ttattttttt ttttttaaga cagagtcttg ctctgtcacc 90600 caggctgggg tacac~tggtg taatctcagc tcaccgcaat ctcggcctcc cgggttcaag 90660 cgattcttct gcctcagcct tctaagtagc tgggactaca g~taCCCt~CC aCCaCa.CCCt 9O72O
gctaattctt gtgttttcag tagagacagg gtttcaccat gttggcaagg ctggtctcga 90780 aCtCCtgaCC ttaagtgagC CaCCCgCCtt ggCCtCCCaa agtCCtggga ttacaggtgt 90840 gagccactgc gcttggccag gaaatatcta atttagtaag tatttatatc tgggaaagga 90900 agggtcaggt ggtgattcat aggaactcta aagtctatgt ataatactta gggggacaga 90960 aggaaataaa gcaaaatgct gatatttgat tgttgagttg tgtatatgtt agaagtataa 91020 cataggagat ctgattgata gtaggagaat gtttttaggt ggtaaaagtg gaaccgtggt 91080 ggtttgtttt ggcagtagaa tcagttggtc atagtttgta tgtggaaggt aataaacaga 91140 ccatgttaag gatgacttcc ggaattttgg tctgagtagt gggtggatga cagtgtcatt 91200 catgagggaa gatgaagact gaggtaggaa caggtttggg agaagatgac atgttccctt 91260 ttagacaagt ggaattatgg aagatggcag gtaggtggtt agctatatga atttgagata 91320 aaagatttag gatggagata taaatttagg agtaacagcg tatctatggt attgtaagcc 91380 ttaagaatgg gtaggatcag ccaggaaata cagatgtata tgcagaagag aggagtcaag 91440 gaagccaaga caagttaatg tttaaagtga gtgatgtagt ccatgggcag atgctgctga 91500 gagggctgca aacaccagtg accctacaac atttttaaat gtcgtcttec tgacagcagt 91560 gatcagtacc tgcaacgatc ttatttattt ttttcatgtt agtctccaca cacttgaatg 91620 tagacttttt gaaggcaaaa tcattgcctt ttctgagctg ggagcatgtc tggcacatac 91680 caagcactca acagttgatg tattgacttc atccagatac tctgagggcg agttatttcc 91740 tgctactagc ctttcacctt tcaatgttta agagcacaaa tacagagatg ggcacgtttt 91800 ggcatttctt attttgataa ccttttcctg gtaagatttt ttaatgttga aaaaaaaaaa 91860 caagaaaaga gggttaaaaa tagtcttatg tcagatcctg tgatagaatt cacacttggc 91920 ttaagctgct gggcaccttc ctatcttgga tgtcatatta gcttatctac agcagaattt 91980 ttactgtttt atgtagtaag gaagcaatta tatgattatt ttacagacaa attattcttt 92040 atcttttatt tttttagacg gagtctctct ttgtctccca ggctggagta cagtgtcgcg 92100 _77_ atctcggctc actgcaacct ccgcctcctg ggttcaagca attctctgcc tcagcctccc 92160 aagtagctgg gcttacaggt gtccgccacc acacccagct cattgttttg tatttttagt 92220 agagatgggg tttcaccatg ttggccaggc tggtcttgag ctactgacct caggtgatcc 92280 acccgccttg gcatcccaaa gtgctggaat tacaggcgtg agccaccgtg cctggcccag 92340 acaaattatt atactctgag tgttagaggc ttaggatgtt ttcacttgat gctatgggag 92400 gaataagtaa taagatatga tacacaacca aagacctttc ttcactatgc ttctagtagc 92460 tagtactatg gatgacacat ggtaataata ttggttagca tttgtcctca atttactgtg 92520 ctagttactc ttctaagccc cttacaggta tatatttttt ttcatcaata atcctctaag 92580 gtagttttta ttattgacct aattttataa atcaagaaaa ttaagaccca gagaagtaag 92640 taacttgtcc aagatcacat ggcttataag tggtagagcc agaatttgac cccagatgtt 92700 gtgactacat tgtctctcca taagcaggtt caactctttt gactggatgc tgttccaagg 92760 tcacttcctt agagaagcct ttgctgacaa ctaccctcct gtgccctcct ccaaggctgt 92820 ccattgttct agaactttga atactcatct tagaataaag ctggtctaat ttttacagtg 92880 ttatagaatg gatctctgac tgcaaaagtt ggtcataatt atctttttat gttctagtga 92940 aaggcaaaga acaagagaag acctcagatg tgaagtccat taaaggtaag ttctgccctt 93000 ggcagtccac tgcattaaaa agtgatgtgc tttgcatttg tgagttcttt aatcctgtta 93060 tactctctct tttggcatta atcatttctg ccttatttta taattactta tgattttgat 93120 ttatttccct ctttaacctg tataatgctt taacatctag catataataa gtaggctttt 93180 tttttttttt tttttttgga gacggagtct tgctctgtta cccaggctgg agtgcagtgg 93240 cgcgatcttg gctcactgca agctctgtct cccgggttca caccattctc ctgcctcagc 93300 ctccccagca gctgggacta caggtgcacg gcgccacgcc tggctaattt tttgtatttt 93360 ttagtagaga cagagtttca ccatgttagc cagtatggtc tcgatctcct gaccttgtga 93420 tCCgCCCgCC tCggCCtCCC aaagtgCtgg gattacaagc gtgagccacc gcacccggcc 93480 gtaagtaggc tttttttacc ttaattttat ttttttgaga tggagtcttg CtCttatCCC 93540 caggctggag tgcagtggtg ccatctcggc tcactgcagc atccacctcc cgggttcaag 93600 cgattctcct gcctcagcct cccgagtagc tgggattaca ggtggccgcc accatgccca 93660 gctaattttt gtatttttag tagagacagg gtttcaccgt gttggccagg ccagtctcaa 93720 actcctgacc tCaagtgatC Ca.CtCgCCtt ggCCtCCCaa agtCCtggga ttacaggcgt 93780 gagccaccat gcctggccat aagtaggctt ttactgagcc ttgtgtgtat tggctatcct 93840 agtgattaca gtgaaccagt gcccttctta ttaatcacac atttaattgt tccctaaaag 93900 tgattagttc actttattta tttagtaaga eaaaaaatga agaatactct taactgagca 93960 gtctgttaac tgtaggaaag cactgacact tataaggctt agttttctgt catttatcca 94020 gaagtatggt tgattacagt ttttactttt ttatttgaat gaacaacctt aatttaaaat 94080 atattttgtt tattttttgt tgggatcgat acattgtcct tgtttataga ttagagcatg 94140 ctttttaaag atgctgtatt actcactgat tttatttgtc cagtgtacag agattgaagt 94200 gggaaaatta taatggaaat tgtttccata gtCattaCat attaatttca tcaatttatt 94260 tccataaaat ctgtagattg ctacttattt agatttttcc ttcaaatgtt tttatgttgt 94320 attgcttgca ctgagtattt attctatatg ctcaatttgc tggagaagaa gactaattat 94380 aacttaggca agttgtaaaa ttagggaaaa aagtaaggta ccttacagcc tagtttactt 94440 atttcttatg taaagccagt tagattccac attagttcaa actgccttct ttgagcaaaa 94500 cttgattggc agtgataaag gcttaaagcc cttctcaagc agagacctgt aaagactaga 94560 tctgactgta gtagaaggaa ggaacttaga tgtttcaggc agtgagaaca ccagtcttcc 94620 actctaaact ttgccactaa cagtatgacc ttgggaagtt gtaactttct tcagattctt 94680 catttgttga atggggggat tggcctagct aatttctaaa tctctactgg gctaaaaaat 94740 tctgtgctta tactctgatt atgaagtaca taatctgtgc ttaacattca ctgacttatc 94800 cttaggataa tacagaagca gtacaagaaa cagcccctca agatgtttgc agtctggtta 94860 gaaagacaaa cttatacaca gaacagtagc aaatagacca aaataataat agctgccatt 94920 tatagaacac ttcttctgtt ctgggcatta gacaaaaact gactataacg gtgaacaaaa 94980 aagacttagg tcctgccctc attgaactta cagattagta ggggagagga acattaatca 95040 agtaattcca cagatggctt agcctagatt ggtagtgatg gaagtaaaga gatgtgaacg 95100 gacttgaaaa aaaattcgga ggcaaaatgg atagaagttt attattgatt aaatatgagg 95160 tgtgagagag agggatattt aagattgata cctaccttct ggcttgccta acagaaccaa 95220 aacaggaaat tatatgttca gttttgttat gttgggtggg aggtgctttt gagtcattca 95280 tttatatatg ttatatatgt tattttatat gcatagtaat tttaaggtct gagttttaaa 95340 ccaaaggtta gagagtgatt ttttagagtc tagcaaacct aagttgaaat cctgcctgtt 95400 gaaatggctg tttactagct cattaaccta gggcaaagta ttcaacttgt tttcattttt 95460 gtcttcatct ctaaaatgag gaaaatatgg tcttacaaga ttgtcctgag agatagatga 95520 aataatatcc aaaaaaaaaa aaggtacata gagaaactcg tatagtgcct ggtatatagt 95580 aggtcctcca ttggtagcta tcattatcta gttttaacat agccttcagt ttgttgaatt 95640 agtcaaactg agtgaagcac tgcaaggaat tcagaggaat ttgagatcaa caaatgattt 95700 ctgaagttta gggaagactt catggcaatg acacttacct tgtataaaag ttgaagaata 95760 agaaagattt gaatgagaga ttctttctct tctccctacc agcccagctt cttatttgag 95820 gatatattgg gcaaaggggc cttcagacaa gtagagggag atttttacag aaagattgag 95880 atgaaggtat agaaggctgt aaagaccaga aaagagaatt gagacagagg aagcaggaag 95940 ccactgtagg tttttgagca agatattgat gctgtaagta tggtgtttat gaaaggttag 96000 DEMANDE OU BREVET VOLUMINEUX
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PLUS D'UN TOME.

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Claims

1. A method for indicating increased susceptibility of a subject to a disease or disorder, comprising:
conducting an EKG examination;
determining the EKG-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present in the subject at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder.

2. The method of claim 1, wherein the disease or disorder is selected from the group consisting of cardiovascular disorders, cardiac disease, proliferative disorders, neurological disorders, neurodegenerative disorders, obesity, diabetes and peripheral retinopathies.

3. The method of claims 1 or 2, wherein the EKG-PR-interval in, the subject is compared to a predetermined age-matched standard EKG-PR-interval.

4. The method of claim 3, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control group that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2.

5. The method of claim 3, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control group that is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2.

6. The method of claim 3, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control group that is selected from either homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2; or heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ
ID N0:2.

7. The method of any of claims 3-6, wherein the predetermined standard EKG-PR-interval is obtained from a control age-matched subject without heart disease.

8. A method for indicating increased susceptibility of a subject to a disease or disorder associated with the cardiovascular system, comprising:
conducting an EKG exam;
determining the EKG-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder associated with the cardiovascular system.

9. The method of claim 8, wherein the EKG-PR-interval in the subject is compared to a predetermined age-matched standard EKG-PR-interval.

10. The method of claim 9, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ
ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2.

11. The method of claim 9, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control group that is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2.

12. The method of claim 9, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control group that is selected from either homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID N0:2; or heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ
ID N0:2.

13. The method of any of claims 9-12, wherein the predetermined standard EKG-PR-interval is obtained from a control age-matched subject without heart disease.

14. The method of claim 8, wherein the EKG-PR-interval is less than 150 for a subject 40 or more years old.

15. The method of claim 8, wherein the EKG-PR-interval is less than 155 for a subject 50 or more years old.

16. The method of claim 15, wherein the EKG-PR-interval is less than 150 for a subject 50 or more years old.

17. The method of claim 8, wherein the EKG-PR-interval is less than 160 for a subject 60 or more years old.

18. The method of claim 17, wherein the EKG-PR-interval is less than 155 for a subject 60 or more years old.

19. The method of claim 17, wherein the EKG-PR-interval is less than 150 for a subject 60 or more years old.

20. The method of any of claims 14-19, wherein the EKG-PR-interval for the subject is less than 146.

21. The method of any of claims 14-19, wherein the EKG-PR-interval for the subject is less than 140.

22. The method of any of claims 14-19, wherein the EKG-PR-interval for the subject is less than 130.

23. The method of any of claims 14-19, wherein the EKG-PR-interval for the subject is less than 120.

24. The method of any of claims 1-23, wherein the disease or disorder is selected from one or more of the group consisting of: cardiac arrhythmia, brachycardia, atrial fibrillation, sick sinus syndrome, sudden cardiac arrest, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, Wolf-Parkinson-White (WPW) Syndrome, Lown-Ganong-Levin (LGL) Syndrome, hypertension.

25. The method of any of claims 1-24, further comprising monitoring the subject for cardiovascular disease.

26. The method of any of claims 1-25, further comprising administering to the subject prophylactic steps.

27. The method of any of claims 1-13 or 24-26, wherein the subject is at least 40 years old.

28. The method of any of claims 1-13 or 24-27, wherein the subject no greater than 70 years old.

29. The method of any of claims 1-13 or 24-26, wherein the subject is in the range of 40 to 70 years old.

30. A method for determining responsiveness of a subject to one or more .beta.-blocking agents, comprising:

detecting for the subject the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has a modulated response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

31. The method of claim 30, wherein the modulated response is a decreased response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

32. The method of claim 31, wherein the decreased response is a non-response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

33. The method of claim 30, wherein the modulated response is an increased response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

34. The method of claims 30-33, wherein at least one .beta.-blocking agent is an antagonist of a .beta.-adrenergic receptor.

35. The method of claim 30-33, wherein at least one .beta.-blocking agent is an agonist of a .beta.-adrenergic receptor.

36. A method for determining responsiveness of a subject to one or more .beta.-blocking agents, comprising:
detecting the presence or absence of Val at position 646 of SEQ
ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ
ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has an increased response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

37. The method of claim 36, wherein at least one .beta.-blocking agent is an antagonist of a .beta.-adrenergic receptor.

38. The method of claim 36, wherein at least one .beta.-blocking agent is an agonist of a .beta.-adrenergic receptor.

39. A method for determining responsiveness of a subject to one or more .beta.-blocking agents, comprising:
detecting for the subject the presence or absence of Val at position 646 of SEQ ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID N0: 1, wherein the presence of a Val at position 646 of SEQ ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is non-responsive to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

40. The method of claim 39, wherein at least one .beta.-blocking agent is an antagonist of a .beta.-adrenergic receptor.

41. The method of claim 39, wherein at least one .beta.-blocking agent is an agonist of a .beta.-adrenergic receptor.

42. A method for determining responsiveness of a subject to one or more .beta.-blocking agents, comprising:
detecting the presence or absence of Val at position 646 of SEQ
ID N0:2 or a -G- nucleotide at a position corresponding to position 2073 of SEQ ID NO: 1, wherein the presence of a Val at position 646 of SEQ
ID N0:2 or a -G- at nucleotide 2073 of SEQ ID N0:1, is indicative of an increased likelihood that a subject is hyper-responsive to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

43. The method of claim 42, wherein the .beta.-blockers is an antagonist of a .beta.-adrenergic receptor.

44. The method of claim 42, wherein the .beta.-blockers is an agonist of a .beta.-adrenergic receptor.

45. A method for indicating susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a subject; comprising:
conducting an EKG exam;
determining the EKG-PR-interval in the subject, wherein if the EKG-PR-interval is decreased; then determining the amino acid at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 646 of SEQ ID NO:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID NO:1, indicates increased susceptibility to morbidity, increased or early mortality, or morbidity and increased or early mortality of a subject.

46. The method of claim 45, wherein the EKG-PR-interval in the subject is compared to a predetermined standard EKG-PR-interval.

47. The method of claim 45, wherein the predetermined standard EKG-PR-interval is obtained from a known age-matched control that is homozygous -AA- at a position corresponding to nucleotide 2073 of SEQ ID NO:1 or homozygous Ile/Ile at a position corresponding to position 646 of SEQ ID NO:2.

48. The method of any of claims 1-47, wherein the amino acid or nucleotide determining step is effected by a method selected from the group consisting of allele specific hybridization, primer specific extension, oligonucleotide ligation assay, restriction enzyme site analysis and single-stranded conformation polymorphism analysis.

49. The method of any of claims 1-48, wherein the amino acid or nucleotide determining step comprises mass spectrometry.

50. The method of any of claims 1-47, wherein the amino acid or nucleotide determining step is effected by detecting a signal moiety selected from the group consisting of radioisotopes, enzymes, antigens, antibodies, spectrophotometric reagents, chemiluminescent reagents, fluorescent reagents and other light producing reagents.

51. The method of any of claims 1-50, wherein the subject is heterozygous -GA- at a position corresponding to nucleotide 2073 of SEQ ID N0:1 or heterozygous Val/Ile at a position corresponding to position 646 of SEQ ID N0:2.

52. The method of any of claims 1-50, wherein the subject is homozygous -GG- at a position corresponding to nucleotide 2073 of SEQ
ID N0:1 or homozygous Val/Val at a position corresponding to position 545 of SEQ ID N0:2.

53. A method for indicating increased susceptibility of a subject to a disease or disorder, comprising:
in a subject determined to have a decreased EKG-PR-interval, determining the amino acid present at position 646 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 2073 of SEQ ID N0:1, wherein the presence of Val at position 645 of SEQ ID N0:2 or the presence of a -G- at nucleotide position 2073 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder.

54. A combination, comprising:
a primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 2073 of SEQ ID NO 1 or 3 of an AKAP10 allele or the complement thereof; and an electrocardiograph.

55. A kit, comprising the combination of claim 54, further containing one or more components selected from the group consisting of instructions for determining the identity of the nucleotide corresponding to position 2073 of SEQ ID NO 1 or 3, instructions for determining a decreased P-R interval, instructions for determining an elongated Q-T interval, and a table of age matched standard P-R intervals

56. A kit, comprising the combination of claim 54, further containing one or more components selected from the group consisting of a reagent for detecting a primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 2073 of SEQ ID NO 1 or 3, and a reagent for amplifying a primer specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 883 of SEQ ID NO 1 or 3.

57. A combination, comprising:
a primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 883 of SEQ ID NO 1 or 3 of an AKAP10 allele or the complement thereof; and an electrocardiograph.

58. A kit, comprising the combination of claim 57, further containing one or more components selected from the group consisting of instructions for determining the identity of the nucleotide corresponding to position 883 of SEQ ID NO 1 or 3, instructions for determining a decreased P-R interval, instructions for determining an elongated Q-T interval, and a table of age matched standard P-R intervals

59. A kit, comprising the combination of claim 57, further containing one or more components selected from the group consisting of a reagent for detecting a primer or probe that specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 883 of SEQ ID NO 1 or 3, and a reagent for amplifying a primer specifically hybridizes adjacent to or at a polymorphic region spanning a position corresponding to position 883 of SEQ ID NO 1 or 3.

60. A method for indicating increased susceptibility of a subject to a disease or disorder, comprising:
conducting an EKG examination;
determining the EKG-PR-interval in the subject, wherein, if the EKG-PR-interval is decreased, then determining the amino acid present in the subject at position 249 of AKAP10/D-AKAP2 (SEQ ID N0:2) or the nucleotide present at position corresponding to nucleotide 883 of SEQ ID N0:1, wherein the presence of His at position 249 of SEQ ID N0:2 or the presence of a -A- at nucleotide position 883 of SEQ ID N0:1, indicates increased susceptibility to a disease or disorder.

61. A method for determining responsiveness of a subject to one or more .beta.-blocking agents, comprising:
detecting for the subject the presence or absence of His at position 249 of SEQ ID N0:2 or a -A- nucleotide at a position corresponding to position 883 of SEQ ID NO: 1, wherein the presence of a His at position 249 of SEQ ID NO:2 or a -A- at nucleotide 883 of SEQ ID N0:1, is indicative of an increased likelihood that a subject has a modulated response to one or more .beta.-blocking agents compared to a subject who does not have the allelic variant.

62. The method of claim 60, wherein the disease or disorder is selected from the group consisting of cardiovascular disorders, cardiac disease, proliferative disorders, neurological disorders, neurodegenerative disorders, obesity, diabetes and peripheral retinopathies.