COMPOSITIONS AND METHODS FOR TREATING AND PREVENTING CORONARY HEART DISEASE

Abstract

The invention pertains to a method of determining a statin dosage for an individual in need of treatment with a statin, comprising determining a SLCO1B1 genotype from a nucleic acid sample of the individual, said genotype comprising the presence or absence of the SLCO1B1-056 polymorphism, and determining an ApoE genotype or phenotype identifying an ApoE polymorphism selected from the group consisting of ApoE2, ApoE3, ApoE4, and any combination thereof, wherein the combination of a SLCO1B1 genotype identifying the presence of the SLCO1B1-056 C polymorphism and the ApoE genotype or phenotype identifying one of the ApoE3/4 or ApoE4/4 genotypes indicates the statin dosage.

Description

RELATED APPLICATION

[0001] The present application is a continuation of U.S. nonprovisional patent application Ser. No. 14/265,862, filed Apr. 30, 2014, which is a continuation of U.S. nonprovisional patent application Ser. No. 13/650,948, filed Oct. 12, 2012, now issued as U.S. Pat. No. 8,765,377, which claims the benefit of and priority to U.S. provisional patent application Ser. No. 61/546,802, filed Oct. 13, 2011, the contents of each of which are incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0003] The present invention relates generally to compositions and methods for assessing the treatment of coronary heart disease (CHD) in individuals based on their individual genetic makeup. Specifically, the present invention pertains to methods for identifying genetic polymorphisms that affect uptake and metabolism of CHD specific therapeutics and assessing treatment/prophylactic protocols to maximize efficiency of CHD treatment.

BACKGROUND OF THE INVENTION

[0004] Coronary heart disease (CHD), the leading cause of morbidity and mortality worldwide, is caused by atherosclerotic plaque deposition in the coronary arteries (i.e. atherosclerosis). CHD is a multi-factorial disease, and independent risk factors include: age, gender, hypertension, smoking, diabetes, family history of premature CHD, elevated levels of low density lipoprotein cholesterol (LDL-C) (>160 mg/dl), and decreased levels of high density lipoprotein cholesterol (HDL-C) (<40 mg/dl for males and <50 mg/dl for females). However, these established CHD-risk factors account for only about half of the variability in CHD events in the U.S. population. Accumulating data indicate that emerging risk factors, including lipoprotein sub-fractions, are better markers of CHD than many of the established CHD risk factors. Additionally, other factors such as the genetic background of an individual may influence how much the major risk factors affect absolute risk.

[0005] A simple paradigm of atherosclerosis is that there is an antagonistic relationship between apolipoprotein-B (apo-B)-containing particles, such as low density lipoprotein (LDL) particles, and apoA-I-containing particles, such as high density lipoprotein (HDL) particles. For example, apo-B-containing particles promote atherosclerosis (i.e. they are atherogenic) because they are deposited on the arterial wall; however, apoA-I-containing particles counteract this effect (i.e. they are atheroprotective) because they remove excess cholesterol from the arterial wall.

[0006] The various HDL subpopulations differ in size and composition, which impart each of the varying HDL subpopulations with different functions and pathophysiological relevance. The many different functions of HDL are not distributed evenly among the various HDL subpopulations. The best illustration of this is the fact that cells have several different ways by which to remove excess cholesterol. Different HDL particles interact with the different pathways specifically depending on the cell type, the expressed receptor protein type on the surface of the cell, and the cellular cholesterol content. Moreover, the different HDL subpopulations participate differently in the anti-oxidation, anti-inflammation, and cell-signaling processes based on the particles' lipid and protein composition.

[0007] Most importantly, the HDL subpopulation profile can differentiate subjects with increased risk for CVD from subjects without such risk independently of HDL-C level. This is very important, as some subjects (or even an entire ethnic group) may have low HDL-C levels but present no history of elevated CVD risk. This is due to the fact that these subjects may have not only hyperactive HDL catabolism, but also hyperactive HDL function. However, some subjects with high HDL-C may experience a CVD event due to low HDL metabolism/catabolism or dysfunctional HDL.

[0008] Statins have emerged as an important class of therapeutic compounds for the treatment of CHD. Statins are drugs that inhibit HMG CoA reductase, the rate limiting enzyme in cholesterol biosynthesis, and thereby lower LDL cholesterol. By lowering cellular cholesterol synthesis, statins up-regulate the LDL receptor on the liver cell surface, resulting in enhanced LDL apolipoprotein B clearance. Lowering LDL cholesterol with statin therapy reduces the risk of CHD morbidity and mortality. It has been documented that the absolute reduction in statin induced LDL cholesterol lowering clearly predicts reduction in CHD events. Moreover the absolute reduction in LDL cholesterol levels is greatest in subjects with elevated LDL cholesterol levels at baseline. Additionally, lathosterol is a direct precursor of cholesterol in the bloodstream, and serves as an excellent marker of cholesterol biosynthesis. Individuals with elevated plasma lathosterol/cholesterol ratios generally have significantly greater LDL cholesterol lowering in response to statin therapy than individuals with low plasma lathosterol/cholesterol ratios.

[0009] The SLCO1B1 gene encodes a liver-specific polypeptide member of the organic anion transporter family. The SLCO1B1 transporter is primarily responsible for the ability of statins to inhibit cholesterol synthesis. About 20% of the population is heterozygous for the rs4149056 allele, while about 3% is homozygous for the rs4149056 allele. The rs4149056 allele (625T>C)) results in an amino acid substitution (V174A) in the SLCO1B1 protein that decreases the function of this transporter, thereby decreasing the efficacy of statin treatment in terms of LDL cholesterol lowering (Niemi M et al. (2006) "SLCO1B1 polymorphism and sex effect the pharmacokinetics of pravastatin but not fluvastatin." Clin Pharmacol Ther 80:356-66).

[0010] Niemi et al. (2006) reported that following a single oral dose of 40 mg of pravastatin in 32 subjects the areas under the curve of pravastatin blood levels were significantly greater for those subjects carrying the uncommon CC phenotype versus the wildtype TT SLCO1B1 genotype. In a study of 28 subjects, the SLCO1B1 haplotype significantly affected the degree of lathosterol (a marker of cholesterol synthesis) lowering induced by pravastatin (Gerloff T et al. (2006) "Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin's cholesterol lowering capabilities and basal sterol serum levels." Naunyn Smiedebergs Arch Pharmacol 373:45-50). In another study of 16 healthy volunteers, Igel and colleagues reported that SLCO1B1 haplotype was associated with a doubling of plasma pravastatin levels as compared to other haplotypes (Igel M et al. (2006) "Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin." Clin Pharmacol Ther 79:419-26). In addition, it was also found that the SLCO1B1 genotype affected pravastatin metabolism and LDL-C lowering response in 20 children with familial hypercholesterolemia and 12 cardiac transplant recipients (Hedman M et al. (2006) "Pharmacokinetics and response to pravastatin in pediatric patients with familial hypercholesterolemia and in pediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes". Br J Clin Pharmacol 61:706-15).

[0011] The Apolipoprotein E (ApoE) genotype predicts LDL cholesterol lowering response to statins, including atorvastatin and pravastatin. The ApoE gene makes a protein that becomes a lipoprotein when combined with fat. The lipoprotein ApoE is a very low-density lipoprotein, which is responsible in part for removing cholesterol from the bloodstream. Genetic variations in ApoE affect cholesterol metabolism, and may alter an individual's chances of having heart disease, and in particular a heart attack or a stroke.

[0012] There are three relatively common variants of ApoE, known as ApoE2, ApoE3, and ApoE4. About 15% of the population carry the ApoE2 allele and are more responsive to statins in terms of LDL cholesterol lowering, while about 20% of the population carry the ApoE4 allele and are less responsive in terms of statin induced LDL cholesterol lowering.

[0013] Combinatorial analysis of an individual's genotype at multiple loci and their blood chemistry profile can be used to assess treatment and/or prophylaxis of the individual with respect to coronary heart disease (CHD).

SUMMARY OF THE INVENTION

[0014] The present invention provides compositions and methods for assessing and treating coronary heart disease; and in particular for managing elevated cholesterol. According to the invention, baseline cholesterol, and especially LDL cholesterol, in combination with certain genetic factors (as provided herein) are useful in combination for determining the amount and type of cholesterol-lowering treatment for patients on an individualized basis. For example, the identification of particular genetic polymorphisms in combination with baseline cholesterol determines whether a statin is indicated and, if so, at what dose. The invention recognizes the synergistic combination of baseline cholesterol levels and genetic polymorphisms in the diagnosis and treatment of coronary heart disease on a personalized basis.

[0015] In a particular application, the SLCO1B1 locus and the apolipoprotein E (ApoE) locus are analyzed to determine which polymorphisms are present. That information is then used in combination with baseline LDL cholesterol in order to determine whether a cholesterol synthesis inhibitor (e.g., a statin) is indicated and at what dose; or whether a statin is contraindicated and, instead, a cholesterol absorption inhibitor (e.g., ezetimibe) should be prescribed. In certain embodiments, the inventive diagnostic algorithm indicates that both a statin and ezetimibe should be prescribed.

[0016] The invention is implemented in any manner consistent with the teachings herein. Provided below are algorithms to guide the analysis of the synergistic effects described herein and their relation to treatment and dosage. In a preferred embodiment, an algorithm according to the invention weights cholesterol baseline and genetic polymorphisms in order to determine treatment and/or dose. An example of weighted approach is provided below. The baseline cholesterol component of the diagnostic algorithm can be total cholesterol, LDL cholesterol, HDL cholesterol, or some combination thereof. In addition cholesterol baseline can be expressed as a balance of different types of sterols; for example a ratio of plasma lathosterol to cholesterol in umol/mmol.

[0017] The invention utilizes biomarkers that correlate with the efficacy of a cholesterol-reducing drug in view of baseline cholesterol in order to provide a proper treatment regimen and proper dose. Methods of the invention allow one to characterize the likelihood that a patient will respond to a drug treatment based on the patient's cholesterol levels and an array of polymorphisms associated with response to cholesterol-lowering drugs. The invention allows a patient to be characterized as hypo-responsive, hyper-responsive, or normally-responsive to statin treatment, which then allows proper prescribing and dosing.

[0018] In one aspect, the invention generally provides a method of determining a statin dosage for an individual in need of treatment with a statin. The method involves determining the genotype of the individual at the SLCO1B1 locus and the ApoE locus, and determining the presence or absence of the rs4149056 polymorphism at the SLCO1B1 locus, and the presence or absence of the ApoE2, ApoE3, and/or ApoE4 polymorphisms at the ApoE locus. According to the method, identifying the presence of the SLCO1B1 rs4149056 C polymorphism and the ApoE genotype or phenotype corresponding to either the ApoE3/ApoE4 or ApoE4/ApoE4 genotypes determines the statin dosage. In one embodiment, the method further involves identifying the plasma LDL cholesterol concentration (mg/dl) and/or the plasma lathosterol/cholesterol (LSC) ratio (umol/mmol) for the individual, where a LDL concentration below about 100 mg/dl and a LSC ratio less than about 70 umol/mmol in men and less than about 85 umol/mmol in women indicates that statin treatment is contraindicated, or at least will not be effective, in lowering LDL-C unless the individual has an ApoE genotype or phenotype corresponding to ApoE2/ApoE2 or ApoE2/ApoE3. Alternatively, LDL concentration below about 100 mg/dl and a LSC ratio less than about 90 irrespective of gender indicates that statin treatment will not be effective in lowering LDL-C unless the individual has an ApoE genotype or phenotype corresponding to ApoE2/ApoE2 or ApoE2/ApoE3.

[0019] In another aspect, the invention provides a method of assessing statin dosage for an individual in need of treatment with a statin, the method involves determining the genotype of the individual at the SLCO1B1 locus and the ApoE locus, and determining the presence or absence of the rs4149056 polymorphism at the SLCO1B1 locus, and the presence or absence of the ApoE3 and/or ApoE4 polymorphisms at the ApoE locus. According to the method, determining that the SLCO1B1 genotype is homozygous rs4149056 C/C polymorphism and the ApoE genotype or phenotype is ApoE3/ApoE4 or ApoE4/ApoE4, indicates that the statin dosage needs to be is in the range of about 40 mg to about 80 mg/day or the patient should receive ezetimibe therapy.

[0020] In another aspect, the invention provides a method of assessing statin dosage for an individual in need of treatment with a statin, the method involves determining the genotype of the individual at the SLCO1B1 locus and the ApoE locus, and determining the presence or absence of the rs4149056 polymorphism at the SLCO1B1 locus, and the presence or absence of the ApoE2, ApoE3, and/or ApoE4 polymorphisms at the ApoE locus. According to the method, determining that the SLCO1B1 genotype is heterozygous rs4149056 C/T or homozygous rs4149056 T/T and the ApoE genotype or phenotype is ApoE2/ApoE2, ApoE2/ApoE3, or ApoE3/ApoE3, indicates a statin dosage in the range of about t 20 mg to about 40 mg/day. In one embodiment, the method further involves identifying a plasma LDL cholesterol concentration (mg/dl) and a plasma lathosterol/cholesterol (LSC) ratio (umol/mmol) for the individual, where an LDL cholesterol concentration of about 100 mg/dL or greater and a LSC ratio about 90 umol/mmol or greater in both men and women indicates that statin treatment is indicated unless the individual has a SLCO1B1 rs4149056 genotype of C/C and an ApoE genotype or phenotype comprising ApoE4/ApoE4. When the latter variants are present the combination of low dose statin and ezetimibe should be used.

[0021] In another aspect, the invention involves a method of treating a patient to reduce serum LDL cholesterol by assessing the patient's ability to respond to statin treatment by obtaining a plasma LDL cholesterol level and a plasma lathosterol/cholesterol ratio, determining a SLCO1B1 genotype from a nucleic acid sample of the patient by identifying the presence or absence of a SLCO1B1 rs4149056 polymorphism, and determining the patient's ApoE phenotype or genotype as either ApoE3/ApoE3 or ApoE4/ApoE4, where the combined characteristics of SCLO1B1 rs4149056 T/C or C/C genotype, ApoE3/ApoE4 or ApoE4/ApoE4, a plasma LDL cholesterol concentration of about 100 mg/dl and a LSC ratio of less than about 90 umol/mmol contraindicates statin treatment in the patient; and instead indicates treating the patient with ezetimibe and/or dietary modification to reduce the patient's cholesterol. In one embodiment, the combined characteristics include a plasma LDL cholesterol below about 160 mg/dl and a LSC ratio between about 90-160 umol/mmol in irrespective of gender indicate statin treatment in the patient. In another embodiment, the ApoE3/ApoE3 or ApoE4/ApoE4 status is determined by analyzing the nucleic acid of the patient. In another embodiment, the ApoE3/ApoE3 or ApoE4/ApoE4 status is determined by analyzing the protein of the patient.

[0022] In another aspect, the invention involves a method of treating a patient to reduce serum LDL cholesterol by assessing the patient's responsiveness to statin treatment by obtaining a plasma LDL cholesterol level and a plasma lathosterol/cholesterol ratio (LCR) and assigning weighted values (A) and (B), respectively, determining the patient's ApoE phenotype or genotype as one of ApoE3/ApoE3 or ApoE4/ApoE4 and assigning weighted value (C), and determining a SLCO1B1 genotype from a nucleic acid sample of the patient by identifying the presence or absence of a SLCO1B1 rs4149056 polymorphism and assigning weighted value (D). The weighted value is assigned to the plasma LDL cholesterol level (A) as follows: an LDL cholesterol concentration greater than about 160 mg/dl is assigned a weighted value of +2, an LDL cholesterol concentration between and including about 100 to about 160 mg/dl is assigned a weighted value of +1, and an LDL cholesterol concentration less than about 100 is assigned a weighted value of 0. The weighted value is assigned to the plasma LCR ratio (B) as follows: a plasma lathosterol/cholesterol ratio greater than about 160 umol/mmol in both men and women is assigned a weighted value of +4, a plasma lathosterol/cholesterol ratio between 90-160 umol/mmol in men and women is assigned a weighted value of 0, and a plasma lathosterol/cholesterol ratio <90 umol/mmol in both men and women is assigned a weighted value of -4. The weighted value is assigned for ApoE type (C) as follows: an ApoE type of ApoE2/ApoE2 is assigned a weighted value of +2, an ApoE type of ApoE2/ApoE3 is assigned a weighted value of +1, an ApoE type of ApoE3/ApoE3 or ApoE2/ApoE4 is assigned a weighted value of 0, an ApoE type of ApoE3/ApoE4 is assigned a weighted value of -1, or an ApoE type of ApoE4/ApoE4 is assigned a weighted value of -2. The weighted value is assigned to the SLCO1B1 genotype (D) as follows: an SLCO1B1 genotype of T/T is assigned a weighted value of 0, an SLCO1B1 genotype of T/C is assigned a weighted value of -1, or an SLCO1B1 genotype of rs4149056/rs4149056 is assigned a weighted value of -2. The weighted values (A), (B), (C), (D) are combined. When the combined weighted value is in the range of +4 to +8, the patient may be characterized as hyper-responsive to statin treatment and requires a statin dosage in the range of about 10-20 mg/day. When the combined weighted value is in the range -3 to +3, the patient may be characterized as a normal responder and requires a statin dosage in the range of about 40 mg/day. When the combined weighted value is in the range -8 to -4, the patient may be characterized as hypo-responsive to statin treatment and requires treatment with maximal doses of statins at 40-80 mg/day and/or ezetimibe treatment. Once the patient is characterized as a particular type of responder, the method involves administering the required statin dosage to the patient, thereby treating the patient so as to reduce serum LDL cholesterol. In one embodiment, the hypo-responsive patient is treated with a non-statin drug. In another embodiment, the non-statin drug is ezetimibe.

[0023] In another aspect, the invention includes an in-vitro diagnostic kit for identifying an appropriate therapeutic regiment to enable an individual in need of treatment to obtain a target cholesterol level. The kit includes a first reagent for detecting the presence or absence of a polymorphism in the SLCO1B1 gene, and a second reagent for detecting ApoE3/ApoE3 or ApoE4/ApoE4 in a biological sample from the individual, where the first reagent includes an rs4149056 specific primer set, and the second reagent includes an rs7412 specific primer set and an rs429358 specific primer set, or an anti-ApoE antibody, and packaging therefore.

[0024] The present invention pertains to compositions and methods for assessing the treatment of CHD in individuals based on their genetic makeup (i.e. personal genome sequence) by identifying genetic polymorphisms at genetic loci that affect uptake and/or metabolism of CHD specific therapeutics, and assessing treatment/prophylactic protocols to maximize efficacy of CHD treatment. In a preferred embodiment, the invention provides compositions and methods for assessing the treatment of CHD in an individual based on their genotype at both the SLCO1B1 and ApoE loci.

[0025] Other and further aspects and features of the invention will be evident from the following detailed description and the accompanying drawings, which are intended to exemplify, not limit, the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 shows the wildtype ApoE nucleic acid molecule (NCBI Accession No. NM_--000041.2) (SEQ ID No. 68).

[0027] FIG. 2 shows another exemplary wildtype ApoE nucleic acid molecule (NCBI Accession No. NG_--007084.2) (SEQ ID No. 69)

[0028] FIG. 3 shows an exemplary ApoE polypeptide wildtype sequence (NCBI Accession No. NP_--000032.1) (SEQ ID No. 70).

[0029] FIG. 4 shows an exemplary SLCO1B1 nucleic acid molecule (NCBI Accession No. NM_--006446.4) (SEQ ID No. 71).

[0030] FIG. 5 shows an exemplary wildtype SLCO1B1 nucleic acid molecule (NCBI Accession No. NG_--011745.1) (SEQ ID No. 72).

[0031] FIG. 6 shows an exemplary wildtype SLCO1B1 polypeptide sequence (NCBI Accession No. NP_--006437.3) (SEQ ID No. 73).

DETAILED DESCRIPTION OF THE INVENTION

[0032] The invention features compositions and methods that are useful for assessing the treatment and/or prophylaxis of coronary heart disease (CHD) in individuals based on their individual genetic makeup.

[0033] The present invention provides methods of assessing the treatment and/or prophylaxis of coronary heart disease (CHD) by determining a subject's genotype and/or plasma LDL cholesterol level and/or plasma lathosterol/cholesterol ratio, and administering a therapeutically effective amount of a compound, such as, for example, a statin, to a subject (e.g., a mammal such as a human). The present invention is based, at least in part, on the inventors' discovery that polymorphisms within genes that encode proteins involved in the uptake and metabolism/catabolism of therapeutic agents used to treat CHD modulate the efficacy of the therapeutic agent, and that this modulation is combinatorial (i.e. polymorphisms at different loci may interact with one another in either antagonistic or synergistic ways). A polymorphism or variant is a polynucleotide or polypeptide sequence that differs from a wild-type or reference sequence by one or more nucleotides or one or more amino acids. A polymorphism may include single or multiple nucleotide insertions, deletions, and/or alterations of the genomic sequence of a specified locus.

[0034] Thus, one embodiment is a method of assessing treatment of a subject suffering from or susceptible to CHD, or a symptom thereof that is based, at least in part, on a knowledge of the combination of an individual's genotype at the solute carrier organic anion transporter family member 1B1 (SLCO1B1) locus and the apolipoprotein E (ApoE) locus. The method includes the steps of determining the subject's genotype at least at SLCO1B1 and ApoE, and administering to the subject an assessed therapeutic amount of a statin dosage, or other suitable therapeutic compounds to treat CHD, or symptoms thereof, under conditions such that the disease is treated in a manner that has been assessed for the subject's own genomic sequence at the SLCO1B1 and ApoE loci. In one embodiment, knowledge of a subject's SLCO1B1 and ApoE genotype may be combined with knowledge of the subject's plasma LDL cholesterol level and plasma lathosterol/cholesterol ratio, thereby further assessing treatment.

[0035] The therapeutic methods of the invention (which include prophylactic treatment) in general comprise administration of a therapeutically effective amount of the compounds herein, such as a statin to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human. Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for heart disease, disorder, or symptom thereof, for example, CHD. Determination of those subjects "at risk" can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, marker (as defined herein), family history, as well as other medically accepted indicators).

[0036] In one embodiment, the invention provides a method of monitoring treatment progress. The method includes the step of determining a level of diagnostic marker (marker) (e.g., any SLCO1B1 and/or ApoE polymorphism delineated herein) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with CHD, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof. The level of marker determined in the method can be compared to known levels of marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status. The controls or reference level can be established by determining the levels of markers in a subject that has not been diagnosed with a disease according to the invention, for example heart disease or CHD, and/or does not exhibit any detectable symptoms associated with this disease. In addition, controls or reference levels can be determined by levels of markers in a subject positively diagnosed with a disease according to the invention. In preferred embodiments, a second level of marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment level of marker in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of marker can then be compared to the level of marker in the subject after the treatment commences, to determine the efficacy of the treatment.

[0037] Methods of the invention are used to assess treatment of heart disease. Heart disease includes but is not limited to coronary heart disease (CHD), cardiomyopathy, cardiovascular disease (CVD), ischemic heart disease, heart failure, hypertensive heart disease, inflammatory heart disease, and valvular heart disease. Heart disease is a systemic disease that can affect the heart, brain, most major organs, and the extremities. Coronary heart disease that causes the failure of coronary circulation to supply adequate circulation to the cardiac muscles and surrounding tissues. Cardiovascular disease is meant any of a number of specific diseases that affect the heart itself and/or the blood vessel system, especially the myocardial tissue, as well as veins and arteries leading to and from the heart. For example, CVD may include, but is not limited to, acute coronary syndromes, arrhythmia, atherosclerosis, heart failure, myocardial infarction, neointimal hyperplasia, pulmonary hypertension, stroke, and/or valvular disease. CVD may be diagnosed by any of a variety of methods known in the art. For example, such methods may include assessing a subject for dyspnea, orthopnea, paroxysmal nocturnal dyspnea, claudication, angina, chest pain, which may present as any of a number of symptoms known in the art, such as exercise intolerance, edema, palpitations, faintness, loss of consciousness, and/or cough.

[0038] Atherosclerosis is a heart disease in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL). It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques within the arteries.

[0039] In certain embodiments, methods of the invention are used to determine an appropriate treatment to lower low density lipoprotein (LDL) cholesterol (LDL-C), which is associated with increased heart risk. Typically, a low HDL-C blood concentration value is below 40 mg/dl in men and is below 50 mg/dl in women. In contrast to LDL, high density lipoprotein (HDL) cholesterol (HDL-C)," is the cholesterol level of "good particles" measured in plasma, after the removal of apo-B containing lipoproteins (very low density lipoprotein cholesterol and low density lipoprotein particles). High blood concentration values of HDL-C are above 60 mg/dl and protect against heart disease. A HDL-C blood concentration value between 40 and 60 mg/dl is considered borderline.

[0040] Methods of the invention can be used to determine a patient's responsiveness to statin treatment to reduce LDL cholesterol and to determine a proper statin dosage for the patient. By Statin is class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Statins may include but are not limited to Advicor® (niacin extended-release/lovastatin), Altoprev® (lovastatin extended-release), Caduet® (amlodipine and atorvastatin), Crestor® (rosuvastatin), Lescol® (fluvastatin), Lescol XL (fluvastatin extended-release), Lipitor® (atorvastatin), Livalo® (pitavastatin), Mevacor® (lovastatin), Pravachol® (pravastatin), Simcor® (niacin extended-release/simvastatin), Vytorin® (ezetimibe/simvastatin), Zocor® (simvastatin), or generic atorvastatin, lovastatin, pravastatin, or simvastatin. In certain embodiments, the proper statin dosage is the amount of a statin required to reduce LDL-C to target levels, relative to an untreated patient. The effective amount of statin(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Additionally, statin dosage may vary depending upon which statin is being administered. For example, a typical statin dosage range for atorvastatin, pravastatin, lovastatin, and simvastatin is from about 10 mg to about 80 mg. For these three statins, a "normal" statin dosage may range from about 10 mg to about 40 mg, while a "high" statin dosage may range from about 40 mg to about 80 mg.

Diagnostic Methods

[0041] The present invention provides a number of diagnostic assays that are useful for characterizing the genotype of a subject. The present invention can be employed to genotype a gene of interest in a subject, where the gene of interest has similar or variant isoform(s). In certain embodiments, genotyping is the characterization of two alleles in one or more genes of interest. Desirably, the methods of the invention discriminate between the genotype of a gene of interest and the genotype of the similar isoform(s). Preferably, both or all alleles corresponding to a gene of interest are identified. Accordingly, the invention provides for genotyping useful in virtually any clinical setting where conventional methods of analysis are used.

[0042] The genotype of an individual may be determined as heterozygous or homozygous for one or more variant alleles of interest. Heterozygous generally means that a chromosomal locus has two different alleles. In one embodiment of the invention, heterozygous refers to a genotype in which one allele has a wild-type SLCO1B1 sequence (e.g., encoding a SLCO1B1 protein that has normal transporter activity) and the other allele has a sequence encoding a SLCO1B1 variant such as, for example, rs4149056 that does not have normal transporter activity (e.g., an alteration of Valine 174 to Alanine). Homozygous generally means a chromosomal locus has two identical alleles. In one embodiment, homozygous refers to a genotype in which both alleles have a wild-type SLCO1B1 sequence (e.g., encoding a SLCO1B1 protein that has normal transporter activity). In some embodiments, homozygous can refer to a genotype in which both alleles have a sequence encoding a SLCO1B1 variant that does not have normal transporter activity such as, for example, rs4149056 that does not have normal transporter activity (e.g., an alteration of Valine 174 to Alanine). In particular embodiments, the SLCO1B1 variant alleles with reduced or eliminated transporter activity are identical at one or more SNPs.

[0043] In various aspects, the methods of the invention determine or detect the presence of both of SLCO1B1 and APOE genetic variants, whether at the nucleic acid or protein level. The present methods provide a genetic means for the analysis of biomarkers in SLCO1B1 and APOE associated with drug metabolism, for example, statin metabolism. Results obtained from SLCO1B1 and APOE genotyping assays may be used to select an appropriate therapy for a subject, monitor drug therapy in a subject, identify a subject as responsive to drug therapy, or identify a subject as sensitive to a drug. This level of genotyping will better enable individualized pharmacogenetic-based therapy.

[0044] An apolipoprotein E (ApoE) nucleic acid molecule is a polynucleotide encoding an ApoE protein that, when combined with fat, becomes a lipoprotein. An exemplary wildtype ApoE nucleic acid molecule is provided at NCBI Accession No. NM_--000041.2 (SEQ ID. No. 68) (see FIG. 1). Another exemplary wildtype ApoE nucleic acid molecule is provided at NCBI Accession No. NG_--007084.2 (SEQ ID No. 69) (see FIG. 2). In certain embodiments, a ApoE polypeptide is a polypeptide or fragment thereof having at least about 85% amino acid identity to the exemplary wildtype sequence of NCBI Accession No. NP_--000032.1 (SEQ ID No. 70) (see FIG. 3). In certain embodiments, an ApoE2 is an ApoE allele that encodes an ApoE protein that has a cysteine residue at amino acid positions 130 and 176 (sometimes listed as amino acid positions 112 and 158 in the early ApoE literature) in the receptor-binding region of ApoE. At the genotypic level, ApoE2 is defined by two SNPs: rs429358 (position 471 of the ApoE cDNA, position 7903 of the ApoE genomic DNA, and position 17680159 of the chromosome) and rs7412 (position 609 of the ApoE cDNA, position 8041 of the ApoE genomic DNA, and position 17680297 chromosome). The ApoE2 genotype is rs429358 (T) and rs7412 (T). In certain embodiments, ApoE3 is meant an ApoE allele that encodes an ApoE protein that has a cysteine at position 130 and an arginine at position 176. At the genotypic level, ApoE3 is defined by two SNPs--rs429358 and rs7412 (see above for nucleotide positions of these two SNPs). The ApoE3 genotype is rs429358 (T) and rs7412 (C). In certain embodiments, ApoE4 is meant an ApoE allele that encodes an ApoE protein that has an arginine at both positions 130 and 176. At the genotypic level, ApoE4 is defined by two SNPs--rs429358 and rs7412 (see above for nucleotide positions of these two SNPs). The ApoE4 genotype is rs429358 (C) and rs7412 (C).

[0045] Exemplary ApoE polymorphisms include rs7412, rs429358, rs769452, rs769455, rs11542029, rs11542031, rs11542038, rs28931576, rs28931578, rs28931579, rs111833428, rs121918392, rs121918393, rs121918394, rs121918395, rs121918396, rs121918397, rs121918398, and rs121918399. The most common ApoE polymorphism are commonly referred to as ApoE2, ApoE3, and ApoE4, respectively. These polymorphic forms differ from each other only by amino acid substitutions at positions 130 and 176 of the ApoE protein. These amino acid changes are caused by SNPs at nucleotide positions 471 (rs429358) and 609 (rs7412) of the ApoE cDNA, respectively. The ApoE2 allele has a cysteine at amino acid positions 130 and 176 in the receptor-binding region of ApoE. The ApoE3 allele has a cysteine at amino acid position 130 and an arginine at amino acid position 176. The ApoE E4 allele has an arginine at both amino acid positions 130 and 130.

[0046] SLCO1B1 is the name for a solute carrier organic anion transporter family, member B1 nucleic acid molecule. In certain embodiments a SLCO1B1 is a polynucleotide encoding an SLCO1B1 polypeptide. SLCO1B1 is a gene that encodes a liver-specific member of the organic anion transporter family. The SLCO1B1 protein is a transmembrane receptor that mediates the sodium-independent uptake of numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. An exemplary SLCO1B1 nucleic acid molecule is provided at NCBI Accession No. NM_--006446.4 (SEQ ID No. 71) (FIG. 4). Another exemplary wildtype SLCO1B1 nucleic acid molecule is provided at NCBI Accession No. NG_--011745.1 (SEQ ID No. 72) (FIG. 5). In certain embodiments, a SLCO1B1 polypeptide is a polypeptide or fragment thereof having transporter activity and at least about 85% amino acid identity to the exemplary wildtype sequence of NCBI Accession No. NP_--006437.3 (SEQ ID No. 73) (FIG. 6). In certain embodiments, a SLCO1B1-056 polymorphism is the rs4149056 polymorphism, which results in a T to C nucleotide change at position 625 within the gene (sometimes referred to as position 521 in the early literature) that causes a missense mutation at position 174 in the SLCO1B1 protein from valine to alanine (V174A).

[0047] Exemplary SLCO1B1 polymorphisms include rs4149056, rs61176925, rs61760183, rs61760245, rs71581941, rs71581978, rs71581987, rs71581988, rs72559742, rs72559745, rs72559746, rs72559747, rs72559748, rs72661137, rs74064211, rs74064213, rs74700754, rs77468276, rs77871475, rs79109623, rs79135870, rs112560299, rs112909948, rs113495867, and rs113635866.

[0048] In particular embodiments, the invention provides for the detection of SLCO1B1 and APOE allelic variants and SNPs listed in Table 1 and Table 2, respectively. In preferred embodiments, the invention provides for the detection of the rs4149056 (corresponding to a T to C change at nucleotide position 625 of the SLCO1B1 cDNA, and a valine to alanine change at position 174 of the SLCO1B1 protein) polymorphism in the SLCO1B1 gene, and the rs429358 (corresponding to a T to C change at nucleotide position 471 of the ApoE cDNA, and an arginine to cysteine change at position 130 of the ApoE protein) and rs7412 (corresponding to a C to T change at position 609 of the ApoE cDNA, and an arginine to cysteine change at position 176 of the ApoE protein) polymorphisms in the ApoE gene. Advantageously, the methods of the invention distinguish between homozygous and heterozygous alleles of SLCO1B1 and/or ApoE.

TABLE-US-00001 TABLE 1 SLCO1B1 Polymorphisms That Alter Amino Acid Identity Position on SEQ Amino Polymorphism Chromosome ID Polymorphism: Acid ID 19 NO. Sequence N in Sequence Change rs2291075 21331625(+) 1 GATTTNGCTAA C/T F rs2306282 21329802(-) 2 CTCTANTGAGT T/C N/S rs2306283 21329738(-) 3 TGAATNGATAT4N C/T D rs4149056 21331549(+) 4 ATATGNGTTCA T/C V to A rs4149057 21331599(+) 5 TACCANTGGGG T/C L rs4603354 21331636(+) 6 AGAAGNACATT A/G E, G rs11045818 21329761(+) 7 ACATCNACCTT G/A S rs11045819 21329813(+) 8 CATCANCTGAG C/A T, P rs11045852 21349885(+) 9 GCACTNTCAGG A/G I, V rs11045853 21349910(+) 10 TTCTCNATGGG G/A Q, R rs11045854 21350034(+) 11 TCACTNTCTTT G/A L rs11045859 21355537(+) 12 GCTGTNATGTC G/A V rs11557087 21294536(+) 13 ATAAANCAGCA A/G T, A rs34671512 21391976(+) 14 ATATTNATTTA A/C L, F rs55737008 21392047(+) 15 GGATGNAGCAA A/G E, G rs55901008 21353529(+) 16 CTATANTGGTG C/T T, I rs56061388 21327529(+) 17 GATTGNATTTG C/T A, V rs56101265 21325716(+) 18 GAAGCNTTGAA C/T L, F rs56199088 21392011(+) 19 GAAAGNTATCA A/T D, V rs56387224 21355583(+) 20 GTGAANACAAA A/T N, Y rs57040246 21353557(+) 21 AAATANGTAGA C/T Y rs59113707 21355489(+) 22 AAATTNAAACT C/G F, L rs59502379 21358933(+) 23 AGCAGNTTGCA G/C A/G rs61176925 21355561(+) 24 CTATTNTATTT A/C L, F rs61760183 21325669(+) 25 CTGGGNTAAAT A/G Q, R rs61760245 21353483(+) 26 AGGGANGGGAA A/G I, V, Y rs71581941 21375289(+) 27 TTATANGAGCA C/T RX rs71581978 21327539(+) 28 GTGAGNTACTT C/T S rs71581987 21370128(+) 29 AATGCNCAAGA C/T P, S rs71581988 21370177(+) 30 AATACNAGTCT A/T Q, L rs72559742 21349993(+) 31 TGCCGNAAAAT -/A K, Q rs72559745 21329817(+) 32 ACCTGNGATAG A/G E, G rs72559746 21331606(+) 33 GGGGCNTTCTT G/T R, L rs72559747 21353478(+) 34 TAATCNCCTGT C/G P, R rs72559748 21358855(+) 35 CTCAGNCTGCA A/G D, G rs72661137 21370183(+) 36 AGTCTNGAATT G/T W, L rs74064211 21358922(+) 37 TCACCNTGTCT C/T P rs74064213 21358965(+) 38 AGCCTNTAGTG A/G I, V rs74700754 21375275(+) 39 TTTCCNCTCAA A/T H, L rs77468276 21355535(+) 40 CTGCTNTGATG G/C L, V rs77871475 21353471(+) 41 TCCTTNCTAAT A/T T, S rs79109623 21353505(+) 42 TTTGANGTTGT C/T T, M rs79135870 21331891(+) 43 CAATCNTTGGC A/G I, V rs112560299 21391957(+) 44 ATCACNTGTTT A/T H, L rs112909948 21370119(+) 45 ATTTGNGTGAA A/G S, G rs113495867 21353483(+) 46 CCTGTNTATGTT -/G Y, V rs113635866 21294538(+) 47 AAAACNGCAGA A/G T

TABLE-US-00002 TABLE 2 Polymorphisms That Alter Amino Acid Identity SEQ Amino CHROMOSOME ID Polymorphism: Acid SNP ID 19 POSITION NO. SEQUENCE N in Sequence Change rs7412 (E2) 45412079(+) 48 AGAAGNGCCTG C/T R to C rs429358 (E4) 45411941(+) 49 ACGTGNGCGGC T/C R to C rs769452 45411110(+) 50 GGAACNGGCAC T/C P to L rs769455 45412040(+) 51 AGCTGNGTAAG C/T R to C rs11542029 45411121(+) 52 TGGGTNGCTTT C/T R to C rs11542031 45411123(+) 53 GGTCGNTTTTG C/T R rs11542038 45411153(+) 54 CAGACNCTGTC A/G T rs28931576 45411151(+) 55 TGCAGNCACTG A/G T to A rs28931578 45412008(+) 56 GCTGCNGGTGC A/G Q to R rs28931579 45412493(+) 57 TGCCCNGCGAC A/C S to R rs111833428 45411042(+) 58 CAAGCNGTGGA A/G A rs121918392 45411034(+) 59 AGGTGNAGCAA A/G K to E rs121918393 45412013(+) 60 GGGTGNGCCTC A/C S to R rs121918394 45412043(+) 61 TGCGTNAGCGG A/C/G K to Q rs121918395 45412289(+) 62 GCGACNGCCTG C/T R to C rs121918396 45412236(+) 63 GGCCTNGGGCG A/G X to W rs121918397 45412041(+) 64 GCTGCNTAAGC A/C/G H to R rs121918398 45412428(+) 65 GCAGCNCCAGT A/G H to R rs121918399 45411100(+) 66 GCCAGNGCTGG C/T H to R rs7412 45412079(+) 67 AGAAGNGCCTG C/T R to C

Types of Biological Samples

[0049] The genotyping methods of the invention involve detecting or determining a genetic variant or biomarker of interest in a biological sample. In one embodiment, the biologic sample contains a cell having diploid DNA content. Human cells containing 46 chromosomes (e.g., human somatic cells) are diploid. In one embodiment, the biologic sample is a tissue sample that includes diploid cells of a tissue (epithelial cells) or organ (e.g., skin cells). Such tissue is obtained, for example, from a cheek swab or biopsy of a tissue or organ. In another embodiment, the biologic sample is a biologic fluid sample. Biological fluid samples containing diploid cells include saliva, blood, blood serum, plasma, urine, hair follicle, or any other biological fluid useful in the methods of the invention.

Genotyping of SLCO1B1 and APOE Polymorphisms

[0050] A SLCO1B1 and/or ApoE isoform is amplified by long range PCR to determine the genotype of the polymorphism, e.g., the rs4149056 (corresponding to a T to C change at nucleotide position 625 of the SLCO1B1 cDNA, and a valine to alanine change at position 174 of the SLCO1B1 protein) polymorphism in the SLCO1B1 gene, and the rs429358 (corresponding to a T to C change at nucleotide position 471 of the ApoE cDNA, and an arginine to cysteine change at position 130 of the ApoE protein) and rs7412 (corresponding to a C to T change at position 609 of the ApoE cDNA, and an arginine to cysteine change at position 176 of the ApoE protein) polymorphisms in the ApoE gene. The amplified nucleic acid corresponding to the SLCO1B1 and/or ApoE polymorphism may be analyzed using a variety of methods for detecting variant alleles to determine the genotype. For example, the presence or absence of one or more of the rs4149056 (corresponding to a T to C change at nucleotide position 625 of the SLCO1B1 cDNA, and a valine to alanine change at position 174 of the SLCO1B1 protein) polymorphism in the SLCO1B1 gene, and the rs429358 (corresponding to a T to C change at nucleotide position 471 of the ApoE cDNA, and an arginine to cysteine change at position 130 of the ApoE protein) and rs7412 (corresponding to a C to T change at position 609 of the ApoE cDNA, and an arginine to cysteine change at position 176 of the ApoE protein) polymorphisms in the ApoE gene may be evaluated using various techniques. For example, the SLCO1B1 gene is amplified by long range PCR and sequenced to determine the presence or absence of a single nucleotide polymorphism (SNP). In certain embodiments, real-time PCR may be used to detect a single nucleotide polymorphism of the amplified products. In other embodiments, a polymorphism in the amplified products may be detected using a technique including hybridization with a probe specific for a single nucleotide polymorphism, restriction endonuclease digestion, primer extension, microarray or gene chip analysis, mass spectrometry, or a DNAse protection assay.

Long Range Polymerase Chain Reaction (PCR)

[0051] Polymerase chain reaction (PCR) is widely known in the art. For example, U.S. Pat. Nos. 4,683,195, 4,683,202, and 4,800,159; K. Mullis, Cold Spring Harbor Symp. Quant. Biol., 51:263-273 (1986); and C. R. Newton & A. Graham, Introduction to Biotechniques: PCR, 2^nd Ed., Springer-Verlag (New York: 1997), the disclosures of which are incorporated herein by reference, describe processes to amplify a nucleic acid sample target using PCR amplification extension primers which hybridize with the sample target. As the PCR amplification primers are extended, using a DNA polymerase (preferably thermostable), more sample target is made so that more primers can be used to repeat the process, thus amplifying the sample target sequence. Typically, the reaction conditions are cycled between those conducive to hybridization and nucleic acid polymerization, and those that result in the denaturation of duplex molecules.

[0052] Exemplary methods for performing long range PCR are disclosed, for example, in U.S. Pat. No. 5,436,149; Barnes, Proc. Natl. Acad. Sci. USA 91:2216-2220 (1994); Tellier et al., Methods in Molecular Biology, Vol. 226, PCR Protocols, 2nd Edition, pp. 173-177; and, Cheng et al., Proc. Natl. Acad. Sci. 91:5695-5699 (1994); the contents of which are incorporated herein by reference. In various embodiments, long range PCR involves one DNA polymerase. In some embodiments, long range PCR may involve more than one DNA polymerase. When using a combination of polymerases in long range PCR, it is preferable to include one polymerase having 3'→5' exonuclease activity, which assures high fidelity generation of the PCR product from the DNA template. Typically, a non-proofreading polymerase, which is the main polymerase is also used in conjunction with the proofreading polymerase in long range PCR reactions. Long range PCR can also be performed using commercially available kits, such as LA PCR kit available from Takara Bio Inc. Polymerase enzymes having 3'→5' exonuclease proofreading activity are known to those in the art. Examples of suitable proofreading enzymes include TaKaRa LA Taq (Takara Shuzo Co., Ltd.) and Pfu (Stratagene), Vent, Deep Vent (New England Biolabs).

Sequencing

[0053] DNA sequencing may be used to evaluate a polymorphism of the present invention. One DNA sequencing method is the Sanger method, which is also referred to as dideoxy sequencing or chain termination. The Sanger method is based on the use of dideoxynucleotides (ddNTP's) in addition to the normal nucleotides (NTP's) found in DNA.

[0054] Pyrosequencing is another method of DNA sequencing that may be used to evaluate a polymorphism of the present invention, for example as described in U.S. Pat. Publ. No. 2006008824; herein incorporated by reference). Pyrosequencing, which is also referred to as sequencing by synthesis, involves taking a single strand of the DNA to be sequenced, synthesizing its complementary strand enzymatically one base pair at a time, and detecting by chemiluminescence the base that is added.

[0055] Pyrosequencing, optionally coupled with amplification of the nucleic acid target, can sequence large numbers of target molecules, usually employing automated sequencing apparati, including long sequences (e.g., 400 million bp/10 hr in a single run). Sequencing methods are well known to those of skill in the art.

[0056] Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e-3 and e-100 indicating a closely related sequence.

[0057] Real-Time PCR (rtPCR)

[0058] The presence or absence of polymorphisms in SLCO1B1 and/or ApoE isoforms may be detected using real-time PCR. Real-time PCR typically utilizes fluorescent probes for the selective detection of the polymorphisms. Various real-time PCR testing platforms that may be used with the present invention include: 5' nuclease (TaqMan® probes), molecular beacons, and FRET hybridization probes. These detection methods rely on the transfer of light energy between two adjacent dye molecules, a process referred to as fluorescence resonance energy transfer (see, e.g., Espy et al (2006) Clin Microbiol Rev. 2006 January; 19(1): 165-256 for a review of various rtPCR approaches that may be used with the present invention).

5' Nuclease Probes

[0059] In certain embodiments, a 5' nuclease probe may be used to detect a polymorphism of the present invention. 5' nuclease probes are often referred to by the proprietary name, TaqMan® probes. A TaqMan® probe is a short oligonucleotide (DNA) that contains a 5' fluorescent dye and 3' quenching dye. Molecular beacons and FRET hybridization probes typically involve the measurement of fluorescence during the hybridization step.

[0060] Genotyping for the 12754T>del ("Asp260fs") or Gly143Glu (428G>A, "Gly143Glu") in the carboxylesterase-1 gene may be evaluated using the following (5' endonuclease probe) real-time PCR technique. Genotyping assays can be performed in duplicate and analyzed on a Bio-Rad iCycler Iq® Multicolor Real-time detection system (Bio-Rad Laboratories, Hercules, Calif.). Real-time polymerase chain reaction (PCR) allelic discrimination assays to detect the presence or absence of specific single nucleotide polymorphisms in the SLCO1B1 and/or ApoE gene, may utilize fluorogenic TaqMan® Probes.

[0061] Real-time PCR amplifications may be carried out in a 10 μl reaction mix containing 5 ng genomic DNA, 900 Nm of each primer, 200 Nm of each probe and 5 μl of 2×TaqMan® Universal PCR Master Mix (contains PCR buffer, passive reference dye ROX, deoxynucleotides, uridine, uracil-N-glycosylase and AmpliTaq Gold DNA polymerase; Perkin-Elmer, Applied Biosystems, Foster City, Calif.). Cycle parameters may be: 95° C. for 10 min, followed by 50 cycles of 92° C. for 15 sec and 60 C° for 1 min. Real-time fluorescence detection can be performed during the 60° C. annealing/extension step of each cycle. The IQ software may be used to plot and automatically call genotypes based on a two parameter plot using fluorescence intensities of FAM and VIC at 49 cycles.

[0062] FRET Hybridization Probes

[0063] FRET hybridization probes, also referred to as LightCycler® probes, may also be used to detect a polymorphism of the present invention. FRET hybridization probe technology permits melting curve analysis of the amplification product. Like molecular beacons, FRET hybridization probes have the advantage of being recycled or conserved during PCR temperature cycling, and a fluorescent signal does not accumulate as PCR product accumulates after each PCR cycle.

[0064] Primer Extension

[0065] Primer extension is another technique which may be used according to the present invention. A primer and no more than three NTPs may be combined with a polymerase and the target sequence, which serves as a template for amplification. By using less than all four NTPs, it is possible to omit one or more of the polymorphic nucleotides needed for incorporation at the polymorphic site. It is important for the practice of the present invention that the amplification be designed such that the omitted nucleotide(s) is(are) not required between the 3' end of the primer and the target polymorphism. The primer is then extended by a nucleic acid polymerase, in a preferred embodiment by Taq polymerase. If the omitted NTP is required at the polymorphic site, the primer is extended up to the polymorphic site, at which point the polymerization ceases. However, if the omitted NTP is not required at the polymorphic site, the primer will be extended beyond the polymorphic site, creating a longer product. Detection of the extension products is based on, for example, separation by size/length which will thereby reveal which polymorphism is present. For example, U.S. Ser. No. 10/407,846, which is which is hereby incorporated by reference, describes a form of primer extension.

[0066] RFLP

[0067] Restriction Fragment Length Polymorphism (RFLP) is a technique in which different DNA sequences may be differentiated by analysis of patterns derived from cleavage of that DNA. If two sequences differ in the distance between sites of cleavage of a particular restriction endonuclease, the length of the fragments produced will differ when the DNA is digested with a restriction enzyme. The similarity of the patterns generated can be used to differentiate species (and even strains) from one another.

[0068] Restriction endonucleases in turn are the enzymes that cleave DNA molecules at specific nucleotide sequences depending on the particular enzyme used. Enzyme recognition sites are usually 4 to 6 base pairs in length. Generally, the shorter the recognition sequence, the greater the number of fragments generated. If molecules differ in nucleotide sequence, fragments of different sizes may be generated. The fragments can be separated by gel electrophoresis. Restriction enzymes are isolated from a wide variety of bacterial genera and are thought to be part of the cell's defenses against invading bacterial viruses. Use of RFLP and restriction endonucleases in SNP analysis requires that the SNP affect cleavage of at least one restriction enzyme site.

[0069] Mass Spectrometry

[0070] Mass spectrometry may also be used to detect a polymorphism of the present invention. By exploiting the intrinsic properties of mass and charge, mass spectrometry (MS) can resolved and confidently identified a wide variety of complex compounds. Traditional quantitative MS has used electrospray ionization (ESI) followed by tandem MS (MS/MS) (Chen et al., 2001; Zhong et al., 2001; Wu et al., 2000) while newer quantitative methods are being developed using matrix assisted laser desorption/ionization (MALDI) followed by time of flight (TOF) MS (Bucknall et al., 2002; Mirgorodskaya et al., 2000; Gobom et al., 2000). Methods of mass spectroscopy that may be used with the present invention include: ESI, ESI tandem mass spectroscopy (ESI/MS/MS), Secondary ion mass spectroscopy (SIMS), Laser desorption mass spectroscopy (LD-MS), Laser Desorption Laser Photoionization Mass Spectroscopy (LDLPMS), and MALDI-TOF-MS.

[0071] Hybridization

[0072] There are a variety of ways by which one can assess genetic profiles, and may of these rely on nucleic acid hybridization. Typically, a probe or primer of between 13 and 100 nucleotides, preferably between 17 and 100 nucleotides in length up to 1-2 kilobases or more in length will allow the formation of a duplex molecule that is both stable and selective. For applications requiring high selectivity, one will typically desire to employ relatively high stringency conditions to form the hybrids. For example, relatively low salt and/or high temperature conditions, such as provided by about 0.02 M to about 0.10 M NaCl at temperatures of about 50° C. to about 70° C. Such high stringency conditions tolerate little, if any, mismatch between the probe or primers and the template or target strand and would be particularly suitable for isolating specific genes or for detecting specific mRNA transcripts. Representative solid phase hybridization methods are disclosed in U.S. Pat. Nos. 5,843,663, 5,900,481 and 5,919,626. Other methods of hybridization that may be used in the practice of the present invention are disclosed in U.S. Pat. Nos. 5,849,481, 5,849,486 and 5,851,772. The relevant portions of these and other references identified in this section of the Specification are incorporated herein by reference.

Pharmacogenetics: Consequence for Drug Therapy

[0073] SLCO1B1 is important for the uptake and metabolism of many known compounds in humans and non-human animals such as, for example, bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4, statins, bromosulfophthalein and rifampin. Thus, the presence or absence of one or more polymorphisms of the present invention may be used to "individualize" or modify a therapy for a subject or patient based on the sensitivity of the subject to a therapeutic due to the presence or absence of a polymorphism of the present invention.

[0074] A number of SLCO1B1 genetic variants alter the coding sequence of the SLCO1B1 protein, including rs4149056, rs61176925, rs61760183, rs61760245, rs71581941, rs71581978, rs71581987, rs71581988, rs72559742, rs72559745, rs72559746, rs72559747, rs72559748, rs72661137, rs74064211, rs74064213, rs74700754, rs77468276, rs77871475, rs79109623, rs79135870, rs112560299, rs112909948, rs113495867, and rs113635866 (see, e.g., Table 1). The SLCO1B1 gene polymorphism rs4149056 (nt 625 T to C) results in Valine at position 174 being replace with Alanine) is termed the SLCO1B1-056 mutation. It is further contemplated within the scope of the invention that any genetic polymorphism that encodes a V174A mutation is equivalent to rs4149056. This genetic variant, especially in the homozygous state, markedly impairs the catabolism of statins, resulting in significantly higher statin blood level relative to statin blood level in an individual after administration an oral dose of statin. High statin blood levels also result in reduced efficacy in suppressing endogenous cholesterol synthesis and LDL-C lowering, and an estimated 50% chance of developing significant adverse effects especially myopathy on statin therapy in homozygotes. The 625T>C SNP due to the rs4149056 allele at SLCO1B1 resulting in the replacement of valine by alanine at residue 174 in the amino acid sequence of the SLCO1B1 protein results in significantly less Pravastatin induced LDL-C lowering in a large elderly population with either established vascular risk or at risk of vascular disease.

[0075] In certain embodiments, evaluating the presence or absence of a polymorphism of the present invention may be used to individualize a therapy and/or determine the sensitivity of a subject to a compound. The compound may be a prodrug, an illicit drug, an opioid, a dopaminergic or noradrenergic drug, an ACE Inhibitor, or an HMG-CoA reductase inhibitor or "statin".

Kits

[0076] The invention also provides kits for genotyping any one or more of a SLCO1B1 and/or ApoE polymorphism. Such kits are useful for the diagnosis of a sequence alteration in SLCO1B1 and/or ApoE relative to wild-type SLCO1B1 and/or ApoE sequences in a biological sample obtained from a subject. Alternatively, the invention provides for selecting a drug treatment regimen for CHD, or adjusting a dosage of a CHD specific therapeutic, such as, for example, a statin. In various embodiments, the kit includes at least one primer pair that identifies a SLCO1B1 polymorphism and at least one primer pair that identifies a ApoE polymorphism (e.g., the rs4149056 (nt 625 T to C; aa 174 V to A) polymorphism in the SLCO1B1 gene, and the rs429358 (nt 130 T to C; aa 130 R to C) and rs7412 (nt 176 C to T; aa 176 R to C) polymorphisms in the ApoE gene), together with instructions for using the primers to genotype in a biological sample. In additional embodiments, the kit also includes instructions for selecting an appropriate therapy for a subject, monitoring drug therapy in a subject, identifying a subject as responsive to drug therapy, or identifying a subject as sensitive to a drug. Advantageously, such testing is carried out prior to drug administration or after an adverse event associated with drug administration. Preferably, the primers are provided in combination with a thermostable DNA polymerase capable of long-range PCR amplification (e.g., a high density array). In yet another embodiment, the kit further comprises a pair of primers capable of binding to and amplifying a reference sequence. The reference sequences serves as a basis for sequence comparison. By "single nucleotide polymorphism" or "SNP" is meant a DNA sequence variation occurring when a single nucleotide in the genome differs between members of a biological species or paired chromosomes in an individual. SNPs are used as genetic markers for variant alleles.

[0077] In various other embodiments, the kit includes reagents or components for genotyping SLCO1B1 and ApoE in combination with reagents or components for the detection of a single nucleotide polymorphism (SNP) or variant of a gene encoding an additional enzyme involved in drug. The kits which contain reagents and components for determining a SLCO1B1 and/or ApoE genotype and for detecting variants in additional enzyme and/or transporters involved in drug metabolism, are useful for guiding disease specific pharmacotherapies. For example, in the treatment of CHD, one or more drugs, including Angiotensin converting enzyme (ACE) inhibitors including Capoten® (captopril), Vasotec® (enalapril), Prinivil®, Zestril® (lisinopril), Lotensin® (benazepril), Monopril® (fosinopril), Altace® (ramipril), Accupril® (quinapril), Aceon® (perindopril), Mavik® (trandolapril), and Univasc® (moexipril)); Angiotensin II receptor blockers (ARBs) including Cozaar® (losartan), Diovan® (valsartan), Avapro® (irbesartan), Atacand® (candesartan), and Micardis® (telmisartan); Antiarrhythmia drugs including Tambocor® (flecainide), Procanbid® (procainamide), Cordarone® (amiodarone), and Betapace® (sotalol); Antiplatelet drugs; Beta Blockers including Sectral® (acebutolol), Zebeta® (bisoprolol), Brevibloc® (esmolol), Inderal® (propranolol), Tenormin® (atenolol), Normodyne®, Trandate® (labetalol), Coreg® (carvedilol), Lopressor®, and Toprol-XL® (metoprolol); and Calcium Channel Blockers including Norvasc® (amlodipine), Plendil® (felodipine), Cardizem®, Cardizem CD®, Cardizem SR®, Dilacor XR®, Diltia XT®, Tiazac® (diltiazem), Calan®, Calan SR®, Covera-HS®, Isoptin®, Isoptin SR®, Verelan®, Verelan PM® (verapamil), Adalat®, Adalat CC®, Procardia®, Procardia XL® (nifedipine), Cardene®, Cardene SR® (nicardipine), Sular® (nisoldipine), Vascor® (bepridil); aspirin; digoxin; diuretic drugs; Heart Failure Drugs including Dobutrex® (dobutamine) and Primacor® (milrinone); Vasodialators such as Dilatrate-SR®, Iso-Bid®, Isonate®, Isorbid®, Isordil®, Isotrate®, Sorbitrate® (isosorbide dinitrate), IMDUR® (isorbide mononitrate), Apresoline® (hydralazine), and BiDil® (hydralazine with isosorbide dinitrate); warfarin; and surgery. In one preferred embodiment, an agent of the invention is administered in combination with a statin, such as Advicor® (niacin extended-release/lovastatin), Altoprev® (lovastatin extended-release), Caduet® (amlodipine and atorvastatin), Crestor® (rosuvastatin), Lescol® (fluvastatin), Lescol XL (fluvastatin extended-release), Lipitor® (atorvastatin), Livalo® (pitavastatin), Mevacor® (lovastatin), Pravachol® (pravastatin), Simcor® (niacin extended-release/simvastatin), Vytorin® (ezetimibe/simvastatin), and Zocor® (simvastatin) may be prescribed depending on their predicted efficacy in a patient. The patient is evaluated for SLCO1B1 and ApoE genotype and/or expression or catalytic activity to predict the responsiveness of the patient to an CHD-specific therapeutic whose metabolism is affected by SLCO1B1 and ApoE genotype. Such kits may contain one or more genomic tests of enzymes or drug transporters documented to have important SNPs. SNPs may be evaluated using a disease targeted panel of tests (e.g., a microarray). Such panels include commercially available microarrays for detecting one or more SNPs (e.g., AmpliChip® CYP450 Test; Roche). In other embodiments, the kit includes instructions for selecting one or more treatments based on the results of genotyping SLCO1B1 and ApoE and detecting one or more genetic variants in an enzyme involved in drug metabolism or drug transporter. Thus, testing performed on a patient using the kits of the invention may guide treatment selection specifically tailored to the individual.

[0078] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLES

Example 1

Determination of Sample Population Baselines for Key Risk Factors

[0079] As summarized in Table 3, the participating subjects were elderly, with a median age of 75±3 years at baseline. Mean LDL-C levels were in the moderate-risk category (130-160 mg/dl), as defined by the United States National Cholesterol Education Program (Expert Panel. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-97). Also, approximately 50% of the men and about one third of the women reported a history of all types of vascular disease. Data on ApoE phenotype distribution in this population are also shown in Table 3. Genotype frequencies for all SNPs examined conformed to Hardy-Weinberg equilibrium (p>0.05, data not shown).

TABLE-US-00003 TABLE 3 Study Subjects (n = 5,418) Study Characteristics Men Women Mean (SD)a (n = 2,621) (n = 2,797) Age (years) 74.99 (3.3) 75.64 (3.4)b BMI (kg/m2) 26.56 (3.6) 27.12 (4.7)b History diabetes mellitus, n (%) 324 (12.4) 251 (9.0)b History hypertension, n (%) 1333 (50.9) 2026 (72.5)b History vascular disease, n (%) 1371 (52.3) 1033 (37.0)b History of MI, n (%) 508 (19.4) 222 (7.9)b Current smoking, n (%) 847 (32.3) 586 (21.0)b Alcohol consumption, n(%) 1851 (70.6) 1165 (41.7)b Total cholesterol (mg/dl) 207.0 (30.7) 231.9 (34.5)b LDL-cholesterol (mg/dl) 138.5 (27.8) 154.9 (35.3)b HDL-cholesterol (mg/dl) 45.6 (12.2) 53.0 (13.4)b Triglyceride (mg/dl) 132.4 (64.3) 140.6 (59.4)b apoA-I (mg/dl) 124.4 (22.2) 139.9 (24.1)b apoB (mg/dl) 110.6 (21.3) 119.1 (22.6)b apoE 2/2 + 2/3 (%) 13.1 11.3 apoE 3/3 (%) 63.1 65.7 apoE 3/4 + 4/4 (%) 23.8 23.0 SLCO1B1_625T > C-rs4149056 MAF C: 0.16 SLCO1B1_388A > G-rs2306283 MAF G: 0.38 LXRA_-115G > A-rs12221497 MAF A: 0.14 BMI: body mass index. MAF: minor allele frequency. aMeans (S.D.) unless otherwise specified; differences between men and women were assessed using a t-test for continuous traits and χ2 test for binary traits. bp < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods section)

[0080] a) Sample Population Baseline TC or LDL-C Levels are not Genotype Dependent

[0081] Genetic analysis of the sample population revealed no association of baseline TC or LDL-C levels with any SLCO1B1 or LXRA genotype as stratified by gender (see Table 4).

TABLE-US-00004 TABLE 4 Adjusted Baseline Lipid Levels (mean ± SD, mg/dl) by Gender and Genotype n TC LDL-C Gene SNP Genotype Men Women Men Women p^a Men Women p^a SLCO1B1 625T > C TT 1871 1997 207.2 ± 30.9 232.3 ± 34.8 0.880 138.6 ± 28.0 155.2 ± 31.8 0.850 TC 674 721 207.2 ± 30.3 231.7 ± 33.4 138.8 ± 27.6 154.6 ± 30.3 CC 73 75 207.1 ± 29.1 232.1 ± 37.6 139.7 ± 26.5 153.9 ± 30.7 SLCO1B1 388A > G AA 1010 1125 208.3 ± 29.5 232.7 ± 33.9 0.161 139.3 ± 27.9 155.1 ± 31.0 0.330 AG 674 1280 206.6 ± 30.9 231.3 ± 34.8 138.2 ± 27.9 154.6 ± 31.5 GG 395 388 206.4 ± 29.9 232.5 ± 35.6 138.3 ± 27.2 155.6 ± 32.6 LXRA 115G > A GG 1924 2076 206.8 ± 30.6 232.6 ± 34.9 0.936 138.2 ± 27.9 155.3 ± 32.0 0.729 GA 647 661 208.5 ± 31.0 230.5 ± 33.8 140.1 ± 27.9 154.3 ± 30.2 AA 46 53 206.8 ± 28.3 231.6 ± 29.9 135.9 ± 24.7 155.3 ± 26.5 ^ap values using the three genotypes, men and women combined; adjusted for gender, body mass index, age, alcohol, smoking, diabetes, ApoE phenotype, and country.

[0082] b) SLCO1B1 SNP is Associated with Lowered LDL-C Response to Pravastatin

[0083] The effect of SNPs at nucleotide positions 388 (e.g. A>G) and 625 (e.g. T>C) of the SLCO1B1 gene and also at nucleotide position -115 (e.g. G>A) of the LXRA gene on responsiveness to Pravastatin in subjects of various genotypes was assessed by analyzing the correlation of different SNP genotypes with the 6 month and 12 month changes in TC and LDL-C levels in treated subjects, as shown below in Table 5. Neither the presence of the LXRA SNP at nucleotide position -115 nor the SLCO1B1 SNP at nucleotide position 388 were associated with lipid lowering. However, subjects carrying the SLCO1B1 SNP at nucleotide position 625 (e.g. T>C) had significantly less LDL-C lowering in response to Pravastatin. For example, subjects who were wildtype (T/T) for the SNP at position 625 represented about 71.5% of the sample population and displayed -37.0% LDL-C lowering, subjects who where heterozygous (T/C) for the SNP at position 625 represented about 25.8% of the sample population and showed -36.0% LDL-C lowering, and subjects who were homozygous (C/C) for the SNP at position 625 represented about 2.7% of the population and showed -31.8% LDL-C lowering (p=0.003 at 6 months, and p=0.022 at 12 months). The percentage reductions in LDL-C given are for the 6 month time point (Table 5).

TABLE-US-00005 TABLE 5 Percent LDL-C Response to Pravastatin by Genotype Adjusted mean percent LDL-cholesterol reduction^a Gene SNP n 6 months P^b n 12 months P^b SLCO1B1 625T > C TT 1345 -37.0 ± 10.8 1331 -35.9 ± 11.8 TC 509 -36.0 ± 10.4 0.003 504 -34.6 ± 12.5 0.022 CC 47 -31.8 ± 12.8 45 -31.8 ± 11.7 SLCO1B1 388A > G AA 772 -36.7 ± 10.5 758 -35.9 ± 11.2 AG 859 -36.6 ± 10.7 0.775 861 -35.3 ± 12.3 0.157 GG 269 -36.2 ± 11.6 260 -34.3 ± 12.8 LXRA 115G > A GG 1412 -36.6 ± 10.7 1403 -35.5 ± 12.1 GA 463 -36.4 ± 10.7 0.822 150 -35.1 ± 11.6 0.871 AA 27 -37.4 ± 10.9 29 -35.3 ± 11.2 ^aValues are provided as mean ± S.D, ^bp values for data combining men and women, adjusted for gender, body mass index, age, alcohol, smoking, diabetes, ApoE phenotype, and country.

[0084] c) SLCO1B1/LXRA SNPs are not Associated with History and Incidence of CVD

[0085] Genetic analysis of the sample population revealed no association of any of the SLCO1B1 or LXRA SNPs with either vascular disease at baseline or fatal or non-fatal CHD events on trial in either the placebo or statin groups (see, e.g., Table 6).

TABLE-US-00006 TABLE 6 Analysis of Incidence of Coronary Heart Disease (CHD) Death or Nonfatal Myocardial Infarction (MI) on Trial by SNP Carrier Status Number of Number of Number of new new case/ new case/ case/ Adjusted^a Total subjects Placebo^b Total subjects Pravastatin^b SNP Genotype Total subjects (%) HR^c p (%) HR^c p (%) HR^c p 625T > C TT 427/3868 1 232/1956 1 195/1912 1 (11.0) (11.9) (10.2) TC 155/1395 1.01 0.996 83/693 1.03 0.738 72/702 0.99 0.659 (11.1) (0.84-1.21) (12.0) (0.80-1.33) (10.3) (0.76-1.30) CC 16/148 0.99 12/81 1.24 4/67 0.64 (10.6) (0.60-1.64) (14.8) (0.69-2.22) (6.0) (0.24-1.73) 388A > G AA 224/2135 1 122/1051 1 102/1084 1 (10.5) (11.6) (9.4) AG 279/2489 1.08 0.426 150/1275 1.04 0.577 129/1214 1.13 0.629 (11.2) (0.90-1.29) (11.8) (0.82-1.32) (10.6) (0.87-1.47) GG 94/783 1.17 54/404 1.17 40/379 1.12 (12.0) (0.92-1.49) (11.4) (0.85-1.61) (10.6) (0.78-1.62) ^ap values for men and women combined; adjusted for gender, body mass index, age, alcohol, smoking, diabetes, hypertension, ApoE phenotype, randomized treatment, and country. No significant differences were noted when men and women were separated. ^bp values for men and women combined; adjusted for gender, body mass index, age, alcohol, smoking, diabetes, hypertension, ApoE phenotype, and country. No significant differences were noted when men and women were separated. ^cHazards ratio (95% confidence intervals). The SNPs 625T > C and 388A > G are within SLCO1B1

[0086] d) SLCO1B1 SNP is not Associated with Myositis and/or Myalgia

[0087] In this randomized study with 5,804 subjects, 2,913 subjects received placebo and 2,891 received Pravastatin (three of whom refused medication). Of the 2,888 subjects started on Pravastatin, 724 discontinued their medication (5 withdrew consent, 219 died, 346 refused to participate or did not attend follow up examinations, and 107 had non-fatal adverse events). This adverse event rate was very similar to the placebo group where 116 subjects discontinued medication because of non-fatal adverse events. There were no reported cases of rhabdomyolysis in PROSPER, and there were 36 reported cases of myalgia in the Pravastatin group versus 32 cases of myalgia in the placebo group. At the 3 month visit there no subjects that had creatine kinase levels >10 the upper limits of normal. There was no association of the SLCO1B1 rs4149056 SNP with myalgia in the Pravastatin group.

Example 2

Assessing Statin Dosage Using Combined SLCO1B1 and ApoE Genotyping

[0088] Elevated levels of plasma or serum low density lipoprotein (LDL) cholesterol are a major risk factor for coronary heart heard disease, a leading cause of death and disability in our society (1,2). Lowering LDL cholesterol with statin drugs has clearly been shown to inhibit cholesterol biosynthesis, and decrease the risk of CHD. Moreover the degree of risk reduction is dependent on the amount of LDL cholesterol lowering. Four factors that are clearly and significantly related to LDL cholesterol lowering response to statins were identified:

[0089] 1) the plasma level of LDL cholesterol,

[0090] 2) the ratio of lathosterol/cholesterol in plasma,

[0091] 3) apolipoprotein (apo) E genotype, and

[0092] 4) solute carrier organic anion transporter (SLCO1B1 rs4149056) genotype.

According to the invention, a novel point system was developed to predict statin induced LDL cholesterol lowering response, as shown below. This model provides an excellent fit (p<0.0001) to actual data with regard to LDL cholesterol lowering generated on over 3,000 subjects studied at baseline and then placed on pravastatin 40 mg/day for 6 months. Moreover this model predicts more than 75% of the marked variability in statin response that is observed. Those with +4 to +8 points are hyper-responders to statins, and are ideal candidate for statin treatment. Those with -4 to +4 points are normal responders and are candidates for statin therapy. Those with -8 to -4 points are hypo-responder to statins (emphasize dietary modification and consider use of ezetimibe and/or anion exchange resins).

TABLE-US-00007 Prediction of LDL Cholesterol Lowering Point System 1. Plasma LDL Cholesterol (mg/dl): >160: +2 100-160: +1 <100: 0 LDL Cholesterol Points = _ 2. Plasma Lathosterol/Cholesterol Ratio umol/mmol cholesterol: >160: +4 90-160: 0 <90: -4 Lathosterol Points: _ 3. ApoE Genotype: ApoE2/2: +2 ApoE2/3: +1 ApoE3/3: 0 ApoE3/4: -1 ApoE4/4: -2 ApoE Genotype Points: _ 4. Statin Uptake Transporter (SLCO1B1) Genotype: T/T: 0 T/C: -1 C/C: -2 Statin Uptake Genotype Points: _ 5. Total Points: +4 to +8 Points = Hyper-responder (ideal candidate for statins) -3 to +3 Points = Normal Responder (candidate for statin) -8 to -4 Points = Hypo-responder to statins (emphasize dietary modification and consider use of ezetimibe and/or anion exchange resins)

[0093] According to one embodiment, the determination of whether an individual having high LDL cholesterol and in need of statin treatment to reduce the level of LDL cholesterol is a hyper-responder, a normal-responder, or a hypo-responder with respect to the ability of the individual to metabolize a statin can be made by solving the equation X=A+B+C+D, where A is the number of points associated with the individual's plasma LDL cholesterol level, B is the number of points associated with the individual's plasma lathosterol/cholesterol ratio, C is the number of points associated with the individual's ApoE genotype, and C is the number of points associated with the individual's SLCO1B1 genotype. The resulting value of X is then used to determine the class of responder to which the individual belongs.

Methods and Materials

[0094] Study Subjects:

[0095] The results and the methodology used in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study have been previously described (see e.g., Shepherd J et al. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet (2002) 360:1623-30 and Shepherd J et al. The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk. Am J Cardiol (1999) 84:1192-97).

[0096] In the present study 2,804 men and 3,000 women between the ages of 70 and 82 with pre-existing vascular disease (n=2,404) or at least one of three major vascular risk factors (diabetes n=575, smoking n=1,433, or hypertension n=3,360) were randomized to Pravastatin 40 mg/day (n=2,891) or placebo (n=2,913) and followed up on for 3.2 years, on average. Over this 3.2 year period of time, the mean LDL-C reduction in the active treatment group was 32%, and the risk of developing CHD was decreased by 19%, which was statistically significant (Shepherd J et al. (2002) Lancet 360:1623-30). This effect translates into an estimated 30% risk reduction in CHD events over 5 years, which is consistent with other statin trials. Additionally, analysis of the treatment group found that HDL-C was increased by 5% and triglycerides were decreased by 12% versus baseline in those subjects placed on Pravastatin. For subjects that were judged to have good compliance (i.e. taking medication more than 75% of the time), these alterations on the lipid levels were even greater: -34% (risk reduction for CHD), +5% (increased HDL-C), and -13% (decreased triglycerides), respectively. No significant lipid changes were noted in the placebo group. Lipid levels were similar at onset of the study in subjects randomized to Pravastatin or placebo.

[0097] Biochemical and DNA Analysis:

[0098] Total cholesterol (TC), HDL-C, and triglycerides were assessed in subjects after an overnight fast at 6 months, and at 12 months, and LDL-C was calculated by the Friedewald formula, as previously described (Shepherd J et al. (2002) Lancet 360:1623-30). Apolipoprotein B (apoB) was measured only at baseline as described. DNA was isolated from cells from this cohort, and DNA from 5,783 subjects participating in this study was also available. ApoE phenotype was determined on plasma samples by Western blotting, using the method of Havekes et al. in the central laboratory of the Royal Infirmary in Glasgow, Scotland (Havekes L M et al. A rapid micro method for apolipoprotein E phenotyping directly in serum. J Lipid Res (1987) 28:455-63). Subjects were classified according to the presence of apoE2, apoE3, or apoE4 bands on gel blotting (Havekes L M et al. (1987) J Lipid Res 28:455-63). This gel phenotyping method has been shown to have 99% concordance with genotyping (Lahoz C et al. Frequency of phenotype-genotype discrepancies at the apolipoprotein E locus in a large population study. Clin Chem (1996) 42:1817-23).

[0099] DNA analysis was conducted by genotyping two single nucleotide polymorphisms (SNPs) of the SLCO1B1 gene--388A>G (rs2306283) and 511T>C (rs4149056)--using standard methods (e.g. Taq Man® SNPs genotyping assays by Applied Biosystems, Foster City, Calif.). The custom assay identification numbers for these analyses were C_--1901697_--20 and C_--30633906_--10, respectively. Additionally, DNA analysis was also conducted by genotyping one SNP of the LXRA gene, rs12221497, and the custom assay identification number for this analysis was C_--30887860_--10. The end points were ascertained after PCR amplification was performed using standard methods (e.g. an Applied Biosystems 7900 HT Sequence Detection System). Genotypes with quality scores below the 95% threshold were repeated and 5% blinded replicates for genotype determinations were performed. In addition, a total of 119 subjects (˜2.2% of the sample size) who had the apoE4/2 phenotype were excluded from these analyses, as well as 246 subjects who had missing apoE phenotype. These subjects were excluded because apoE phenotype or genotype can affect statin-induced LDL-C lowering response, as well as CHD risk, in an allele dependent manner. For example, subjects carrying the apoE4 allele having the greatest response in terms of LDL-C lowering and the highest CHD risk, however, apoE2 and apoE4 phenotype have opposite effects in this regard. The subject characteristics for these individuals representing the 5,418 subjects are shown in Table 3.

Statistical Analysis:

[0100] Observed genotype frequencies were compared with those expected under Hardy-Weinberg equilibrium using a χ2 test. For data analysis, multivariable analysis of covariance (ANCOVA) was performed to detect associations between the lipoprotein levels at baseline as well as changes in response to the treatment with Pravastatin at 6 months and with SLCO1B1 genotypes adjusted for gender, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country of origin, since subjects participating in PROSPER were either from Scotland, Ireland, or the Netherlands. Prevalence at baseline of myocardial infarction (MI) and all types of vascular disease (history of angina, claudication, MI, stroke, transient ischemic attack, peripheral arterial disease surgery, or amputation for vascular disease more than 6 months before study entry) at baseline, as well as incidence of primary endpoints (CHD death or nonfatal MI or fatal non-fatal stroke), and all cardiovascular events (primary endpoints and coronary artery bypass grafting, coronary angioplasty, and peripheral artery surgery or angioplasty), were compared between carriers of different SLCO1B1 SNP genotypes using multivariable logistic regression analysis in all subjects and stratified by gender and treatment. All analyses were fully adjusted for age, gender, country, history of vascular disease, body mass index, history of diabetes, as well as history of hypertension, alcohol use, current smoking, and apoE phenotype. To evaluate the modifying effects of genotypes and gender on the response to treatment, gene-treatment and gene-gender interaction terms were added to the regression models. Lewontin's D value was calculated to assess the linkage disequilibrium (LD) between the two SNPs of interest (Lewontin RC. The interaction of selection and linkage. II. Optimum models. Genetics 1964; 50:757-82). There was no interaction between these SNPs and also no interaction between these SNPs and apoE genotype. All analyses were performed using SAS/STAT and SAS/Genetics [including proc haplotype procedure] (SAS Version 9.1, SAS Institute Inc., Cary, N.C.). A two-sided p<0.05 was considered statistically significant.

OTHER EMBODIMENTS

[0101] From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims.

INCORPORATION BY REFERENCE

[0102] All citations to sequences, patents and publications in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Sequence CWU 1

1

73111DNAHomo sapiensmisc_feature(6)..(6)n is c or t 1gatttngcta a 11211DNAHomo sapiensmisc_feature(6)..(6)n is t or c 2ctctantgag t 11312DNAHomo sapiensmisc_feature(6)..(6)n is c or t 3tgaatngata tn 12411DNAHomo sapiensmisc_feature(6)..(6)n is t or c 4atatgngttc a 11511DNAHomo sapiensmisc_feature(6)..(6)n is t or c 5taccantggg g 11611DNAHomo sapiensmisc_feature(6)..(6)n is a or g 6agaagnacat t 11711DNAHomo sapiensmisc_feature(6)..(6)n is g or a 7acatcnacct t 11811DNAHomo sapiensmisc_feature(6)..(6)n is c or a 8catcanctga g 11911DNAHomo sapiensmisc_feature(6)..(6)n is a or g 9gcactntcag g 111011DNAHomo sapiensmisc_feature(6)..(6)n is g or a 10ttctcnatgg g 111111DNAHomo sapiensmisc_feature(6)..(6)n is g or a 11tcactntctt t 111211DNAHomo sapiensmisc_feature(6)..(6)n is g or a 12gctgtnatgt c 111311DNAHomo sapiensmisc_feature(6)..(6)n is a or g 13ataaancagc a 111411DNAHomo sapiensmisc_feature(6)..(6)n is a or c 14atattnattt a 111511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 15ggatgnagca a 111611DNAHomo sapiensmisc_feature(6)..(6)n is c or t 16ctatantggt g 111711DNAHomo sapiensmisc_feature(6)..(6)n is c or t 17gattgnattt g 111811DNAHomo sapiensmisc_feature(6)..(6)n is c or t 18gaagcnttga a 111911DNAHomo sapiensmisc_feature(6)..(6)n is a or t 19gaaagntatc a 112011DNAHomo sapiensmisc_feature(6)..(6)n is a or t 20gtgaanacaa a 112111DNAHomo sapiensmisc_feature(6)..(6)n is c or t 21aaatangtag a 112211DNAHomo sapiensmisc_feature(6)..(6)n is c or g 22aaattnaaac t 112311DNAHomo sapiensmisc_feature(6)..(6)n is g or c 23agcagnttgc a 112411DNAHomo sapiensmisc_feature(6)..(6)n is a or c 24ctattntatt t 112511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 25ctgggntaaa t 112611DNAHomo sapiensmisc_feature(6)..(6)n is a or g 26aggganggga a 112711DNAHomo sapiensmisc_feature(6)..(6)n is c or t 27ttatangagc a 112811DNAHomo sapiensmisc_feature(6)..(6)n is c or t 28gtgagntact t 112911DNAHomo sapiensmisc_feature(6)..(6)n is c or t 29aatgcncaag a 113011DNAHomo sapiensmisc_feature(6)..(6)n is a or t 30aatacnagtc t 113111DNAHomo sapiensmisc_feature(6)..(6)n is - or a 31tgccgnaaaa t 113211DNAHomo sapiensmisc_feature(6)..(6)n is a or g 32acctgngata g 113311DNAHomo sapiensmisc_feature(6)..(6)n is g or t 33ggggcnttct t 113411DNAHomo sapiensmisc_feature(6)..(6)n is c or g 34taatcncctg t 113511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 35ctcagnctgc a 113611DNAHomo sapiensmisc_feature(6)..(6)n is g or t 36agtctngaat t 113711DNAHomo sapiensmisc_feature(6)..(6)n is c or t 37tcaccntgtc t 113811DNAHomo sapiensmisc_feature(6)..(6)n is a or g 38agcctntagt g 113911DNAHomo sapiensmisc_feature(6)..(6)n is a or t 39tttccnctca a 114011DNAHomo sapiensmisc_feature(6)..(6)n is g or c 40ctgctntgat g 114111DNAHomo sapiensmisc_feature(6)..(6)n is a or t 41tccttnctaa t 114211DNAHomo sapiensmisc_feature(6)..(6)n is c or t 42tttgangttg t 114311DNAHomo sapiensmisc_feature(6)..(6)n is a or g 43caatcnttgg c 114411DNAHomo sapiensmisc_feature(6)..(6)n is a or t 44atcacntgtt t 114511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 45atttgngtga a 114612DNAHomo sapiensmisc_feature(6)..(6)n is - or G 46cctgtntatg tt 124711DNAHomo sapiensmisc_feature(6)..(6)n is a or g 47aaaacngcag a 114811DNAHomo sapiensmisc_feature(6)..(6)n is c or t 48agaagngcct g 114911DNAHomo sapiensmisc_feature(6)..(6)n is t or c 49acgtgngcgg c 115011DNAHomo sapiensmisc_feature(6)..(6)n is t or c 50ggaacnggca c 115111DNAHomo sapiensmisc_feature(6)..(6)n is c or t 51agctgngtaa g 115211DNAHomo sapiensmisc_feature(6)..(6)n is c or t 52tgggtngctt t 115311DNAHomo sapiensmisc_feature(6)..(6)n is c or t 53ggtcgntttt g 115411DNAHomo sapiensmisc_feature(6)..(6)n is a or g 54cagacnctgt c 115511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 55tgcagncact g 115611DNAHomo sapiensmisc_feature(6)..(6)n is a or g 56gctgcnggtg c 115711DNAHomo sapiensmisc_feature(6)..(6)n is a or c 57tgcccngcga c 115811DNAHomo sapiensmisc_feature(6)..(6)n is a or g 58caagcngtgg a 115911DNAHomo sapiensmisc_feature(6)..(6)n is a or g 59aggtgnagca a 116011DNAHomo sapiensmisc_feature(6)..(6)n is a or c 60gggtgngcct c 116111DNAHomo sapiensmisc_feature(6)..(6)n is a, c, or g 61tgcgtnagcg g 116211DNAHomo sapiensmisc_feature(6)..(6)n is c or t 62gcgacngcct c 116311DNAHomo sapiensmisc_feature(6)..(6)n is a or g 63ggcctngggc g 116411DNAHomo sapiensmisc_feature(6)..(6)n is a, c, or g 64gctgcntaag c 116511DNAHomo sapiensmisc_feature(6)..(6)n is a or g 65gcagcnccag t 116611DNAHomo sapiensmisc_feature(6)..(6)n is c or t 66gccagngctg g 116711DNAHomo sapiensmisc_feature(6)..(6)n is c or t 67agaagngcct g 11681223DNAHomo sapiens 68gggatccttg agtcctactc agccccagcg gaggtgaagg acgtccttcc ccaggagccg 60actggccaat cacaggcagg aagatgaagg ttctgtgggc tgcgttgctg gtcacattcc 120tggcaggatg ccaggccaag gtggagcaag cggtggagac agagccggag cccgagctgc 180gccagcagac cgagtggcag agcggccagc gctgggaact ggcactgggt cgcttttggg 240attacctgcg ctgggtgcag acactgtctg agcaggtgca ggaggagctg ctcagctccc 300aggtcaccca ggaactgagg gcgctgatgg acgagaccat gaaggagttg aaggcctaca 360aatcggaact ggaggaacaa ctgaccccgg tggcggagga gacgcgggca cggctgtcca 420aggagctgca ggcggcgcag gcccggctgg gcgcggacat ggaggacgtg tgcggccgcc 480tggtgcagta ccgcggcgag gtgcaggcca tgctcggcca gagcaccgag gagctgcggg 540tgcgcctcgc ctcccacctg cgcaagctgc gtaagcggct cctccgcgat gccgatgacc 600tgcagaagcg cctggcagtg taccaggccg gggcccgcga gggcgccgag cgcggcctca 660gcgccatccg cgagcgcctg gggcccctgg tggaacaggg ccgcgtgcgg gccgccactg 720tgggctccct ggccggccag ccgctacagg agcgggccca ggcctggggc gagcggctgc 780gcgcgcggat ggaggagatg ggcagccgga cccgcgaccg cctggacgag gtgaaggagc 840aggtggcgga ggtgcgcgcc aagctggagg agcaggccca gcagatacgc ctgcaggccg 900aggccttcca ggcccgcctc aagagctggt tcgagcccct ggtggaagac atgcagcgcc 960agtgggccgg gctggtggag aaggtgcagg ctgccgtggg caccagcgcc gcccctgtgc 1020ccagcgacaa tcactgaacg ccgaagcctg cagccatgcg accccacgcc accccgtgcc 1080tcctgcctcc gcgcagcctg cagcgggaga ccctgtcccc gccccagccg tcctcctggg 1140gtggacccta gtttaataaa gattcaccaa gtttcacgca aaaaaaaaaa aaaaaaaaaa 1200aaaaaaaaaa aaaaaaaaaa aaa 12236910612DNAHomo sapiens 69tggagagctg gtctaccacc ggcggcctgg agaggagggc actgtcatgt ctctagctgg 60gaaatacaca tgtgagcctg gcgcctgggt ccgagggtgg aggggctggg cccctggact 120cctcctgggt ctgagggagg acgggctagg gccctggaca ctcaggtctg agggaggagg 180cctgggttcc cagatgccca aatccccttg gtaatgagac cccgcctcca ccccactctc 240tgacagtgaa caactggttg gcaacggtaa cgttgggcca ggcgggcatg cacgcaacat 300actaccacaa agccagtgac caggtgagtg ggtgcaggga ctagctggtg ctgccagggg 360ctgctgggcc tggaagtcca ggtggggcca cttgctaatt ctcatgtgtt gctccggccc 420ctccagctgc aggtgggtgt ggagtttgag gccagcacaa ggatgcagga caccagcgtc 480tccttcgggt accagctgga cctgcccaag gccaacctcc tcttcaaagg taaaggtctc 540ggttccccta cgcgggaaac aggcaggagg tgactcaact ctgagtggat gtgtgggcca 600ccacaggtgc tggaggacag tgtgctgcca ccctgtgggc ctccacatta ccagggaaca 660cttgttaaaa ggtaggtggg gccgggtgcg gtggctcacg cctgtaatcc cagcactttg 720ggaggccaag gcgggccgag gtaaggagat tgagaccatc ctggctaaca cggtgaaact 780ccgtctctac taaaaataca aaaacaaaat tagccgggtg tggttgcggg tgcctatagt 840cccaactact gaggctgagg cgggaaaatg gtatgaaccc aggaggcgga gcttgcggtg 900agccgagatc gtgccaccgc actccagcct gggtgacaga gcaagactcc atctcaaaaa 960aaaaaaagta ggtggacaac cctctactat gttttatgct tggaaaaaaa aagtaggtag 1020agcagccagg cgtggtgact cacgcctgta atcccagcat tttgggaggc caagccaggt 1080agaatacttg aggccaggag ttggagacca gcctggccaa cgtggtgaaa tcccctctct 1140actaaaagta caaaaattag ccaggtgtgg tagcgtgctg caactgtagt ccccgctact 1200taggaggctg aggcacaaga atcacttgaa cctgggaggc ggaggttgca gggagttgag 1260actgcaccac tgcactccag cctgggtgac agagtgagac tccatctcca aaaaaaataa 1320aatgaaataa ataaataaat gttaaaaaaa atctggtgga gcatctgatg ggtgtttggg 1380ccaagctgga gctttgtcca tcccctctta tttttctgca cttgactctc ttatttttct 1440gagactggtc tccctctgtc gcccaggcta gagtgcagca gtgcaactgc ggctcactgc 1500agcctccacc tcccgggctc aagcagcctt cccacctcag cctcctgagt agctaggacc 1560acaggtgtat gccaccaggc ccagctaatt tttttgatag ttttgggaga catgggggtt 1620tcaccatgtt gcccaggctg gtctcgaact cctggactca agccttggcc tcccaaagtg 1680ctgggattat aggtgtgagc caccacaccc agccagggta gaaggcactt tggaagcctc 1740gagcctgccc cattcatctt acgttagtgg aaactgaggc ttccagaggt ttcaaggtca 1800caactaaatc cagaacctca tctcaggcac actggtcgta gtcccaatgt ccagtcttaa 1860gtcttcttgg atatctgtgg ctcacagatt ttgggtgttt gagcctcctg ctgagcactg 1920ctggggccac agcggtgacc agccctgtct tcacgggact cagtgagagg aacagattca 1980tccgcagagt gggcaggact aggttggggg aacccagggg tctagagggc ttttcagagg 2040gcaggggtca ctgagcggag agcagaggag gagtgagcca tttgctccag cgtgaagttg 2100ttggtgtgat ggggtttcag ggtggcagga gcagtgtggt taaaggtctg gaagctgtcg 2160gcatgtggct ggtatccaag gtggccagga actctgcatg gatatggtgg gaagctggca 2220cgcctctcac ctcagctctt ccctgcaggc tctgtggata gcaactggat cgtgggtgcc 2280acgctggaga agaagctccc acccctgccc ctgacactgg cccttggggc cttcctgaat 2340caccgcaaga acaagtttca gtgtggcttt ggcctcacca tcggctgagc cctcctggcc 2400cccgccttcc acgcccttcc gattccacct ccacctccac ctccccctgc cacagagggg 2460agacctgagc ccccctccct tccctccccc cttgggggtc gggggggaca ttggaaagga 2520gggaccccgc caccccagca gctgaggagg ggattctgga actgaatggc gcttcgggat 2580tctgagtagc aggggcagca tgcccagtgg gcctggggtc ccgggaggga ttccggaatt 2640gaggggcacg caggattctg agcaccaggg gcagaggcgg ccagacaacc tcagggagga 2700gtgtcctggc gtccccatcc tccaaagggc ctgggcccgc cccgaggggg cagcgagagg 2760agcttcccca tccccggtca gtccaccctg ccccgtccac tttcccatct cctcggtata 2820aatcatgttt ataagttatg gaagaaccgg gacattttac agaaaaaaaa caaaaaacaa 2880caaaaaatat acgtgggaaa aaaaacgatg ggaggcctcc gttttctcaa gtgtgtctgg 2940cctgttttga gcatttcatc cggagtctgg ccgccctgac cttcccccag ccgcctgcag 3000ggggcgccag agggccggag cacggaaagc agcggatcct tgatgctgcc ttaagtccgg 3060ctcagagggg cgcagcgtgg cctggggtcg ctatcttccc atccggaaca tctgccctgc 3120tgggggacac tacgggcctt cccttgcctg agggtagggt ctcaaggtca cttgccccca 3180gcttgacctg gccggagtgg ctatagagga ctttgtccct gcagactgca gcagcagaga 3240tgacactgtc tctgagtgca gagatggggg cagggagctg ggagagggtt caagctactg 3300gaacagcttc agaacaacta gggtactagg aactgctgtg tcagggagaa ggggctcaag 3360gactcgcagg cctgggagga ggggcctagg ccagccatgg gagttgggtc acctgtgtct 3420gaggacttgg tgctgtctgg attttgccaa cctagggctg gggtcagctg atgcccacca 3480cgactcccga gcctccagga actgaaaccc tgtctgcccc cagggtctgg ggaaggaggc 3540tgctgagtag aaccaacccc aggttaccaa ccccacctca gccacccctt gccagccaaa 3600gcaaacaggc ccggcccggc actgggggtt ccttctcgaa ccaggagttc agcctcccct 3660gacccgcaga atcttctgat cccacccgct ccaggagcca ggaatgagtc ccagtctctc 3720ccagttctca ctgtgtggtt ttgccattcg tcttgctgct gaaccacggg tttctcctct 3780gaaacatctg ggatttataa cagggcttag gaaagtgaca gcgtctgagc gttcactgtg 3840gcctgtccat tgctagccct aacataggac cgctgtgtgc cagggctgtc ctccatgctc 3900aatacacgtt agcttgtcac caaacatacc cgtgccgctg ctttcccagt ctgatgagca 3960aaggaacttg atgctcagag aggacaagtc atttgcccaa ggtcacacag ctggcaactg 4020gcagagccag gattcacgcc ctggcaattt gactccagaa tcctaacctt aacccagaag 4080cacggcttca agcccctgga aaccacaata cctgtggcag ccagggggag gtgctggaat 4140ctcatttcac atgtggggag ggggctcccc tgtgctcaag gtcacaacca aagaggaagc 4200tgtgattaaa acccaggtcc catttgcaaa gcctcgactt ttagcaggtg catcatactg 4260ttcccacccc tcccatccca cttctgtcca gccgcctagc cccactttct tttttttctt 4320tttttgagac agtctccctc ttgctgaggc tggagtgcag tggcgagatc tcggctcact 4380gtaacctccg cctcccgggt tcaagcgatt ctcctgcctc agcctcccaa gtagctagga 4440ttacaggcgc ccgccaccac gcctggctaa cttttgtatt tttagtagag atggggtttc 4500accatgttgg ccaggctggt ctcaaactcc tgaccttaag tgattcgccc actgtggcct 4560cccaaagtgc tgggattaca ggcgtgagct accgccccca gcccctccca tcccacttct 4620gtccagcccc ctagccctac tttctttctg ggatccagga gtccagatcc ccagccccct 4680ctccagatta cattcatcca ggcacaggaa aggacagggt caggaaagga ggactctggg 4740cggcagcctc cacattcccc ttccacgctt ggcccccaga atggaggagg gtgtctgtat 4800tactgggcga ggtgtcctcc cttcctgggg actgtggggg gtggtcaaaa gacctctatg 4860ccccacctcc ttcctccctc tgccctgctg tgcctggggc agggggagaa cagcccacct 4920cgtgactggg ggctggccca gcccgcccta tccctggggg agggggcggg acagggggag 4980ccctataatt ggacaagtct gggatccttg agtcctactc agccccagcg gaggtgaagg 5040acgtccttcc ccaggagccg gtgagaagcg cagtcggggg cacggggatg agctcagggg 5100cctctagaaa gagctgggac cctgggaacc cctggcctcc aggtagtctc aggagagcta 5160ctcggggtcg ggcttgggga gaggaggagc gggggtgagg caagcagcag gggactggac 5220ctgggaaggg ctgggcagca gagacgaccc gacccgctag aaggtggggt ggggagagca 5280gctggactgg gatgtaagcc atagcaggac tccacgagtt gtcactatca tttatcgagc 5340acctactggg tgtccccagt gtcctcagat ctccataact ggggagccag gggcagcgac 5400acggtagcta gccgtcgatt ggagaacttt aaaatgagga ctgaattagc tcataaatgg 5460aacacggcgc ttaactgtga ggttggagct tagaatgtga agggagaatg aggaatgcga 5520gactgggact gagatggaac cggcggtggg gagggggtgg ggggatggaa tttgaacccc 5580gggagaggaa gatggaattt tctatggagg ccgacctggg gatggggaga taagagaaga 5640ccaggaggga gttaaatagg gaatgggttg ggggcggctt ggtaaatgtg ctgggattag 5700gctgttgcag ataatgcaac aaggcttgga aggctaacct

ggggtgaggc cgggttgggg 5760ccgggctggg ggtgggagga gtcctcactg gcggttgatt gacagtttct ccttccccag 5820actggccaat cacaggcagg aagatgaagg ttctgtgggc tgcgttgctg gtcacattcc 5880tggcaggtat gggggcgggg cttgctcggt tccccccgct cctccccctc tcatcctcac 5940ctcaacctcc tggccccatt caggcagacc ctgggccccc tcttctgagg cttctgtgct 6000gcttcctggc tctgaacagc gatttgacgc tctctgggcc tcggtttccc ccatccttga 6060gataggagtt agaagttgtt ttgttgttgt tgtttgttgt tgttgttttg tttttttgag 6120atgaagtctc gctctgtcgc ccaggctgga gtgcagtggc gggatctcgg ctcactgcaa 6180gctccgcctc ccaggtccac gccattctcc tgcctcagcc tcccaagtag ctgggactac 6240aggcacatgc caccacaccc gactaacttt tttgtatttt cagtagagac ggggtttcac 6300catgttggcc aggctggtct ggaactcctg acctcaggtg atctgcccgt ttcgatctcc 6360caaagtgctg ggattacagg cgtgagccac cgcacctggc tgggagttag aggtttctaa 6420tgcattgcag gcagatagtg aataccagac acggggcagc tgtgatcttt attctccatc 6480acccccacac agccctgcct ggggcacaca aggacactca atacatgctt ttccgctggg 6540cgcggtggct cacccctgta atcccagcac tttgggaggc caaggtggga ggatcacttg 6600agcccaggag ttcaacacca gcctgggcaa catagtgaga ccctgtctct actaaaaata 6660caaaaattag ccaggcatgg tgccacacac ctgtgctctc agctactcag gaggctgagg 6720caggaggatc gcttgagccc agaaggtcaa ggttgcagtg aaccatgttc aggccgctgc 6780actccagcct gggtgacaga gcaagaccct gtttataaat acataatgct ttccaagtga 6840ttaaaccgac tcccccctca ccctgcccac catggctcca aagaagcatt tgtggagcac 6900cttctgtgtg cccctaggta ctagatgcct ggacggggtc agaaggaccc tgacccacct 6960tgaacttgtt ccacacagga tgccaggcca aggtggagca agcggtggag acagagccgg 7020agcccgagct gcgccagcag accgagtggc agagcggcca gcgctgggaa ctggcactgg 7080gtcgcttttg ggattacctg cgctgggtgc agacactgtc tgagcaggtg caggaggagc 7140tgctcagctc ccaggtcacc caggaactga ggtgagtgtc cccatcctgg cccttgaccc 7200tcctggtggg cggctatacc tccccaggtc caggtttcat tctgcccctg tcgctaagtc 7260ttggggggcc tgggtctctg ctggttctag cttcctcttc ccatttctga ctcctggctt 7320tagctctctg gaattctctc tctcagcttt gtctctctct cttcccttct gactcagtct 7380ctcacactcg tcctggctct gtctctgtcc ttccctagct cttttatata gagacagaga 7440gatggggtct cactgtgttg cccaggctgg tcttgaactt ctgggctcaa gcgatcctcc 7500cgcctcggcc tcccaaagtg ctgggattag aggcatgagc caccttgccc ggcctcctag 7560ctccttcttc gtctctgcct ctgccctctg catctgctct ctgcatctgt ctctgtctcc 7620ttctctcggc ctctgccccg ttccttctct ccctcttggg tctctctggc tcatccccat 7680ctcgcccgcc ccatcccagc ccttctcccc gcctcccact gtgcgacacc ctcccgccct 7740ctcggccgca gggcgctgat ggacgagacc atgaaggagt tgaaggccta caaatcggaa 7800ctggaggaac aactgacccc ggtggcggag gagacgcggg cacggctgtc caaggagctg 7860caggcggcgc aggcccggct gggcgcggac atggaggacg tgtgcggccg cctggtgcag 7920taccgcggcg aggtgcaggc catgctcggc cagagcaccg aggagctgcg ggtgcgcctc 7980gcctcccacc tgcgcaagct gcgtaagcgg ctcctccgcg atgccgatga cctgcagaag 8040cgcctggcag tgtaccaggc cggggcccgc gagggcgccg agcgcggcct cagcgccatc 8100cgcgagcgcc tggggcccct ggtggaacag ggccgcgtgc gggccgccac tgtgggctcc 8160ctggccggcc agccgctaca ggagcgggcc caggcctggg gcgagcggct gcgcgcgcgg 8220atggaggaga tgggcagccg gacccgcgac cgcctggacg aggtgaagga gcaggtggcg 8280gaggtgcgcg ccaagctgga ggagcaggcc cagcagatac gcctgcaggc cgaggccttc 8340caggcccgcc tcaagagctg gttcgagccc ctggtggaag acatgcagcg ccagtgggcc 8400gggctggtgg agaaggtgca ggctgccgtg ggcaccagcg ccgcccctgt gcccagcgac 8460aatcactgaa cgccgaagcc tgcagccatg cgaccccacg ccaccccgtg cctcctgcct 8520ccgcgcagcc tgcagcggga gaccctgtcc ccgccccagc cgtcctcctg gggtggaccc 8580tagtttaata aagattcacc aagtttcacg catctgctgg cctccccctg tgatttcctc 8640taagccccag cctcagtttc tctttctgcc cacatactgg ccacacaatt ctcagccccc 8700tcctctccat ctgtgtctgt gtgtatcttt ctctctgccc tttttttttt ttttagacgg 8760agtctggctc tgtcacccag gctagagtgc agtggcacga tcttggctca ctgcaacctc 8820tgcctcttgg gttcaagcga ttctgctgcc tcagtagctg ggattacagg ctcacaccac 8880cacacccggc taatttttgt atttttagta gagacgagct ttcaccatgt tggccaggca 8940ggtctcaaac tcctgaccaa gtgatccacc cgccggcctc ccaaagtgct gagattacag 9000gcctgagcca ccatgcccgg cctctgcccc tctttctttt ttagggggca gggaaaggtc 9060tcaccctgtc acccgccatc acagctcact gcagcctcca cctcctggac tcaagtgata 9120agtgatcctc ccgcctcagc ctttccagta gctgagacta caggcgcata ccactaggat 9180taatttgggg gggggggtgg tgtgtgtgga gatggggtct ggctttgttg gccaggctga 9240tgtggaattc ctgggctcaa gcgatactcc caccttggcc tcctgagtag ctgagactac 9300tggctagcac caccacaccc agctttttat tattatttgt agagacaagg tctcaatatg 9360ttgcccaggc tagtctcaaa cccctgggct caagagatcc tccgccatcg gcctcccaaa 9420gtgctgggat tccaggcatg gggctccgag cccggcctgc ccaacttaat aatacttgtt 9480cctcagagtt gcaactccaa atgacctgag attggtgcct ttattctaag ctattttcat 9540tttttttctg ctgtcattat tctccccctt ctctcctcca gtcttatctg atatctgcct 9600ccttcccacc caccctgcac cccatcccac ccctctgtct ctccctgttc tcctcaggag 9660actctggctt cctgttttcc tccacttcta tcttttatct ctccctccta cggtttcttt 9720tctttctccc cggcctgctt gtttctcccc caaccccctt catctggatt tcttcttctg 9780ccattcagtt tggtttgagc tctctgcttc tccggttccc tctgagctag ctgtcccttc 9840acccactgtg aactgggttt ccctgcccaa ccctcattct ctttctttct ttcttttttt 9900tttttttttt tttttttttt ttttgagaca gagtcttgct ctgttgccca gcctggagtg 9960cagtggtgca atcttggttc actgcaacct ccacttccca gattcaagca attctcctgc 10020ctcagcctcc agagtagctg ggattacagg cgtgtcccac cacacccgac taatttttgt 10080atttttggta gagacaaggc ttcggcattg ttggccaggc aggtctcgaa ctcctgacct 10140caagtaatct gcctgcctca ccctcccaaa gtgctgggat tacaggcatg agccacctca 10200cccggaccat ccctcattct ccatcctttc ctccagttgt gatgtctacc cctcatgttt 10260cccaacaagc ctactgggtg ctgaatccag gctgggaaga gaagggagcg gctcttctgt 10320cggagtctgc accaggccca tgctgagacg agagctggcg ctcagagagg ggaagcttgg 10380atggaagccc aggagccgcc ggcactctct tctcctccca ccccctcagt tctcagagac 10440ggggaggagg gttcccacca acgggggaca ggctgagact tgagcttgta tctcctgggc 10500cagctgcaac atctgcttgt ccctctgccc atcttggctc ctgcacaccc tgaacttggt 10560gctttccctg gcactgctct gatcacccac gtggaggcag cacccctccc ct 1061270317PRTHomo sapiens 70Met Lys Val Leu Trp Ala Ala Leu Leu Val Thr Phe Leu Ala Gly Cys 1 5 10 15 Gln Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu 20 25 30 Arg Gln Gln Thr Glu Trp Gln Ser Gly Gln Arg Trp Glu Leu Ala Leu 35 40 45 Gly Arg Phe Trp Asp Tyr Leu Arg Trp Val Gln Thr Leu Ser Glu Gln 50 55 60 Val Gln Glu Glu Leu Leu Ser Ser Gln Val Thr Gln Glu Leu Arg Ala 65 70 75 80 Leu Met Asp Glu Thr Met Lys Glu Leu Lys Ala Tyr Lys Ser Glu Leu 85 90 95 Glu Glu Gln Leu Thr Pro Val Ala Glu Glu Thr Arg Ala Arg Leu Ser 100 105 110 Lys Glu Leu Gln Ala Ala Gln Ala Arg Leu Gly Ala Asp Met Glu Asp 115 120 125 Val Cys Gly Arg Leu Val Gln Tyr Arg Gly Glu Val Gln Ala Met Leu 130 135 140 Gly Gln Ser Thr Glu Glu Leu Arg Val Arg Leu Ala Ser His Leu Arg 145 150 155 160 Lys Leu Arg Lys Arg Leu Leu Arg Asp Ala Asp Asp Leu Gln Lys Arg 165 170 175 Leu Ala Val Tyr Gln Ala Gly Ala Arg Glu Gly Ala Glu Arg Gly Leu 180 185 190 Ser Ala Ile Arg Glu Arg Leu Gly Pro Leu Val Glu Gln Gly Arg Val 195 200 205 Arg Ala Ala Thr Val Gly Ser Leu Ala Gly Gln Pro Leu Gln Glu Arg 210 215 220 Ala Gln Ala Trp Gly Glu Arg Leu Arg Ala Arg Met Glu Glu Met Gly 225 230 235 240 Ser Arg Thr Arg Asp Arg Leu Asp Glu Val Lys Glu Gln Val Ala Glu 245 250 255 Val Arg Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg Leu Gln Ala 260 265 270 Glu Ala Phe Gln Ala Arg Leu Lys Ser Trp Phe Glu Pro Leu Val Glu 275 280 285 Asp Met Gln Arg Gln Trp Ala Gly Leu Val Glu Lys Val Gln Ala Ala 290 295 300 Val Gly Thr Ser Ala Ala Pro Val Pro Ser Asp Asn His 305 310 315 712800DNAHomo sapiens 71aaagggtgga cttgttgcag ttgctgtagg attctaaatc caggtgattg tttcaaactg 60agcatcaaca acaaaaacat ttgtatgata tctatatttc aatcatggac caaaatcaac 120atttgaataa aacagcagag gcacaacctt cagagaataa gaaaacaaga tactgcaatg 180gattgaagat gttcttggca gctctgtcac tcagctttat tgctaagaca ctaggtgcaa 240ttattatgaa aagttccatc attcatatag aacggagatt tgagatatcc tcttctcttg 300ttggttttat tgacggaagc tttgaaattg gaaatttgct tgtgattgta tttgtgagtt 360actttggatc caaactacat agaccaaagt taattggaat cggttgtttc attatgggaa 420ttggaggtgt tttgactgct ttgccacatt tcttcatggg atattacagg tattctaaag 480aaactaatat caattcatca gaaaattcaa catcgacctt atccacttgt ttaattaatc 540aaattttatc actcaataga gcatcacctg agatagtggg aaaaggttgt ttaaaggaat 600ctgggtcata catgtggata tatgtgttca tgggtaatat gcttcgtgga ataggggaga 660ctcccatagt accattgggg ctttcttaca ttgatgattt cgctaaagaa ggacattctt 720ctttgtattt aggtatattg aatgcaatag caatgattgg tccaatcatt ggctttaccc 780tgggatctct gttttctaaa atgtacgtgg atattggata tgtagatcta agcactatca 840ggataactcc tactgattct cgatgggttg gagcttggtg gcttaatttc cttgtgtctg 900gactattctc cattatttct tccataccat tctttttctt gccccaaact ccaaataaac 960cacaaaaaga aagaaaagct tcactgtctt tgcatgtgct ggaaacaaat gatgaaaagg 1020atcaaacagc taatttgacc aatcaaggaa aaaatattac caaaaatgtg actggttttt 1080tccagtcttt taaaagcatc cttactaatc ccctgtatgt tatgtttgtg cttttgacgt 1140tgttacaagt aagcagctat attggtgctt ttacttatgt cttcaaatac gtagagcaac 1200agtatggtca gccttcatct aaggctaaca tcttattggg agtcataacc atacctattt 1260ttgcaagtgg aatgttttta ggaggatata tcattaaaaa attcaaactg aacaccgttg 1320gaattgccaa attctcatgt tttactgctg tgatgtcatt gtccttttac ctattatatt 1380ttttcatact ctgtgaaaac aaatcagttg ccggactaac catgacctat gatggaaata 1440atccagtgac atctcataga gatgtaccac tttcttattg caactcagac tgcaattgtg 1500atgaaagtca atgggaacca gtctgtggaa acaatggaat aacttacatc tcaccctgtc 1560tagcaggttg caaatcttca agtggcaata aaaagcctat agtgttttac aactgcagtt 1620gtttggaagt aactggtctc cagaacagaa attactcagc ccatttgggt gaatgcccaa 1680gagatgatgc ttgtacaagg aaattttact tttttgttgc aatacaagtc ttgaatttat 1740ttttctctgc acttggaggc acctcacatg tcatgctgat tgttaaaatt gttcaacctg 1800aattgaaatc acttgcactg ggtttccact caatggttat acgagcacta ggaggaattc 1860tagctccaat atattttggg gctctgattg atacaacgtg tataaagtgg tccaccaaca 1920actgtggcac acgtgggtca tgtaggacat ataattccac atcattttca agggtctact 1980tgggcttgtc ttcaatgtta agagtctcat cacttgtttt atatattata ttaatttatg 2040ccatgaagaa aaaatatcaa gagaaagata tcaatgcatc agaaaatgga agtgtcatgg 2100atgaagcaaa cttagaatcc ttaaataaaa ataaacattt tgtcccttct gctggggcag 2160atagtgaaac acattgttaa ggggagaaaa aaagccactt ctgcttctgt gtttccaaac 2220agcattgcat tgattcagta agatgttatt tttgaggagt tcctggtcct ttcactaaga 2280atttccacat cttttatggt ggaagtataa ataagcctat gaacttataa taaaacaaac 2340tgtaggtaga aaaaatgaga gtactcattg ttacattata gctacatatt tgtggttaag 2400gttagactat atgatccata caaattaaag tgagagacat ggttactgtg taataaaaga 2460aaaaatactt gttcaggtaa ttctaattct taataaaaca aatgagtatc atacaggtag 2520aggttaaaaa ggaggagcta gattcatatc ctaagtaaag agaaatgcct agtgtctatt 2580ttattaaaca aacaaacaca gagtttgaac tataatacta aggcctgaag tctagcttgg 2640atatatgcta caataatatc tgttactcac ataaaattat atatttcaca gactttatca 2700atgtataatt aacaattatc ttgtttaagt aaatttagaa tacatttaag tattgtggaa 2760gaaataaaga cattccaata tttgcaaaaa aaaaaaaaaa 280072115603DNAHomo sapiens 72gattcctctg cagtgtaact tcatggtttt tgaggcaaag gaaggctggc agtaaacaaa 60atatgtgagt aaaatttata gtatgatggt gagagaataa aaattgagtg tcaaagggag 120taatattaaa aaattgttag agaagacttc gctgggaaag tgtcatttgt ttgggtacta 180gaatatggtg agggagtaag ttatgcagct atagggaaag aacattccag acagaaagaa 240aaataggaac aaagattctc agtagaggat ctataactta taaggcctta aagctgttct 300ttggattttt gagtgatatg tgaagccaat gggggatttg agcagagcta tgacatggta 360tgaccctcac ttatatgtta agatttacac aggggaagga ggttggggaa gaggggctgt 420gagtggtcag gaggaaagct gagatacaag tatgagggta ttgcaataat tcaggaccag 480cctgaaagtt gtggaggagg taagaaatca tcagattctg ggtatatttg gaaattagag 540cctaatgtga gtgtgagaaa tagagaagaa tgattctaat attgtatgtg gctgtgcatg 600tgcacgcatg tgtgcaactg gaatgacaga attacaatgt atggggatta ttgtcttccc 660tggacaataa tccctggaaa tggggattat tacaagagga gaggttgggg aaggaaagac 720aaagatacca tgttagaaaa tattaagtgt aagatgccta ttagagatat ataggaagat 780ggtgagaagt caatggataa atctagagtt catgagtaac ttggctagag aaaaaatttt 840ggaattatca acgtatggat aagatttaaa gacatgagaa tagatgaggt cacaaacaca 900cacagtaagg ttattgtctg acatgcttca atttagaaga caaagataaa gaatttagag 960taaatgaagt gtaaataagt aagtcagtga gttagaaggc aaaccacaaa gggtagtgtc 1020ctgcaaagtt ttgcttaggg agggaattct cagttctgaa aaatgctgct aatagttcaa 1080gtcagatgag gactattaga tgtagcattt aggtaattta tgacttagga aaagtagttt 1140cagtggaaat ttgggggcaa aagcctgata agagtgtgct caagagagaa tgtagagaga 1200gagattgaaa gcaataatta gacaagctat ttctctgtaa aaatagcaca gaaatagggc 1260aatattagga aaaaatggga tcaaaagaga gatttttgga agatgaaaaa gtgacagcat 1320tcttacatgc tgatggaaac atttaaaaag aggatagtgc tatccttaaa aacacaaggg 1380gaggagtcaa tgtcatatgc aagtggagat tggccttagc ttaaacttgg gtagttcact 1440aaggcagacc atgtggtggt actggggctt tacatagata aatgtggtca agggagcttt 1500tgaagtttct tctttattta tttatttttt cagtaaaata attcatcagc tgaaggtggg 1560gaagggatgt attagaattt caaaaaaaaa aaaaaaagat gaaggcacaa aatgctcaga 1620gtgcaaaatg gcgtgaatga tttcttggca aaatgaaagg tccatttggg cttcctaatc 1680atacgtttaa agtcagcatg gttgagagat tttcctcagt tacatttagc ttcataaggg 1740aaatgtgcag agttatttga gagttaaatt taatcaagat tgtggctttg acatgcaatt 1800aaaataatgc aaaacagtca aaattatatg aagttatata gaagagagtg attaccgtga 1860ccattaaatt aacccagatg tatagataag gaacaccgaa atctctggca aaatcaaatt 1920gtaggttata catcctggtc agtggaagca tgtggatcta gggtgttact gagtgtgagc 1980taggagtgat aaagagtggt gctccaatct ttgatattat ggagagatta cagtggtgtg 2040aaaagcatag gatatgccca tagcagtagg tagaagccaa gatcattgag gagaaggcta 2100aaaaataaaa agaaaataaa aagaaaacag agaattaaaa agattctctt catggtcatt 2160accatcatga ataattaaaa tagtagtagc attttgagag aatggctttg gatcgagagc 2220taaaattgtc atgaaatgag tgggagtgac tgagcgttga tagatgattt caacaagagg 2280aataagtgat agagtctttc aatatgagat ccaaaactat ggattatgag tgtaaagggt 2340ggggaaatgt aaagaaacta gcaaagtgag gcacattgga aaccagccca tctggtttgc 2400agcaatatgg gggataaggc aacccctatg tatcactgct gcaggagagg gagtgtctca 2460gggaagacca atttttaagt tcaaggcaga agtgaagcag aataactcag agaagaggta 2520aaggtaaggg gagtttcagt catgactagt gatgggttcc agaaaactca agagaagaat 2580ttcagtccag gattgggaga aagagagaag atgggggcaa acataggaat gtgcagagcc 2640ctgtggggat tagagaagag gtgatgagtc atcagggaat ccctaccttc ttatggtggt 2700cactaccata agagcgataa ttgccatggt aatattagtc ttgatgatgc cagagctttg 2760atcattggtg ggtatagaaa catgtttgga gaataatatg tagaatagga gttctttcca 2820ggagagtgta gctttctgga gctgtctctt aatcagcacc aacagaagtg aaatgttcgg 2880gtaagggcgg atctgcttgg agcctgacgg ttccctcttg aggtgtgcct gtggtacaca 2940cctgagaact ctggggctaa aacctattgg acataggttt tacagatcta caggatacag 3000atctcagaga ttttatttgt attcatttaa tataaattaa ctgctctaaa atttataata 3060tgcaaatatc atacaattaa tctaattagg tgttgaatct ataatgtgcc aggcattatg 3120taaggcactt tacatacact aaatctttat tccaaatata gacttcttac tttatagatg 3180agtgcactga tgctcagaaa tggtaaataa cctactgatg tttatactgc tggcaggtag 3240cagagacata tcggcattta agtctttcag acttcaaagg ccatgatatt tcatcagagc 3300tgtgatagcc gttcctgaaa aaaatatcag ctgattcttt aaatcaattt ttgtcatcta 3360actgatgcgt ggctgttagc ataatattga tcttgaaaga tgttttgcaa catctttccc 3420ctggtgtact cttgtttttc catgatccca caaaatgagc agtctaatta tttacacaat 3480taggaagaga aaaggggcac agagaatgct ctttgacctc tgaaaatatt ggagaatttt 3540acaactggca cctttagctc aggattataa aggttgttag ttagtttgta ctgttttatc 3600ttcattgtat ataatatata tattagtctc caaacatgtt gatgtgtttt caatgaaatg 3660gatgtctgag gagaaaacca ttagcctgag aaaacccaaa ctgtattccc attgtgaata 3720aaaggaagtc cataaaaatg atggaaaatg ttctgcattc ctgttatgat atcaaaatct 3780ggcagtacat gaaaattttt caaagtgctt atttaacagg cataatcttt ggtctcctga 3840gccagaatct gctgggtatg ggactggatt gctattttga caactcgcca gtagattctt 3900actcagcaga gtatttggaa gccttactct aatattttgg ccttgggtct acatttctca 3960gttctgcaca gtcattcttc ccctctacac tactctttag tttgtctcat gattccaata 4020ctctcaataa ttaaccaaga atagaactaa tcaatcagat aactgtggca cagacatcaa 4080atacattttg ctgcaaccat atcaacaaat gtcccatgaa tgataagggg taaccatatt 4140ctcatatatg catcctcaca ttaccacata tatatatgtg catatgtgta tacaggtaaa 4200agtgtgtata tatgtataca tgtatgtttg tgtgtatata catacatata tcttcacact 4260tttctgaaat atatatattt atgtgagaga agggtctgta ctttatttca gaagagagct 4320taatgtccaa ggtataattg agagtctaaa atgtttgagt tattgaatta attaaacttc 4380atctctactc aagaaaactt ttaactgagt taagctcttc ctttctccac aagtcaagtc 4440aataaaagga aactgtgata ttaataattc tttcctgttt tgatgtaaag aatctatcgc 4500ataaagcagt cttaattttc atcattcaga aaaatggtct tgcagttaat tgggactctc 4560ttattccagg tggtatctcc agtctccata cataccacgt tagaaccata cttatgtacc 4620aagcaaagag ggtatatttt aatttttaaa tgccaatgta acctgtaggc atatttttta 4680tttgtcttaa attatttcct atttggaagt tttaaatacc tggaataatt tattgtactc 4740atatttttaa agaaaaaaat cttatgccac caacttaatt gaataaacaa gtaaaagcca 4800ttcccaaaag taaggtttac ttgttaagat taacaaaaaa taatgtgaga attctgagaa 4860atataatctt taaatattgg caactggagt gaactcttaa aactaactag gttttatatg 4920tttgactaga gcaatgacat aataaggtgg ttaatcatca ctggacttgt tttcaaaaag 4980ccaactactt taagaggaat aaagggtgga cttgttgcag ttgctgtagg attctaaatc 5040caggtaagaa ccattgagat tctctaattt ttacatatat tttatgtaag aaattttcac 5100ggaagaagat tttgatggtc ttgaaaaata ttacgaattt tatgctctgt gtcttccaca 5160cgcttacatt ctgagccctt aaaacatagt aaatattcct tctgggagta gaagagcctc

5220aggtttatat actgttaaaa ataaagtaga gaaaataata cctttatata tttaaatata 5280aagtttcaaa tcttggtctt attaatttcc aaacaaataa aaatcaagtc tcaaaaatga 5340agctctagtt accttcttaa aatatgctac aggataatta tttttgtcaa ctacattgac 5400tgatcacact agactcctta tttctttgat gtcttcttaa ctggatgaag gcagccaagg 5460gtgggagtag agggaagagt taattggcaa acataaaaaa caggtgtctc aaagtcacat 5520aaccacctca gtttccttgt ttcaactcaa gtttgataca gggtgaaggg aaatatattt 5580tctagataat ttatctccaa ttaaataagc aaaaagtctt ctcagtacag tttttttctt 5640tttttatttc attattatta tactttaagt tttagggtac atgtgcacaa catgcaggtt 5700tgttacatat gtatacatgt gccatgttgg tgtgctgcac ccattaactc atcatttaac 5760attgggcata tctcctaatg ctatccctcc cctctccccc accccacaac agtccccggt 5820gtgtgatgtt ccctttcctg tgtccatgtg ttctcattgt tcagttccca cctatgagtg 5880agaacatgcg gtgtttggtt ttttgtcctt gcgatagttt gttgagaatg atggtttcca 5940gtttcatcca tgtccctaca aaggacataa actcatcatt tttatggctg catagtattc 6000catggtgtat gtgtgccaca ttttcttaat ccactctatc gttgttggac atttaggttg 6060gttccaagtc tttgctactg tgaatagtgc cgctataaac atacgtgtgc atgtgtcttt 6120atagcagcat gatttataat cccttgggta tatatccact tatgggatgg ctgggtcaaa 6180tggtatttcc agttctagat ccctgaggaa tcgccacact gtcttccaca atggttgaac 6240tagtttacag tcccaccaac agtgtaaaag tgttcctatt tctccacatc ctctccagca 6300cctgttgttt cctgactttt taatgatcgc tattctaact ggtgtgagat agtatctcat 6360tgtggttttg atttgcattt ctctgatggc cagtgatgat gagcattttt tcacgtgttt 6420tttggctgca taaatgtctt ctgttgagaa gtgtctgttc atgtccttca cccacttctt 6480gatggggtcg tttgtctttt gtaaatttgt ttgagttcat tgtagatttt gggtattagc 6540cttttgtcag atgagtaggt tgcaaaaatt ttctcccatt ctgtaggttg cctgttcact 6600ctgatggtag tttcttttgc tgtgcagaag ctctttagtt taattatatc tcatttgtca 6660tttttggctt ttgttgccat tgcttttggt gttttagaca tgaagtcctt gcccatgcct 6720atgtcctgaa tggtattgcc taggttttct tctagggttt ttatggtttt aggtctaaca 6780tttaagtctt taatccatct tgaattaatt tttgtgtaag gtgtaaggaa gggatccagt 6840ttcagctttc tacatatggc ttgccagttt tcccagcatc atttattaaa tagggaatcc 6900tttccccatt gcttgttttt ctcaggtttg tcaaagatca gatagttgta gatatgcggc 6960actatttctg agggctctgt tctgttccat tggtctatat ctctgttttg gtaccagtac 7020catgctgttt tggttactgt agccttgtag tatagtttga agtcaggtag ggtgatgcct 7080ccagctttgt tcttttcgct taggattgac ttggtatgcg ggctcttttt tggttccata 7140tgaactttaa agtagttttt tccaattctg tgaagaaagt cattggtagc ttgatgggga 7200tggcattgaa tctataaatt accttggaca gtatggccat tttcatgata ttgattcttc 7260ctgcccatga gcatggaatg ttcttctatt tgttcgtatc ctcttttatt tcattgagca 7320gtggtttgta gttctccttg aagaggtcct tcacatccct tgtaagttgg attcctaggt 7380attttattct ctttgaagca attgtgaatg ggagttcact catgatttgg ctctctgttt 7440gtctgttatt ggtgtataag aatgcttgtg atttttatac attgattttg tattctgaga 7500ctttgctgaa gttgcttatc aacttgagga aattttgggc tgagatgatg gggttttcta 7560gatatacaat catgtgatct gcaaacaggg acaatttgac ttcctctttt cctaattgaa 7620taccctttat tttcttctcc tgcctgattg ccctggccag aacttccaac attatgttga 7680ataggagcag tgagagaggg catccctgtc ttgtgcccgt tttcaaaggg aatgcttcca 7740gtttttgccc attcagtatc atattggctg caggtttgtc atagatagct cttattattt 7800tgagatacat cccatcaata cctaatttat tgagagtttt tagcatgaag ggttgttgaa 7860ttttgtcaaa ggccttttct gcatctattg agatgatcat gtagtttttg tctttggttc 7920tgtttatatg ctggattaca tttattgatt tgcgtatgtt gaaccagcct tgcatcccag 7980ggatgaatcc cacttggtca tgttggataa gctttttgat gtgctgttgg atttggtttg 8040ccagtatttt attgaggatt tttgcatcaa tgttcatcaa ggatattggt ctaaaattct 8100ctttttttgt tgtttctctg ccaggctttg gtatcaggat gatgctggcc tcataaaatg 8160agttagggag gattccctct ttttctattg attggaatag tttcagaagt attggtacca 8220gttcctcctt gtacctctgg tagaattcgg ctgtgaatcc atctggtcct ggactttttt 8280ttgttggtaa gctattgagt attgcctcaa tttcagagcc tgttattggt ctattcagag 8340atgcaacttc ttcctggttt agtcttggga ggatgtatgt gtcaaggaat ttatccattt 8400ctgctagatt ttctagttta tttgcctaga ggtgtttata gtattctctg atggtagttt 8460gtatttctgt gggatcggtg gttatatcct ctttatcatt ttttattgca tctatttgat 8520tcttctctgt tttcttcttt attagtcttg ctagtggtct atcaattttg ttgatgcttt 8580caaaaaacca gctcctggat tcattaattt tttgaagggt tttttgtgtc tctatttcct 8640tcagttctgc tctgatggta gttatttctt gccttctgct agcttttgaa tgtgtttgct 8700cttgcttttc tagttctttt aattgtgatg ttggggtgtc aattttggat ctttcctgct 8760ttctcttgtg ggcatttagt gctataaatt tccctctaca cactgcttta aatgtgtccc 8820agagattctc gtatgttgtg tgtttgttct cattggtttc aaagaacatc tttatttatg 8880ccttcatttc attatgtacc cagtagtcat tcagtagcag attgttcagt ttccatgcag 8940ttgagcagtt ttgagtgagt ttcttaatcc tgagttctag tttgattgcg ctgtggtctg 9000agaaacagtt tgttataatt tctgttcttt tccatttgct gaggagagct ttacttccaa 9060ctatgtggtc aatttcagag taggtgtggt gtggtgctga aaagaatgta tattctgttg 9120atttggggtg gagagttctg tagatgtcta ttaggtccgc ttggtgcaga gctgagttca 9180attcctgggt atccttgtta actttctgtc tcattgatct gtctaatgtt gacagtgggg 9240tgttaaagtc tcccattatt attgagtgga attctaagtc tctttgtagg tcactaagga 9300cttgctttat gaatctgggt gctcctgtat tgggtgcata tatatttagg atagttagcg 9360cttcttgttg aattgatccc tttaccatta ggtaatggcc ttctttgtct cttttgatct 9420ttgttggtat aaagtctgtt ttatcagaga ctaggattgc aacccctgcc tttttttgtt 9480ttccatttgc ttggtagatc ttcctccatc cctttatttt gagcctatgt gtgtctctgc 9540atgtgagatg gatttcctga ctacagtgca ctgattggtc ttgactcttt atccaatttg 9600ccagtctgtg tcttttaatt gcagcattta gcccatttac atttaaagtt aatattgtta 9660tgtgtgaatt tgatcctgtc attgtgatgt tagctggtta ttttgctcat tagttgatgc 9720agtttcttcc tagccttgat ggtctttaca atttggcatg tttttgcagt ggctggtacc 9780agttgttcct ttccatgttt agtgcttcct tcaggagctc ttttagggca ggcctggtgg 9840tgacaaaatc agcatttgct tgtctgtgaa ggattttgtt tctccttcac ttatgaagct 9900tcgtttggct ggatatgaaa ttctgggttg aaaattcttt tctttaagaa tgttgaatat 9960tggtccccac tctcttctgg cttgtagagt ttctgccgag agatcagctg ttagtctgat 10020gggcttccct ttgtgggtaa cccaaccttt ctctctggct gcccttaata ttttttcctt 10080catttcaact ttggtgaatc tgacaattat gtgtcttgga gttgctcttc tcgaggagta 10140tctttgtggc gtactctgta tttcctgaat ctgaacgttg gcctgccttg ctagattggg 10200gaagttctcc tggataatat cctgcagagt gttttccaac ttggttccct tctccccatc 10260actttcaggt acaccaatca gacgtagatt tggtcttttc acatagtccc atatttcttg 10320gaggctttgt tcgtttcttt ttattctttt ttctctaaac ttctcttctc acttcatttc 10380attcatttcg tcttccatca ctgataacct ttcttccagt tgatcctatc agctactgag 10440gcttctgcat ttgtcatgtg gctctcttgc cttggttttc agctccatca agtcctttaa 10500gaacttctct gcattggtta ttctagttat ccatttgtct gatttttttt caaagctttt 10560aacttctttg ccattggttt gaatttccac ctgtagctca gagtagtttg atcatctgaa 10620gccttcttct ctcaacttgt caaagtcatt ctccatccag ctttgttccg ttgctggtga 10680ggagctgcat tcctttggag gaggagaggc gctctgatct ttagagtttc cagtttttct 10740gctctgtttt tttctcatct ttgtggtttc atctatcttt ggtctttgat gatggtgacg 10800tacagatggg tttttggtgc ggatgtcctt tctgtttgtt agttttcctt ctaacagaca 10860ggaccctcag ctgcaggtct gttagagttt gctagaggtc cactgcagac cctgtttgcc 10920tgggtttcag cctcagtggc tgtagaagag cggatattgg tgaaccacaa atgctgctgc 10980ctgatcgttc ctctggaagt tttgtctcag aggagtaccc gaccgtgtga ggtgtcagtc 11040cgcccctact ggggggtgcc tcccagttag gctactcggg ggtcagggac ccacttgagg 11100aggcagtctg cctgttctca gatctcaagc tgcgtgctgg gagaaccact gctctcttca 11160aagctgtcag agagggacat ttaagtctgc agaggttact gctgtctttt tgtttgtctg 11220tgccctgccc ccagagatgg agcctacaga ggcaggcagg tgtccttgag ctgtggtggg 11280ctccacccag ttcgagcttc ccagccgctt tgtttaccta atcaaacaac taactcagca 11340atggtggccg cccctccccc agcctcgctg ccaccttgca gtttgatctt ggatggctgt 11400gcttgcaatg agcgagactc tgtgggcata ggaccctcca agccaggtgc aggatataat 11460ctcctggtgt gctgtttttt aagccggttg gaaaagcaca gtattagggt gggagtgacc 11520caattttcca ggtgccgtct gtcacccctt tctctgacta ggaaagggaa ttccctgacc 11580ccttgtgctt cccgggtgag gcaatgcctc gccctgcttt ggcttgcgca cggtgcgctt 11640cacccactgt cctgcaccta ctgtctggca ctccccagtg agatgaaccc ggtacctcag 11700ttggaaatgc agaaatcacc agtcttctgt gttgctcatg ctgggagctg tagaccagag 11760ctgttcctat ttggccatct tggctcctcc cctcagcaca gtttttagca tgaactaagg 11820cctcaataaa tattagttcc cttctccaat tcagaaagtt gtctgccttg ataagacaat 11880tgtttttatt gtgaaagtga ggtggagatg ggggattgtc tctcctataa aaggtctaag 11940aagttagcaa atgctgtttt tcctttttgc tcctcagttg cataagtaca tggtagaaat 12000tgggtcactt tgcctaaacc ggttttctat aacctattaa gtattaaaag cttgacacag 12060ataagtagag gctgataaga ttctgtcctg caccccactc ctatcaaatt tggaagaact 12120gacctcttcc gggaagaatt gcaatgctaa atccaaatgc ctatggttct atcttataaa 12180caaatggtgt cctcaaaatt catttatgta aatcatttga aatttaagaa aaaaatatgt 12240tcagagaaaa atatgttaaa tgtcaaggtg aattagaaag tgtggcattt agtcaagcat 12300aaattaatat tccaactttc tagttacttt gtagtaactt atttaacatt ttggtgaaat 12360gaggaacaaa gtgtccacct ttttttcctg aatattttat ctgaagatct aggagagaga 12420tgtgaaatag tatttttctg gggaagtagg ggaaatacaa agaaaagtaa tgacttcagg 12480tatattctcc actggtacag caggatggga gatattatca acaggtggta agtataaaaa 12540tattgaagag gtacaatttg gatcagcatt acaaccaaga atggagaatg acattcagga 12600ttgaaagaaa catacaagag ggcagaaagc tttcttcttg ggactgtggt ttcatgtgtc 12660tgcaggtgct atgggtatat tgagaatggt tctaaaaaca ggggcttggt ttaggttgtg 12720aagaccatca aatagaaact gtgaatttta ttttgtgtcg ttaaagggat ctttgaaaga 12780ttcttaggat aaatatgata tgcataggat agaaagaaag gtgggagaca ggacaaacag 12840aagttaatca attgaaataa accaggtttg gagtggtggg acaatagcct tcaagacatc 12900aagaatattt gttagtagaa agaaaatcga agcctaaaac taaaggaaga ctatccacct 12960tgcaagtcat acagagatat ttgctattat ataatttttt taaaaaaaga tttcctaata 13020tttaaattat gaagaaagag atagaaacag atattcatgg aaaaaatggg gtgaaattaa 13080tcaaagggca gcttattacc ttgagactaa acagccattg acttttttct tacctcactg 13140aacccagaaa cccgacatat ctaggtacag gcatgcataa aacatgtaca cacacaaaat 13200gtaataattg gagttcactt agaggtacac atgtatgggt ttctgtattc aaccatatgt 13260tgatatatac tcacatatat gtaagtgata atatcctgtt tgttacttcc acatttatgc 13320actatccctt aaatatgtat tatatatatt tatattattc agaatccatc agcccttgtt 13380gaataaatta gtgaataaaa tatagagtcg agtctcatta ttcacagatt ctatataaga 13440aaatttgtct attcactaaa attcctttgt aacaccaaaa tcaatactgc tggactttca 13500tgggcattca catgcatgtg caaagtggtg aaaaatttga gctgccatgt tcccaactaa 13560ggttgaacaa aatgaagctc tgtcttcttg tttctgctca catatgataa agaaatatcc 13620ttttcacact gtatttattg ccacattttt ggcatttttg tgttttgtgt ttctgagttg 13680aatgtttcga atgggcccca aagatagtgc tgaagtgctc tccggtgcac aagagtatct 13740gagggaaaag atacatatgc tgtataagct tcctccaggc ctgaactaca gtgttgttga 13800caactaattc aatgttaatg aatcaatagt atgtattaaa taaagtgtct ttaaacaaaa 13860catacataaa acacagttct atattgaaca atttaccaaa atattgtgac cagaggcaga 13920caggcatata actaacccca catctctcca aggaacaatg gttcaatatt tgctaattca 13980gtgttcccag caactttata aaacataact actgcaacaa gtatcaactg tacatataat 14040atatattaga catattgtat aattactgcc ctattaaaaa tcatgtatct atgctgtgtc 14100tgcttatata gatatcttag atacataaat atgtattgtt tacatacata ggagcaagaa 14160tgtatttcta aaactccatg aagaacacat tatattctat ataaaagagt cagttgaagt 14220aaaaagttaa ctcattttac tagtctttaa agtaggactt taatgactct caaaataaca 14280atttctctca tacattgact ccaaaacttt agttgttgaa tttattctgc agatatggcc 14340acataaaacc aaaatggcat atgatatatt aagaacatct ttaatatgaa atgattagat 14400acaacctaaa agctgatgaa tatagaacca gttgcatata ttatggacaa cttaataccc 14460tgctaccata agaaaaatga gaaagactta ttaagattaa gtatatagag aagataaaaa 14520ggtagagaat gatgtttaag gtatgctacc atttgcattg aaaaggaaaa tattatgtac 14580ttaatgaaaa atccatatta tatttctgga taatgggaca agagttagag gaagaatctt 14640tgttttattt ttttaatttg cattttcaac tatatgcatt ttctcttgga aaagaaatga 14700acaaaatcaa aataaagtaa catcatgatg gtggtaaggt caagcaatac cagagttgct 14760ctgagaagta cttggagtac actttgctct ttttaacaaa tccaaattct gtttgctttt 14820tgagcctgat tccagtggtg tctcctttat aaaactgagg ccattctaat ttaattcttt 14880atattatttt tgtatctgtt ttgaatatct actctgtgca aggggctaat aggcacattt 14940taaaactaga aggataaaga aaacatatat ttgcttttat aaattttaca atataggtgt 15000gtagaaaaga taataattta aatttctata atttaaaatg ttcatgtaat ctggtgtgtg 15060attctatatt acttacttgt ttcaaatttc tctccacaaa tttatttttc tattaaattg 15120taatctcctt aggctagaat ttgtgtctgt ctttcctact tttgtttcca gcattgacct 15180agcagagtgg taacgacata gtagaccctg agtgaatgtt agtgaatggt tgattgattg 15240atgatgatct tgtggctttt cttatttcta aattatatat tgtaaaaata aaataaacta 15300tactttttct tccttaatag gtgattgttt caaactgagc atcaacaaca aaaacatttg 15360tatgatatct atatttcaat catggaccaa aatcaacatt tgaataaaac agcagaggca 15420caaccttcag agaataagaa aacaagatac tgcaatggat tgaaggtaga ataagtttta 15480tgtttttgag ctaaaataag taaataggga actttaatgt atagaaaagc aagttgttaa 15540aaagaacatt atgtttcaaa ttataatttt caattgaagc atatattgaa atattaacat 15600aatgattcat accttgattt aaaccagtct tttaatctga ttaagtattt ctttggcgaa 15660atttttgatg cttaatagtt tatcaatgta gaaaatttag aaatattttg atagcttctc 15720tttggttttg gattgatcac gacatattta ggaatgtgat taaaataaaa aatgcataat 15780gaataatatt ttaaaattct tagaattgac ttataaactt agaatattaa tgtcttgaga 15840ctcactttgt gatactgact tatttaaaaa ttcttttaaa aaaaaaaaca aaaaacagga 15900tttaaaaaag ttctgataag taatttaggc tcatggaacg gaggtctatg atagtcaaaa 15960acttggccaa aagacctgtt tgacgattta gaaaagccat ttaatgtttt catttgccag 16020ctggtaaaag taataattct gctttttgct tttggcacaa actgtattaa atgatacagt 16080tgaggtatta agtgatgctg gcatttttat aaacaggaat gagtactcct aagcacaatg 16140ctaaatgaga agccaagact cagaaaagtt aagaaatttt cctgaagtca tctacattgt 16200gaattgaaaa ccctggaacc caagacaaag cctttaaatc cccatatgga agtcttgagg 16260aaatcaagaa ataagggtca ccttttatca atgttttaac ttttttattt agtcaaattt 16320gtagtcttat acagctgaat aaaggccacc aagattggag tcaattacaa taatgttata 16380aaaggttcct tttagctcct tccagggaac ataaaatttg tttgttttct gagattactg 16440ataaagcctt ctctgatgaa atatttgagt aacatttagg ccaagtggca gtcataagga 16500aaaagtattg gttaatgcaa gtgaattatg ttctatattc taaggataat ataatgtact 16560gaattgtttt tatttttaaa tactgagtgt tacagtaatt tcactgacat gtgcatagca 16620aaatggcagc aaactgcctg aagcaataaa atttccagag tgatccctta tagcatatct 16680ggagaagctg ggagttaggg aattagcagt gtgtggaaag gacattaact gcagcccaat 16740aaagaagact agagctagag gaagatactg ggataagact ggcatcccta atgctggtat 16800ttcagaaaca tcgctaaatt ggttaatcat gtctacaagt gatatttaaa ataatatttt 16860cactcactta aattgttaac attgatatgt tgttgataaa gaatattaaa ctcaacaatc 16920attttacaat aattctgtaa agacttgcgt gcctgtagtt gaggtttgtt gcatttctga 16980gcttactttt tattcatgag aaatgaaaac ataatgggag aaaatttttt aaataaaggg 17040tattttaatt ttttatgaag tttgggactt caaagtatta acaaaagttg ctgaaaatat 17100attgactttt actttcatta aattacattt tatcatctaa tttcttaatt ttctgtattt 17160gaaatattat gatttagaga tatctctgta gatagaaaga taatgaaaac aatagtaaaa 17220caaatgtaat tcaggagcat aaaaaaagat gagagaaacc ttaataatag tagctaacat 17280ttatcaagca tttactatat gccagacatt gatttagtgt tttacttttg ctaacagatt 17340ttttccttac cataattcta tcaactggat ggtattatct ccccttttca gatgaaaaaa 17400cctagatata gacagggcaa atgtcttctc ctaggtctca aagttggtaa ttggtacact 17460gaaggtctga actcaggcaa tctgattcca aatcctatgc tctcaactgt attccatatt 17520gctaaaataa atgtggattt ttgtaatatt agtaccctca agatgttatg gcaagcaggc 17580ttttataagt ggtgtcttta ataactttcc tcattccata cttctaaaaa attatcttaa 17640ggttaaatta ttgagtgtca agcaactgtg gattctaaca cttgctaaca tgcatgcaca 17700cacccaaata tacatgttgt tactgactta catatacaga cacagcaggt ggcaatatat 17760aagtgcaaat tgataatata tccgtggaaa tacaaacaaa actttgagaa atcaaatact 17820tgaattcttt tctacccctt ctcctcaatt tttgtactga actaactaca ttacatagaa 17880cctgctagta tatgtttcat cattacactt gtcatttctt ctcttcaaat ttaaacccaa 17940caagatacag gggaagattt aaatgcaatc caaagaaaac aggaaaacaa ttcaagagtt 18000taaagatgac atagtcattt taagaaagaa ccaaaattaa cttctgaaat taaatatttt 18060actacaggaa tttcataata caattatagt aattaacaac aaaatagacc aagcttaaga 18120aagaatctca gagtttgaag attacccctt tgaatcaaca caagcagaca aaattaaagg 18180aaaaatatta atgaaaaaaa cctctgagaa atatgggatt atgtaaagag accaagcctg 18240tgactcattg gcattcctga aagaggagaa agagtaagca acttggaaaa tgtctttgag 18300gataaagtcc atgaaaaatt tcccagtctt gctagagagg tggatatgca agttcaaaaa 18360attcaaagaa tcccttcaag atactataca agatggtcat ccacaagaca cataatcatc 18420agattctcca aggtaaacaa gaaagaaaaa aaccttaaag gcagctagag agaaggggca 18480ggtcacttac aaaaggagcc ccatcagtct aacaatagat ctttcagcag aaagcttaca 18540agctagaaga gattggggac ctattttcac catccttaaa gaaaagaaat tgcaactaag 18600aattttatat tctgccaaac taagcttcat aagtaaagaa aaaatattat tttcggtcaa 18660gcaaatgcta acagaatttg ttaccattag acctgcctta ccagagatgc ttaagggagt 18720cctaaacatg gaaatgaaag aatgatacct gtcaccacaa aaatagactt aactacagag 18780cccacagaca ttataaagca attatgcaat caagccaaca taataaccag ctaacaacac 18840tatgacagaa tcaaatcctc acatatcagt attaatcttg aatgtaaatg ggttaaatgc 18900ctacacttaa aaggcataga atagcaagtt ggataaagaa gcaagaccca accgttttgt 18960tgtcttcatg actcatgtat catgacatcc ataagataga aaatgaataa attgaaataa 19020tatttatctc agagttgtca ggatatttat aaggtgctta gcacagtgtt acatagaaac 19080tcaataaatt ggaaagttcc aacatagtag cattatagtt gctgcacttt ttttgagaca 19140gggcctctgt cacccaggct ggagtgcagt ggcataatct tggctcactg caaactccac 19200ctcccaggct caagtgattc tcccacctcc tgagtagctg gaactacagg cacatgccac 19260ttcacccagc atttttttca tttttttttt tttttttttt ttttttagta gagatgaggt 19320cttaccttgt tgccaggctg gtcttaaatt cctaggctca agcaatcagc ccgccttggc 19380ctcctaaagt gctggaatta caggtatgag ccatcacatc tggaagctgt ttctttttaa 19440agtgactaca ttaatttact tgatcacgag taatacataa atgaaaattt gagaatacat 19500tcactccaat atttggaatt atgtgacttc tagatttttg caatttaagt aggcataaaa 19560tggtactttg ttttagtatt tgtctgtgct ccttgattct tataaatatt atattttgtg 19620aaatccattg ctgaatgcaa gtggtgctgg ttacatttgc ctatttccaa gttttagtac 19680atttattttt gaaatatatt ttatcagttt aaggacttac ttgtaatatc tttgtgtggt 19740cttggtatta ggttaatgtt ggcctcaata aatgagatag gaagtatttt tttctgcttc 19800taacctctga aaaaaactgt agagaattga tataaattaa ttcttaggta tttggtagaa 19860ttcaacagtg aaaccatgta ggcctgtttc tttctgtttt ggaaagttat taaaatcagt 19920tcaatttctt aaacagaaat agtcctttta atattgtcta tttattcttg tacaaaattg 19980ggtagatcgt gtctttcaat atattggtct attttatata ggttatcata gttgtaggca 20040gagtgttgct tatagtattt ctttattatc cttttcatgt atattggatc tgtagttatg 20100tccccgcctt tatttctgtt attagtaatt tgtgccttcc ctcatcttct taggtaacct 20160ggctgggtca attttattaa tctttctaaa gaattaactt gtggttttgt caatttcctc 20220tattgatttc ctgtttatga tttaattgat ttcaggtcca atttttattc tattttttct

20280tgtgcttact taaaatttaa tttgcttttc tttttgattt tcccaaggtg gaaacttaga 20340tattgatttt agcattttct tgttttctaa catatgcatt cagtgcaata aatctctaag 20400tcttgatttt gctacctttc acaaattttg atcacttgta tgtttaattt tatttttttc 20460aagatgtttt aaaatttttc ttcagatttc ttttgactca taagttactt aaaagtgtgg 20520tagttaatct ccacatattt tggtattttt ccagttatct ttctgttata ttctagctta 20580atttcattgt catctaagag aagacattat tagtttaaat gtgttaaggt gtgttttatg 20640gcttaggctg tggtatatat tggtgaatat tccatgtaag cttaagaaga atgtgtattc 20700tgttgttgtt ggatgaaata acatatagat gtttattata tccagttaat tgatgatgtt 20760gttaaggtca atcatgttct tcctgttttt acctgctgga tctttccatt tctagagaga 20820tgtagagtct ccaaatacca tagtgtattc atttatttct ccttgtattt ctactggctt 20880ttacttcaga tagtttgcag ctctgttgtt tggtgcctct atgttaagaa gtgttatgtt 20940ttcttaagaa ttgacccctt taacattttg taatgccccg tttttacctc tgttaatttc 21000cttgctttag agtctgctgt gtccaaaatt aatttagatt gtcttgcttt gttttggtta 21060ttgttaccat ggaatgtttt tctccacttc tttacttttt taaaaaatta cactttaagt 21120tctgggatac atgtgcagaa tgtgcacatt tgttacatag gtaaacacat gccatggtgg 21180tttgctgcac ccatcaaccc gtcatctaca ttaggaattt ctcctaatgc tactccctag 21240ccccccaacc cccaacaggt gctggtgtgt aatgttcccc tccctgtgtc catgtgttct 21300cattgttcaa ctcccactta tgagtgggaa catgcagtgt ttggatttct gctcctatgt 21360tagtttactg agaatgatgg tttccagctt catccatgtc cctgcaaagg acataaactc 21420attctttctt ttggctgcat agtattccat ggtgtatatg tgccacattt tatttatcca 21480ttcaattatt gatgggcatt tgggttggtt ccaagtcttt gctattgtga atagtgctgc 21540aataaacata catgtgcatg tgtctttata gtagaatgat ttataatcct atggatacat 21600tcaacaatgg ttgaattaat ttacactccc accaacaggg taaaagcatt cctatttctc 21660cacatcctct ccagcatctg ttgtttcctg actttttaat gatcgcttcc aactggcgtg 21720agatagtatc tcattgcagt tttgatttgc attctctaat gaccagtgat gatgagcttt 21780tttaatatgt ttgttggcca cataaatgtc ttattttgag aagtgtctgt tcatatcctt 21840ggcccacttt ttgatggcat tgtttgtttc tttcttgtaa atttgtttaa gttccttgta 21900gattctggat attagctctt tgtcagatgg atagattgta aaaattttct cccattctgt 21960aggttgcctg ttcactctga tgatagtttc ttttgctatg caggagcttt ttagtttaat 22020tagatcccat ttgtcaatct gggtttttgt tgccattgct ttttgtgttt tagtcatgaa 22080gtatttgtcc atgcctatgt cctgaatggt attgcctagg ttttgttcta gggtttttat 22140ggtgttaggt cttacattta agtctttaat ccatcttgag ttaatttttg aataaggtgt 22200aagaaagggg tccagtttca attttctgca tatggctagc cagttttccc aacatcatat 22260atattaagaa gggaatcctt tttccattgc tttttttggt cagacttgtc aaagatcgga 22320tggttgtaga tatgtggcat tatttctgag gtctctgttc tgttccattg gtctatatat 22380ctgttttggt aaaagtacca tgctgtgttg gttactggag gcttgtagta tcatttaaag 22440tcaggaagca tgatgcctcc agctttgttc tttttgctta ggattgtctt ggctatatgg 22500gctttttttt tttttttttt ttggttccat atgaaattta aagtagtttt ttccaattct 22560gtgatgaaag tcaatggtag cttgatgggg atagcattga atctataaat tactttgggc 22620agtatggcca tttttacaat attgattctt cctatccatg agcatagaat gtttttccat 22680ttatttgtgt cctctcttat ttcattgagc agtggtttgt agttctcgtt gaagaggtcc 22740ctcacacccc ttgtaagttg tattcctagg tattttattc tcattgtagc aattgtgaat 22800ggaagttcac tcatgatttg gctctctgtt tgtctattat tggtgtatag gaatgcttgt 22860gatttttaca cattgatttt gtatcctgag actttgctga agttgcttat cagcttaagg 22920agattttggg ctgagacaat ggggttttct aaatatacaa tcatatcatc tgcaaacaaa 22980gacaatttga cttcctctct tcttatttga gtatctttta tttatttctc ttgcctgatt 23040gccctggcca gaacttccaa tactatgttg aataggagtg gtgagagagg gcatccttgt 23100cttgtgccgg ttttcaaagg gaatgcttcc agctttcacc cattcagtat gatattggct 23160gtgggtttgt tatagatagc tcttattatt ttgagatata ttccatcaat acctagttta 23220ttgagagatt ttagcacagc tccagtgtgc agctcccaaa aagatcaacg cagaaggtgg 23280gtgatttctg catttccaac tgaggtaccc agctcatctc tttgagactg gttagacagt 23340gggtgcagcc aacagggggc aagccgaagc agggtagggt gtcacctaac ctgggaagtg 23400caagttgtca ggaaacttcc tcccctagcc aagggaagcc acgagggact gtgccctgag 23460gaaaagtgca ttctggtcca gatactatgc ttttcccagt ctttgccact ggcagaccag 23520gagattccct cgggtgccta caccaccagg gccctgggtt gcaagcacaa aactgggtgg 23580ctgtttgggc agacactgag atagctgcag gattttcttt ttaaacccca gtggtgcctg 23640ggacaccagc aagacagaac ccttcactcc cctggaaaag gggctgaagc tagggaacca 23700agtggtctag ctcagtggat cccaccccca tagagcccag caagctgaga tccactggct 23760tgaaattctc cttgccagcc gagcagtctg aagtcaaccc gggatgctcg agcttggtag 23820ggggaggggt gtctgccatt actgaggctt gagtaggtgc ttttccctca caatgcaaac 23880aaagccacta ggaactgggt ggagcccacc gcagctccac aaagcccctg tagccagact 23940gcctctctag attcctcctc tctgggcagg gcatctctta aagaaaggca gcagccccag 24000tcacgggctt atatataaaa ttccctctat ctgggacaga gcacctggga gaaggggcag 24060ctgtgggcgc agcttcagca gacttaaact atcctgcctg ctggctctga agagggcagt 24120ggatctccta gcaccattct caagctctgc taagggacag actgcctcct taagtgggtc 24180cctgactccc gtgcctcctg actgggagac acctcacagc agggttcaac agacacctca 24240tgcaggagag ttctggctgg catctggtgg gtgcccctct ggaatgaagc ttccagagga 24300aggaacaggc cgcaatctct gctgttctgc agccactgct ggtgatacct aggcaaacag 24360ggtctggagt ggacctccag caaactccag cagacctgca gctgaggggc ctgactgtta 24420gaagaaaaac ctacaaacag aaaggaatag catcaacatc aacaaaaagg atgtccacac 24480aaaaacccca tctgaaaggc accaacatca aagaccaaag gtagataaat ccacgaagat 24540gaggaaaaac aagtgcaaaa aggctgaaaa ttccaaaacc cagaatgcct catctcctcc 24600aaaggatcat gtttactttt aatctatatg tgtttatata tttaaagtgg gtttcatgta 24660gacaacatat agttggttct tgttacttga tctactgtgt caatttcaat cttttaatta 24720atacatttag atcatttgcg ttaaaagtga ttactgatat atagtcatgt gtcatttaac 24780aacaggaatg cattatgaga aatgcattgt tagataattt tgtcattgtg caaacatctt 24840agcgtgtaca tacataaacc tagatattat agcctactac acacctaagc ttatggtata 24900ggctattact ttgatgctac caaaacctgt acattattgt agtttactaa atactaatta 24960caacacagtg atattggtgt atctaaacat atctgagcac agaaaagata aagtaaaaat 25020atggtattat aatcttatgg gaccatcatt gtatatgctc tccaacattg acttaaatgt 25080cattatgaca tgtgtgactg tagttagatt agtatctacc atagcggttg ggttgcctgg 25140gtgtttgcaa gataaattta caaataattc aagtccactt tcacgtgacg tcataccact 25200tcatgggtag tatgagtacc tgataatagc aaattattta taatactttc cttccatttc 25260ttgtatcatt attgtcattc atttcaattt tgtgtcagca tacataatca aatacattat 25320agatattatt ttaaaaacag ttatgtctta gattaagaat aagaaaagta ataatttata 25380ttttatgctc acttatttct cctccaatgt tttccttgct ttaagtagat ctgagtttct 25440gatttatatt attttatctt tctgtaaaga actcctttta acaccttgca aggctgatct 25500aaaggcaaaa catttctttc agtttcattt ctcagaggaa gttttatttc tccttcatgt 25560tagatggata aatacacagg gtatggggaa ggtatttttt cctctgtatt cttttgggat 25620ttttttcctt tgtctgtgat tttctatagt tttaaaatga catgactagg tgtaactttt 25680tgggcattta tacaacttgt tattctatgg acttccagga tctgtggttt gttgtctgat 25740actaatttgg ggaaattctc ggttgttatt gtttcaaata tttctttagt ctctatttct 25800ccttctagtg attccattat gtatatgcta tacctttttt agttggccca cagttttttg 25860atactttgtt ctgatttttt tgtctttgtt atttttattt gctttttagt tttgcagatt 25920ttaattcata tatcctgaat ctcagatatc ctgttttcag tcttgtgcag tatactgatg 25980tgtttaccaa aggcattctt catttctgct acgatgttgt gacattataa tttttttaat 26040gaaattttta tctgtctgct tacattgctc tgttcttgtg tgcttcttta ttttaccact 26100agaacactta gcatattaat cacagttgtt ttaaattctc agtccaataa atccaacatc 26160ctttctgtat ctgagtttgg ttctgattct tgctctgtct cttcaaaatt atatatattt 26220tttttctttt agatgactgg taatatattc tggatatcca gacataatgt attgagtttt 26280gtaaaacctg ctatacatag gccttcaata attgttgcta aggtgtggga gaggagaggc 26340tttttttttt ttttttttgc ctctggactg taaccttcac aagtgttttt ttagtatttt 26400ttttccttct tggtcagaat gggtttggta gagtgagatg gattttggta ttttccttct 26460gtcacatgga agactagaat tggctggagc tgggtatttc ctttcccttc ggtcagttag 26520gctctaataa cacaccatct tatgaggctc tgataaacta gttctgccta agggcaagca 26580ctaaaagtcc tattaaaaac agagggctct agtctatttc aaaaatgagt cttgtctcct 26640catgctactg aaagaacaag ataatttttc tccaacattt actataagaa cctggtcaag 26700ctcctggagg gaaaactcaa aatgtggagg tcaccgactg ggttcccttg gagtgtttag 26760tgctcagact taaccacact gagtgagact ctagcagttt atcaattata gtgaaggtat 26820ttctaccttg tcactggttc ctgtgcagtt tctgttcatg agtctctact gctataagct 26880gtgacacttt gtaatcacct atttgtctct ccaatcttga aggcagtcga ttgccattgg 26940tcctcacctc ttttacagat ccagaaagag ttgctgcatt ttaaattggt tcagtgtttt 27000tcttgttgtt actataaaat ggcaagctcc aagctccttg aaggtttcca gagcctagaa 27060accagaaata ccagcatata ttttttattg tattttctta tctcatgtct tacagttcta 27120cattttactt aagaattcat tgtgattgct tgattaatat acaagttatt ttaaaataac 27180attttcttca aatatttgga gatttttcgt aataaatttt ttgccagtaa tatttgtcat 27240aattgcattg tggaagctat gacaactaat ttttgaaatt agttgagact tctctatgtc 27300ctagtacatc attgatgttt gtaagtctcc ctgatgtact taataaaaat gcatattcca 27360tattctttca attgttggat gtataatttt atatgtgtct gagaggtcag tcttgttaat 27420tgtgttattc agatcttcta tgtccttgct aatattttaa ctatttcact tatcataatt 27480gaaagaaaga tgttgaattt ttttcttaca aaagcagttg tattgatttt tgcttatata 27540ttttgcatct actaagtgca ttattatata accgttttat cttttaggat gatataattc 27600aatatatgga ggacttctct atccttaatg atgtttctat gtctatttgg gctattattt 27660atacacctat aaaattttct ctaagtggtt atattttctt atcattttac tatcacgaag 27720aatttcttcg tgatttagga atatctctta taaaaagcac agaggtaaat tttgaagaaa 27780aatccaaact aaaaattatc tatctttaaa ctagcaattt tctacactta tgtttattgt 27840atctattgat atagttagac ttgcttttac tatcttacat tattatggtg attttcccct 27900tttttaatgc tcccttaaaa ttctttctta tactttttga atgtatatgc ctatctctct 27960cataacaaga caaacattct agcatgattc tatgatctga atgtttgttt ccccccaaat 28020ttgtatgtcg agtcataatc accaaggtga ttctattaga aggtggagac tttggaaagt 28080gattagttca tgaaggtaga gtcctcatga acaaaattag tgtccttatg aaagagaccc 28140aatagagctt ccttgcctct tctaacatgt gaggttacag tgagaagatg gttctcacca 28200aataccaaat atgttggtgt cttgatctca gacttcccag gctccagagc tgcaaaaagt 28260aaatttctat tgtttataaa gtacacagtt ttcttatatg ctatattttg ctatattttc 28320ttacagcacc ccaaacagac tgagacatat gttcacatac tcttttatat gcctctttac 28380cctctataca atatgatgct atctggattt tcaatctaaa attttaaatt ctagacacta 28440tgactatttt acctcctttc ctgtttttag ttttttttta agacattgag aaaatttatc 28500aagtatttta ttcactttgc tttacaaatc tcatgcaaca ccttcagaat tggattcttc 28560ttttatttaa gcaattcttc caaaattgtt tccagtacgt gtttggttgc agtatttttg 28620aggccttata tgcttgagca tatatctctt tatagctgag aggctgttta tctcaatgta 28680aaattatggg ttcaatgctc ttttacttca gtacttaaaa aatatatttc tttgtctttt 28740gtgtacccac ttttgctgtt agaaagtgat atactttctt tcctgaaagg cctcaatttt 28800ttttcttgtc tttgatattc ataaatttta atatacttct tccaaatatg tctgtgttct 28860tacttatctc ttgtgttgag cattcaatgg gcactctcaa cctgcatttt ttgttttttt 28920taatcttagt aaattatttg aaaattttca tttattattt ctttaaatat ttctcctctt 28980caacttattt tttctcattt taaggcatta ataattaaat tattctcaat tttagttaaa 29040aattatgtat atcttaacct tttacctata tatgctttca atgttttaaa tgaaataacc 29100aattttattt tccaattctt tcttgtttta agcccatata ttattttata ctattttaca 29160tcttgtactc catattttct acttgttctt ttttgttatc ttattttgct tttatttcat 29220tttgctaata ttcttttctt atatattttg tgtatttgta atgcttaaac tcctgttaag 29280tgttttgtaa aacaattact ccttatggtg tcttcaaacc agtttacttt tttctttctc 29340ttttgaaatg ttttctcaaa gacatcacta ttttgccctg aagtcacatt tacttagtta 29400tgatagtttc ttttttatag taattgcaca ggggaagagc taaaggatag aactctgtca 29460ttgtgaaccc tgaaagctca gaaaaagggg agggaaatga gcctcaaggt gatgaccagt 29520aaccaataaa tcacgtcact ctgccctttg acaaacattt ctttatccat ggctccctca 29580gtcccctgaa tgcgaaattg ctttgaggag attgttaact agtactgcag aaatactgag 29640gggattacct gtagaaggga atgctcaagg ctagtcagcc tttcctcctt tgctcagctg 29700ctctgattca gagctactct gattttactc tggaggacac atgcaaccaa tgtctgaaca 29760gtcatactca atccctgcat tgaggtagaa agcactgatt cctagaggct gatctgaatc 29820atgcaactgt attgaaggca acaaaaaata ataaaatagc catgtatttt aatagggaaa 29880gtatatagta attgaaaaga aaaaccaaaa tcaatacaag tagtattgtg accgagagac 29940aaaggtaaat ttgaagatag gtttgtgatt tcataatgga gacctttgaa tgctagaagc 30000taccccctcc ctttgtaaag aacaacatta ggtaaatgat taaaaaatta tgtcaaagtc 30060tatgattttg aaactctacc atatttgaaa atattatatt aaaataatga tactaaacaa 30120agaatttatg acaaatgttc atcttttaag taaaagaacc ttaaaatttg taagcagcta 30180aatctaatga tataggcaac tgctaggata tcacaaaaga atgggatttt aatagtgaac 30240ttatacaatt tgcctgaaat taatcaaatc agcacagaaa tgcacagatg acaaacactg 30300taagatgtaa gaggaattaa tcataagagg tttatttggc taaagtgaca attgttaaag 30360atagaattgc ctaacgttag ttaataacag aaaaaatatc agaaatttta aaaaatgctg 30420tcttaatcta ttaaaattat ataaagataa agcaaaacaa tgtaggttta taaacaagaa 30480cctttaaaaa agcataatac tgatgcttat tacaaattta tatcttgagc tggggtacat 30540catccaattt acgcatgaga aaagtgtttt ataatttttc actctgtaat tcatatttta 30600agttcatctg aaatgtattt tacagaggta agaacaagca acttggtgct caactctctt 30660cctgctcttc gcctagtgct aaaataattt gtgtaaatga actgtgaatg aatttaagtt 30720tcagaaataa aatttatatt aatagagaga aagaaggata aatcaatagt cttccaaata 30780tgatacatgt acaatgcaat gatattcaca aacatcttca tgaacacacg aacataattt 30840cttttgaatc ttaccatgac cttctaaaat aagtaagcta aatattctat attatactac 30900tatttatgag gaaactacat ttctgtgaat tgtgtaactt tttcatcttt ataaggttag 30960caagcaaaaa caaacaaata acaaaataaa caaaaaaaca aaaacttggc ccagatctga 31020ctttaaagta ccttcacttt tattgtatca catacgatct cagtccacag atgggttcct 31080gatttagcca agaatatagt aaagtgagtg taaagtagaa gaaaaaagaa ggaaaatatt 31140aggtatagaa acctacatga aataaaatga aataaagaga gcctactctt tctgaaatgc 31200accagtaaaa tgtactccta tcttgtgtat taagtttata atcatacatt caattcaaaa 31260tttaactaaa actatggaaa ctgagagcta ataataaaat gatatacaca gcattctaac 31320cagaaaatct tctaagcaat tgtacaattc agataagaag aaataattac aaatgttcag 31380aaattaagat taattaagac tgtaaaattt tttttttttt ttttttgaga cagggtctca 31440ctctgtcacc caggctggag tgcagtggcg cgatcttggc tcactgcaag ctctgcctcc 31500caggttcacg ccattctcct gcctcagcct cccaagtagc tgggactaca ggcgcccacc 31560accacgccca ctaatttttt gtatttttag tagagacggg gtttcatcat gttagccagg 31620atggtctcga tctcctgacc tcgtgatctg cccacctcgg cctcccacag tgctgggatt 31680acaggcgtga gccaccgtgc ccggccaaga ctgtataatt tgttcctgaa gggcagggaa 31740aatgtagtgg taatttttca agatgaattg gaagataaag aaagagaggt cacattattt 31800gtgttattca actgaaatag ttttgaattt caataaaaca agctaagaaa tgccctttgt 31860catcaaattg atgtgaagag taaaaaaatt ttaaaaatga aattctctaa gataatatgt 31920gaaaataaga ctatttaaat ttcaacaaac atttaacaag tgtataccca tcctatgttc 31980gttttatcca acttcttatc attcctaagt atattaagta aagtaatagc tattaatatg 32040ttgacgtcat tagcagaaaa ataactttgc aaatgattaa gtgatgacag ttgtatatcc 32100atgttattag atgtttaaaa ttcaaaaaat aattaattca ataaattttt gaaacaaatc 32160catagaataa aaacatagtt tttcaaaatg tatttttcaa aggtaaaaat ttctcacatt 32220aggctaggtg cgtggctcat gcctgtaatc ccagcacttt gggaggccaa ggcgggcaga 32280tcacgagctc aggagttcaa gatgagcctg gccaacatag tgaaacccca tctctactaa 32340aaatacaaaa attagccagg tgtggtggtg cctgccttta gtcccagcta ctcaggaggc 32400tgaggtgaga gaatcgcttg aacccaggag gcagaggttg cagtgagcca agaccacgcc 32460attgcactcc agccttgggg gaagagtaag agtctgtctc aagaaaaaaa aaattctcac 32520attattgtaa atactattac aatagctaac ataaattcaa gatttataat tatttttttc 32580tgatgctcat acaaatacac attttactgg atcttgggtg ttgtagtaaa aaacaattta 32640ctaaaacaaa aaaaaagaat gtatacctta aatacataga attttatttg tcaatcatac 32700cttaatatga gaaaataatg ttcttctttt ccaaagtaaa aagaaattaa tagagcaaag 32760ctatatttta caacaatgta catataatcc ataattctgt ctaatacttg atattctact 32820aactgaattg aagcagtact tgccaacatt tacatatata tgaataattg aattataaaa 32880gttatgagat gctgatctga attacaaaag tccctctgtg atagtaaaca catgcataaa 32940ttaattctat aaagtgttat tgcattttct caaaatacat tgaagttctg tagtcaaagt 33000aatcaataga gagccaaaac tgtttttgaa cagtttagca tattttcatt attaaaaaca 33060aaacttgcca atagatataa gaaaaagagc tgaccaaatt agagtttaaa tagcataaaa 33120taataatttt gaaattctaa aattgtattt tagaaaatca tgacacgtag aaaaattatt 33180ttaatacagg tctcatttga attagataaa cttatattct atacctgaat aaaaagtaat 33240tgaaaatacc tatgactttg cagcaataaa aaatggcaaa tgataaaaaa ttcaaatttt 33300tcttacataa atatttgtga aaaggggaaa ctgaagagag aaaatatgat agtttattta 33360aagtgaaaca tttacatagt ttgatgtaga taaaagtaaa ttgagaaaat tcctatttgg 33420cattatttgc tgtgagttta ccaagataat gtttttctcc attttaaaaa caatggtcta 33480tggtcaaaaa gtaagtcaaa ctatccctgt ttgcaggtga catgattcta tatctagaaa 33540accccaaaag ctccttcagc tgataaacaa cttcagcaaa gttacaggac acaaaatcaa 33600tgtacaaaaa tcagtagcat tcctatacac caacaacagc caaaccgaga gccaaatcag 33660gaaggcaatc ccattcacaa ttgacacaaa aagaataaaa tactttgaaa tatagctaac 33720tagggaggtg aaaaatctct acaatgagac ttatgaaaca ctgctcaaag aaattagaga 33780tgaaacaaac aaagagaaaa acatgcttat agataggaag aatcaatata attaaaatgg 33840tcatactgcc caaagcaatt tataggttca gtgctattcc tattaaacta ccagcaatat 33900tcttcacaga actaaaaaaa aaaaaaaaaa aaactatttt gaaattcata cagaaccaaa 33960atggccaaat agcgaagaca atctaagcaa aaagaataaa gctagagaca tcatgccgtc 34020tgatttcaaa ctatactaca ggactatagt aaccaaaaca gcatggtact agtagaaaaa 34080cagacacata aaccaatgga acaaaataga gagcccagaa attaggccgc atgcctatga 34140acatttgatc ttcaacaaag ctcacaaaaa caagcaatgg ggaaaaaaaa ccctgttcaa 34200taagtgattc tgggataact agctggtcat acacagaaaa ttgaaattgg accccttcct 34260tacaccatac ataaaaattc taaaaattca aattataaaa aaggaaaaaa aaaatcaact 34320ccaggcagac taaagactta aatctaaaac ctcaaactac aaaaaccctg gaagacaacc 34380taggcaatat catcctggac ataggaatgg caaagatttc atgacaaatg acaccgaaag 34440caatcaaaac aaaagcaaat attgacaaat gagatataat taaacttaag agcttctgca 34500cagaaaaaga aactgtcaac agcataaaca gacatcctac agaatgggag aaaatattta 34560caaatatgca tctaacaaag gtctaatatc cagcatctat aagaaactta aatttacaag 34620agaaaaacaa acggcctcat taaaatgtag gcaaagggta tgaacagaca cttttcaaaa 34680gaagacatac acatggccaa caagcacttg aaaaaaaggc caatattact gatcattaga 34740gaaattcaaa tcaaaaccac aatgagacat tatctcacgc tagtcagatt attattatta 34800aaaaataaaa aactaacaga tgcctggcaa ggttgtggag aaaagtgaac acttatacac 34860tgttggtggg agtgtaaatt agttcaacca tgtgcaaagc agtgtggcaa ttcctcaaag 34920agctaaaacc agaactacca ttcaacccag caacctcatc actgtgtata tacacccaga 34980ggaatataaa tcattctact ataaagacac aggcatgtga atgttcattg caacattatt 35040cacaatagca aagaaagaca tggaattaac ctatatgccc atcaatgaca gattggataa 35100agaaaatgtg gtacatacta tggaatacta tgcagccata aaagaacaag atcatgtctt 35160ttgtggaaac atggatggag ctggaagcta tcatctttag caaactaaca caggaagaga 35220aaaccaaata cttcatgttc tcacttataa gtgggagcta aatgatgaga actcataaag 35280acaaaaaagg gaatgacaaa cactggggtc tagctgaggt tggagggtgg agggtgggaa

35340gagagagaga agcagaagaa ataactattg agtactaggc ttaatacctg agtgatgaaa 35400taatctgtac cacaaacccc cgtgacacgt gtttacctgt acaataaacc ttcacatgta 35460cctctgaaca taaaagttag aaagaaaata ttaacaactt taaatttagt aatcataaat 35520gtcaaattaa aaaaaaaaga ttttagactc acacttataa tcatagcact ttgggatgcc 35580gaggtgggcg aatcacttga ggtcgggggt ttgagatcag cctggccaac atggtgaaac 35640cctgtctcta ctgaaaatat aaaaattagc caggtgtgat ggcatgtgcc catagtccta 35700gctattcagg aggccgaggc aggaaaatct ctggaacctg ggaggcagag gttgcagtga 35760gccgagatca caacagtgca ctttagcctg ggtgacaaag tgagactctg cctcaaaaaa 35820tacatataaa ataaaaaaga ttttaaataa tattataaat aaactaaaat ttctaggaac 35880aattttttaa aatcagaaaa ataagtcata tgataataca gatactctta agaaatgcat 35940aaaatatatg aatatacatg tgtacttatt gatgtgcatg aagatacact aatatatcca 36000acaagaataa gcacatccat tattttataa tattaaagta agcaataaaa ggaacactta 36060aaaatatttt cttcaattta attgactata tttttttatt tggaaaacaa ttttaacaca 36120tattttaaat agtttaaata gagaaaaatg taaataaagc tgtattacaa agatattcat 36180tgataaacac ttcaaaaaat ttttcaactt ccttattttt atcacgtatt ttgctctaga 36240aaatttccat tccacatgat acatttgttg tataagagat acaaaacaaa ttcctactag 36300gggaaataaa gcttcagtaa ggaggtggca ttaagctggg ctttaaaatt catgcagaat 36360tcccgttgct tcaaatggag agaagcagca gtgtaccaca gataaatgaa gtgagacgta 36420ataagggttt ggctcaagat aataaggaga tgtataatac ttttttatgt ataatacttt 36480tgttccaatt ccctttatgc tttacttcag ttttgtttct ctagttaaat aactttgcat 36540ctctaaactt tattattctt atttgtataa tgaagagagt aacttatgcc aggcaaagat 36600tttacagaca ctagaaataa tatatacaaa atagttggaa tagttcctga aaaatagtag 36660gttccacatg ataacaagat ttatgcttgt gctctttctg tattatttgg aaagaaatat 36720gtgaagtgca ggaaagtggt gtgaagttat ttttgtggga tatctggtgt aatctttctc 36780ttttatctat gttatcaaat atttttcaaa agctgtattt ctcattagtg ctttttgtga 36840ataaattaac taggaaaatt agaagaatgg caacaatata catcatagaa aggcatagat 36900tacaaagaga gtatatacac aatacctgtc cagaagatgt ggtataagcc aatattttaa 36960ttatacttat ttacttcaga tattgcaaat ttttcttatt tttatacctt ctttctttta 37020atgacatttc ctatattttc attcactatg acattgtttt ctttatatca atacttatga 37080agagaactaa ctattctaac tagggagtag ttagactagt tattttaaaa tacttcatta 37140aaggactaca acgtgtgtac catctatgac ttagtattga ttgattgtca tctttcatgt 37200tcttcataag tgggtaattt tgaacactgt tatattattt caaagggtgt tatttgtttg 37260ttcagatgtt ttacaaagta attaactttg ttggcttgaa attgcaaact ctgtcttctt 37320ggtgtcttag tcaattcagg ctgctatgac aaaaatacca cagactgggt agcttaaaca 37380acaaacattt atttctcaca gttcagtagg ctgggagacc aagatcaggg tgccagtatg 37440gttagcttct ggtgacagtt ctcttcttgc tttcctgaca tggctaaaag agaaagagaa 37500tggaagtgag ttctcttctt aaaagggtac aaatctcatt catgagggtt ccacagccat 37560tatctaatca ccccccaaaa gcttcacctc ctgataccat cacattgggt taggatttga 37620catgcgcatt tgagagggac acaaacattc attctatgac agatggtaat cgaagcaaag 37680acaatgaatg ggtttgccca gcaagagtat gtagagtaaa aagagaagac ggtatgaaac 37740aaatcactga aaaaaaaaaa atgtaacagc cagaataaca tgatctaagg atacttggga 37800ggaattatgc aaaaaatagg atttgagtca tgcaggcaaa ctctttaaat ttttactgga 37860aaagacatga gagacagagt tatggaaaag aaagcatttg gtggaggcag atccattttt 37920tctaataaaa taaattaata tggatgaatt gtacaatcat tccttagtaa atttcaaaac 37980tgcatccagg caaatctctt atgcaacagg cctgccttag ttgtgtctac tgggtacttg 38040tttattttta ggcatgtcaa attcgacttg tgaaaagatg attatattgt ctttaatgct 38100gtcttctttt tcccaccaaa tgacagttat tcaaaccaga aactataaaa caaacataca 38160gttatccgaa ctagaaaaca aaatcagaat ttacattttc tattttcccc acctcctgtt 38220ggttctcctc ttaaacttct ccttgtgtgt ctgtaagctt gttatacact tttcatctct 38280actctttttt attttctgaa gtcagctttc taacagatct ctttttccta agttcttctt 38340cttcatggct gccagaatta accatctaaa atttaatttt gttatgtaac attttaaagt 38400gcatattgac tcctcaatgt tgaacatatt tctatcctta cacttcacct acacaaataa 38460tatttctgtt tttcaaataa tccgtgttat ttcacttctt aggggctttt catgtgcttc 38520ctattttgtt ttaagtattt tgtgtcttca atatctaagc ttctataatc aactgaagac 38580ttagccccaa tgtcaacaca tctttaagaa ctttaacctg taaggtcaga atagtccctt 38640tttcctatct gcacataaca ttacaaactt atggcaatta taaaactcaa tacatattat 38700actgtcatta ttggtttatt gctgctgaag attataattt tcagtgcatt gattatgtct 38760tatttgtttt tactgccctt gttcctgttc ctctgtacct gcctcaacta catagcttag 38820cagactaact gctatattac agttgctcaa tgaatgtttc ttgagtaaat cagttgagtt 38880ccaaagctaa tccaagttgt gcgtttgaca aattagaagc ttggaactgt cttctgactt 38940taagtttaga actattgcca taataaatta atgaccgatc tgccatgatt gcaggcaagt 39000agagacttta tttcttatct caatgtcagt tgtctctttc tgccaatgca cattttattt 39060gatgattgtg cacatttata tctctggttt ttatttaaat aaatttagaa catatagctg 39120gagacggtag ctcaaactga ggatgaaaat agacatttat caaggttatt atgtagctag 39180cactgcatgt acacagaggt atttagggag ccacacatat gtccaaggca agacatatgc 39240tcataaaacg tctgagaaga ttgtatcctt ttacctaatg ctaatcccca agcttagaac 39300aaggcaagtg aaaggtcaaa gggataaaaa aatacaataa acaaaataaa aatttacaag 39360aagttgttat ggactaaata tttgttcccc tctccccaaa attgtgtatt gaatttcaaa 39420atccaatgtg atagtatttg ggagtctttg ggagctaaag agatcatgag aaatttgctc 39480ttataatgtg agtagtgcct tacaagaaaa tgctggagag ctcactagat ttttttcctc 39540catgtgagaa tacaaagaga agttagctgt ttgcagccta ggagagggcc ctcaccagaa 39600attgaccatg ctggcaccct tatctcagac ttctcaccct tcagaactgt gagaaataaa 39660tgtttgttgt ttaagccatc cgttccatca taatttgtga tagcagtctg aactgactta 39720gacaaaagtt caacagcaaa tttgagcagt tagaacacag aatccgcaaa cttgaagata 39780agacaattga aatgattagt ctgagaagca gaaagaaaaa aaaaacgaag aaaaattaac 39840aaaacatacg gaactgtggg acactatcag gtgaaccagc ataacaatta cagtagttct 39900agaaagagaa gagacagaga aaagggaaga aataatattt gaaaaaaaag tggccgagaa 39960cgtcccaaat ttgataaaat atatgatctc aatatcgtag aagcataaga aaatccaaat 40020aaactcagag atccactttg aggcacatta tgatcaaact gtcaaaggcc aaaaaaataa 40080aaataaattc agaatcttga cagcaacaag agtaggaaat aatcatgggc aagagttcct 40140taataagatt aacaactgat ttctcatcag agaccagaag acattgaaat gatatatcca 40200ataaagaact gatattcaaa agtatgcaaa gaacatctaa aactcaataa ttagaaaaat 40260aacccaatga taaaatgagg atgatatctg aacagatgcc tcactgaaga agatatagag 40320acaacaaatg agcatgtgga aaaatgctcc acatcccgtc attagggaat tgtaaattaa 40380acaataagct atgtcactgt atacttgtta aaaggactaa aattccaaac acaaaaatat 40440accaaatact ggcaagaatg tggagcgaca agaactctta tttactgcca gtgagaatgc 40500aaaatagtgc agccactttg gaaaatattc taatagtttc ttacaaattt aaagataggc 40560ttaccataca atcaagcatt tgtagtcctt ggtatttact gaaataagta tcaagtggaa 40620agcatgtcta cacaacagcc tacaaagagg tgtttatagc agccttattg ataattgcca 40680taagttagaa gcaaccaagg tgtccttcaa tatgagaata ggtaaagcga ccttggtaca 40740ttcatgcaat agaataagaa tatttttagt gattaacaag aaatgagaca taaccaatga 40800aaagacatga aacattaaaa gtatatttat aagtaaaaga acgcaatatt aaaatgttac 40860ctactatatg attccaacta tatgacaaat tttattttat aaatgcttta ccacaaaagt 40920taattctaaa aatgtttgcc accaaaaaac aaacaaaaaa catggtagag atcatcttta 40980tagtttttta taataatcct cttgataaag attatatcat aagaaatctt gacagtttac 41040attcaaggat atgacatttt atttacaaat taatgaaatc taataaaatg tgacaatgaa 41100aatttagctg agtataaaag aacctaaatt agtagacagt gagagaggaa tgggggaggg 41160gatgtttaca agaagttcta catcagtaca gaacttcata aattagtgga taagagcatg 41220gtgaagagca attgtaaatc aaatgaaaat gttgtggaac tcttattagt atctgcagcc 41280actctggcac tttaaacata tccagtagga gaggttaatt ctctcagcag gagaccactc 41340acattacttt tttctcccta taaaataatg catcgttttg tcatgctggt aaaaaacaca 41400taacattaaa tgtacctttt caaccaattt ttaagtgtac aattaaaaag tgtaaagtac 41460actcacattg atgaacaaca gatctcttga actttttcat tttccattgc tgaaactttg 41520tatccactaa actatcttct cctcagttct aagtaagtac ctttccactt tctgtttcta 41580attttttgac tactttaaat atttctttct tttttctttc ttttcttttt tttttttttt 41640taagatggag tctcgcactg tcacccaggt tggagtgcag tggtgtgatc tcgtctcact 41700gcaaccgccg cctcctgggt tcaagcgatt ctcctgcctc agcctcccaa gtagctggga 41760ttacaggtga ctaccaccat gcgcaggtaa tttttttttt tgtattttta gtagagatgg 41820ggtttcacta tgttggctag gctggtctca aactcctgac ctcgtgatcc gcccaccttg 41880gcctccaaaa gtgctgggat tacaagtgtg agccactatg cttggactac tttaaatatt 41940tcatatgata gaatcataca gtatctctcc tttcgtgact ggcttattta gcttagcata 42000atgtccttga ggttcatcca tattgtagca catgatgtaa tttacttatt ttttaagtct 42060gcataatatt ccattgtgta tgtataccac attttcttta ttcattcatc agtagacatt 42120tgggttgctt ctacatcttg gccgttgtta ataatgctgc atgaatatgc atgtacaaat 42180atctctgcta gatcctgttt tgaattactt tgactatata cccagaagaa taattaatgg 42240cttgtatggt gattctattg tttagtattt gtggaacctc caaactcttt ttcatgaaag 42300ctgaaccatt ttatatttcc atcaacaaac atgaagttcc taacttctct tactcgttat 42360tttctattct tgaaatagtg gcttttctga tggttgtggg gtgatatctc attgtggttt 42420taatttgcat ttccctgata agtagaaagt tgagcatctt ttaatgtgct tattggctct 42480ttgtatatct tctttgcaga aatgtctatg taagtccttg acccattttt aaattgggtt 42540gttctttgtt gttgtttcct tggaaaagtc catatattct agatattaac tcctcatcac 42600ttatattatt tgcatttatt ctgtgccatt ccataggtta tcttttcacc tgttgttttc 42660ttttatgtgc agatgattta agtttgatat agtctgattt gtgtattttt aattttgttg 42720cctgtgcttt ttgtatcaca ttttaaaaat tgccaaattg aatgtcctga agcttttctt 42780ttattttttt ctggaagttt aaggtcttac atttaggtat ttagttcatt ttgagttaat 42840ttttgcatat agtatagggt aagggcccaa tttcatttca ttgcatgtgg gtatccagtt 42900tcccaaacat catttgaaga ggctgtccgc ttccttgtac taaatgaatg gtgttttgct 42960gcttctttta agagtctctg tttgtgtgta acttttgaca gtttgattat actgtgtctt 43020ggtatagagt tttttagatt tatcttattt ggaattactt gagcttctta aatgtttagg 43080ttcctttatc tcttaagatt taaaaaaatg gggtccataa tttacaagtt ttcagacctt 43140tctcatttac ttctcttctg gtattcccat aatgcatatg ttgccctgct ggatggagtc 43200ccataatttc tttaggctct tcttttcttt ttgctcctgt gactctaatt ttagaagttc 43260tgtctttgat tttcctgatt ttttcttctg cctagccaag ttacctgttg agtctttcta 43320gtgaattttt cagttcagtt actttataat tcaactccag aatttctgtt tggttcttca 43380tagtttataa tctgttaata ttgctatttt gtttatttgt tatgttcctc atttcattta 43440attgtctgtt catattctct tttaattcat tgcactactt gactaatttc aagttctatg 43500tctggcaatt cctatatctt catttgtttt tggtcagttt ctggagatgt aatttttttt 43560tccttttaat gtgtgagaat cctttctttc tttttatact ttgtattatt ttgttgttga 43620gattttaaca tttaaaaaat cagtcaactc tcccagattt tgtgagatga ttttccataa 43680ggagaactct cctcactaat tctgaataga gattctgtgg cctactcatg ctttttttct 43740agtatgtttt cctttctttc tcctttaggc ttgtgtgtgt gatctgtttg aaaaggtttg 43800ttggtttcta tagaagaccc tcccctgggg cttgaggtac agtggccttt ctggggctgc 43860attaaattgt tgtactggtg ctccacctcg tgtctctgtc tggaactgca gtttttggtg 43920tacctttgct tgcaaagacc gcatttttat tagtacttga atataggcaa gtcagaagcc 43980tgtccttggg caacctccct aaaagtcaaa atattgaaca taggagattt aaatgtttcc 44040ttccaattgc attgcacagg gtggagtgag aaagactcta gtgagagaga ctggaaacaa 44100tcatgatttt tcttgccagg ttgttttcac gatagcctgg aggtacagaa accttgtaat 44160tggttctgaa gttctcacag aggcatttag tacatatgtt gttaatattg tgtcttgctg 44220ttgaggttcc agggctgttc tgctctcttg ctgatgtcac tctcttccac atttcttagt 44280cctttttaat aaaatgattt tttaatgatt aggacctgaa caattttcat cactattcta 44340tggcacaaag actgcataca tttttacaag atgttagaat tgactatctt tgaagaaaat 44400cttcataatt tttgtctaac tctgttgccc ctttctcctg ttttattatt cccatcatca 44460acttaataca actagttttg atactcttct acattttatg ctgtttctta gataactttt 44520tacattttat tttaaaactt ttagttatct ctataagttg tatcatttaa taaatctttt 44580gaattccttt tatcttcatt gatagcatat atcatttgat agtttcttat gcagaaagga 44640acacacccac attttgtcgg ctatcaaaga gttttgttgg gccttttatc tctgtccccc 44700aaacatggcc tagggccaga cacagagtag gttttggtta tataaatgtt cactcattat 44760ttcttaagca tctttgtgac agacactgtc ctaatcactg gggacggagc aatgaacaaa 44820acagacaaaa acctatgact tgatggggct aatattctgc tgtggcaata taaaataaac 44880tcataaagga ataaatgtat tgtgagcaga aaggggtgca attttaaaga gattgatcaa 44940ggaaaacctc actgtgaaag ttccactgag caaaactctt aagggtgtga aggaatgaat 45000gatagaaata cgactatggg gaagagcctt tcatgtcaag tgaaaagcaa gaacaaaaag 45060cctggagcaa tataatgaat ctggaatgct caatatacag caacaaggtc taatgtagct 45120ggagaggaat gaccaaggac aagagtaaca aagtataaga ttagaaagat aaagaggaat 45180atttgtgggg aggtgggtgt aaaaaagagg ataggttgtt tatggtctca taggttattg 45240gaaaaacttg atatgactat aagttacata ggaaaacaga ggggcagcat gatctatttc 45300tgatttgtaa aggacttctt tagctacttt gttgagaaga gactgttagg cagatgtgca 45360cagaagtaga aacatggctc aggaggctct tgcaataatt gaagctaggc atggtggtgg 45420aaaccactgg gaaatatagg aggtaattag aagaggtcgt ttagtcagtt caggctgaca 45480gaatagaata gacttggtga cttaaacaac aaatatttgt ctctcacatt tccggaggct 45540gagaattctg atatcagggt tctggcataa ttgagttctg ataagggccc tattcctggt 45600ttccagaagg ccatatcctc attgtgtcat cacttggggg taggggagag agagagagaa 45660agagagaaat agagggaatc cctaatttct tgtcttataa gggcactgat cttatcaaga 45720gggctccatt ctcatgacct aatttcctca aaaagaccct atcaccaaac atcaacacac 45780tggaaattag agtttcaaca tataaatttg aggtagggga tataaagatg taatacataa 45840cagggtaaat attaatagta gagagcccaa agaaatttgt ttatggatat aaatgtgagc 45900tgtaatagaa atgattaatc gatacatttt attaacatga aattgacaaa taaaacatct 45960ataaccactg catcttacac tggatgtcag tcacttgtgt tggtcataga atttttcttt 46020gcctctgcaa agttctgttt ttcagctggc ttcctggaaa tgctgccttt gagaatgtac 46080tgccactccc ctcccagtta gccaatgcta ttcatatgga aataaagaat agctcaccat 46140catggccatc tgagaacatg atgtagcttt ctataaatca gttaatgaga ttaatttaaa 46200aataacaacc ttaactgtag tgctctaata ttttgatatt ataaccaaat tagaaatgat 46260gctttatcag tgtagtgata ataacattta aatggctgag tagtagtacc tggtaaaagg 46320gaaaactaag tatggttttt aagatacaaa taatgttttt aagtaaagaa gaaagctatt 46380ataattccat gtgcctattg acattatata gtccttcgat taaccatttt ccccctttcc 46440ttctgatttt tcttagatgt tcttggcagc tctgtcactc agctttattg ctaagacact 46500aggtgcaatt attatgaaaa gttccatcat tcatatagaa cggagatttg agatatcctc 46560ttctcttgtt ggttttattg acggaagctt tgaaattggt aacatttatt ttctatttta 46620ataaccaaac ttgcaaagtt aaaaaatata tatgctttac accactggtt atcaactggg 46680gtaaatttat ctctcacagg caatttggca ataactaaaa acatttgtgg ttgtcataac 46740tgcacagggg ttgggggcaa tggaagtgct actggtatct aaaggtagag gtcaggggta 46800ctgctaaata ttctataatg cacaaagaat gatgtaactg aaaatgttga tagtgaggat 46860gttcagaaac cctgattcta cacaaattca ttttttgcaa actaacgcca tgtcatactt 46920tacctcccct ctctcaagat gaagaaactt tgggagagga ctgttattct taaggagaaa 46980ggaatctttt cagagcaacc tacgttagac ctctattgtt tcactgagca cacaaaaatc 47040tttcctttga aatactgaag atattttgtt gtcttcattt tatgttggat ttctccaata 47100acagctcagg gaaaacattt tctggttcat atttgtgttt ttccctatta gtaatttttt 47160tctagataat ttataagatg aatattaaat tttctgggaa tttttctctt taaatttttt 47220tcttctaaat ttccattgtt tttctttatg tttcattaat ctttgatgcc atcatccatc 47280ttaccatatt aagttctaat ttgtatattt aatctgtatt ttatatttac aacagcactt 47340tattattccc ttattatttt taggctgcca gttctgattt catggatgca atgtgccctt 47400gtacccgtaa aggtactaaa ttttttataa agtaaaaaaa aaatttactc attcattttg 47460gtgcttttat tccaaattat ttttatgcta ttttttttca gaagtgctca gttatcctta 47520actgctattt gtttattgtt atgcctgagg ctccagatgg attagaagtg gtcatgactt 47580tttttttttt tttttttgag acggagtctc gctctgtcgc ccaggctgta gtgcagtggt 47640gcgatctccc ctcactgcaa gctctgcctt tctcctgctt catcctcccg agtagctggg 47700actacaggca cccgccacta tgcccggcta attttttgta tttttagtag agacgggatt 47760tcactgtgtt agccaagatg gtctcgattt cctgacctcg tgatccaccc acctcagcct 47820cctaaagtgc tgggattaca ggtgtgagcc accatgcctg gcctctggaa gttcttaatt 47880aagttccgcc tttctgtggt ttaatagcac ctctgtccat ctatttttat cgttagtatg 47940aaacttcttg aagacagatg ccatggttta ttctttttca agtaactttc ttatttctgg 48000ctctgagctt catgtcaggt tcatgttaga aatttaaata atattaagaa taaataaaga 48060aacgcatgaa ggagcacctt accctcatca ggaagattca tctccatttt tcttcattcc 48120agtataatcc agtcaactcc aaatttttca ataaaatttt acttcactaa tattgccaag 48180taattcaagt gctttttttt tgtatttaaa acaacttttc aatgagtggt ctaatgtagg 48240tgaattcacc ttctcaatta aatcacattg tctttgaggg aaggcactat gtcttggact 48300ctatttgcat ccattctggg gttttcaatt ctagacgcaa aattgaacta agctgtatca 48360acataatttt gttccctttc taggaaattt gcttgtgatt gtatttgtga gttactttgg 48420atccaaacta catagaccaa agttaattgg aatcggttgt ttcattatgg gaattggagg 48480tgttttgact gctttgccac atttcttcat gggatagtaa gtgttaaaaa aaaaaaaaac 48540ctctgtgcca ctatcagtac cttgtaaatt aggagtagaa ttttattatt atccctttaa 48600ataggcagtt accttttgag aagataccca ctaagtgtgt acagaaatga aatagtgtct 48660atttgtctac ataatcattt tatttatcgt agctttcata tactttgaaa taacaaaaag 48720actaaactgt agagtttcaa atgaaataaa taggcttttt atgaattttt agtataacgt 48780atatactgta cgtctttgcc tataagattt tgattatttt ttataagacc tcaacactta 48840cacctatacc cactgaagta tagttgttcc catcatttca ctgaagctgt tattcctaag 48900gtcactgtgt agttataatt acagtcagat gctcctgaga gaaaagttaa aatggcacat 48960gggggagaaa cttatttttc acattacagt taatgtagcc agttcaagga tgatatgatt 49020ctacctcttt ccatcatagt gctatgcctt gcatggtctt ggcttcatga tccaaattgt 49080ggcaacgtat ttccaggcaa caagatagaa gaagaaaaga ataagaagca acaaacagtc 49140cacacaggct gaggcttaag aagcattttc agaagcaaaa tatctctact gactttacat 49200ttaccagatg ttagttacat ttcacacata gatatataaa tgctgaaaaa aatagacatt 49260attccaagtt accaagttcc cggttaaaaa tcccaagtat aattactgtg gaaggaaaga 49320agagaggata ttaggagaca atgagcagtt tctgttagag acaccaatta cttactcatt 49380gccaaatcca gcaatgacat catttgctca ccatattaaa tccattcacc caccatattt 49440ggcccttata ggaagtttct tcttagtggt actgctctag cttgttttca tcatactgca 49500ctctcttgat tcattttcta tctttgtgtc ttcttcatca tgtccatttt ttttcatctg 49560cttttggcac cataccgtca gagtcctcta atttcctttt taatctttat ttatgattct 49620tcatgagttg tatggaaaat aaaccttaaa ggcaagtatc acagcttcat cttccattct 49680accctaaaat taaggaccac aatctagatc agcattgctc taaatatgcc ataatatgtg 49740acacttttgc acctggtatt tctacagcct tgaatacctt tgtttctttg tctacccttc 49800tattcatctt ccagattcgt tttacctgtc attctcatgt tgatgtcttc tctgatctat 49860tcccgcaacc tccaagcaaa gttgatcata tcctttgtct ttgtgacaac tcaggacctt 49920atatattaaa cttataactt ttatcatcta tgtttatact agtgtgaaat tccctaagta 49980caaaaactgt gtgttttatt tctagctctt tgaagcttag cataatgcct ggaatacagt 50040aggctgcctt tagagctcac gtggtaccta attatttatg gatattaaca tctctgttat 50100tcctatcaag ttttctctca tctagttgaa atggattaga ttttattttt actacatttt 50160gaagagtcat acattagagc gtgtgtgtga atatgtgtcc atgaaagaaa atctgacaga 50220ctgatcatct ttgaagataa ttcaaaagga tgaatggtta cacacaatta ataattactt 50280tttaaaaagg tgaaactagg atatttcata tcttgaccaa gatataacca ctcctaggat 50340aatagcaagg tgataaccca cttagcctgg ggtgtattga attatctttc ttgctggaca

50400cttccatttc acttttaccc atcacatctc ttaaaacaca tgctgggaaa ttgacagaaa 50460gtactctggt aatttgggga agataatggt gcaaataaag gggaatattt ctctgtattt 50520ctaggaaaag tgaaaatatt cagtagataa gcaaaatgtt taattcagtg atgttcttac 50580agttacaggt attctaaaga aactaatatc aattcatcag aaaattcaac atcgacctta 50640tccacttgtt taattaatca aattttatca ctcaatagag catcacctga gatagtggga 50700aaaggtaaga attaatattg acagtaaaaa gtcttctaaa atgtatacat ttaattacat 50760ctctaaaaat tgttgtgata ttcattagca aaatttaatt aagaatgaat aggaaaaaca 50820tttgactctt acagacataa ttatagtgtt aatatacaca gttcgcccat taacaacaca 50880ggtttaaact acgcgttttc acttctatgc aaattttgtc catctgaact ggatgataaa 50940cctgccggta agaatatctg acattttcta tatttggatt gaacagggcc aactgcagaa 51000cttaagtgtg catgaatttg agaacacaca ggcagccctg taacaaattc cttaatatac 51060caagggatga ctgtattata tgtaaaagca tttagaagta gatcagaaaa gagaatattt 51120tcaataggaa attgacaaag aatatatgca ttaaagtaaa acagaaggaa atggtataaa 51180tatgtaaata atataacttt gctttcattg caaaaggcaa actattatat catttaaaga 51240ctttttgcct attataacac aaattataaa ttataattgc aaattgtact gctaaagatt 51300tttttaacct attaaataga aaaagactaa aaatacatag agacgaggta gaggcaaaaa 51360aggatttcac attgtatata ttgctggaag tgtatacgtt tgtaaatctt tctggagatt 51420cattatcaat atatgttaag aacaaaaata tacttaccta cttagtctga aattctgcta 51480ttattgatta atcttaagga aataaccagg aaactgcaaa aggacttatt tacagttata 51540gtcatgataa acctaataga ataaaacaac aaaaaagaaa ttaaaacata agatactgaa 51600taaacacatt tggaaactta ttcagcacat tactgtccag tcattaaagt tttgatatta 51660aagaaatctt aacaacatgg aacaattgtt ataatatggt gttaactgtg tataccattt 51720aacaatatga actagatttt taaatatata atggatataa tgaatataat gtatatgttt 51780tgtgcaaatc tagaagatat ataaaaaagc ttgaggtgat cttctgtgtg taatgtgatt 51840acagataatt tttacttgtt tgtgcttttc tgtatgatat ggcttgactg tgtccccact 51900caaatatcac cttgattgta ataatctcca catgccaaga gtggggccag gtagagataa 51960ttgaattttg ggggcggttt cccccatact gttctcgtgg taatgaagaa gtctcacaag 52020atctgatgat tttataaatg agagttcccc tgcaaaagct ctcttgcctg ccaccatgta 52080agacatggct ttgctcttcc ttcatcttcc gccatgattg tgaggccccc cagccatgag 52140gaactatgag tccattagac ccttttcctt tataaattac ccagtctcag gtatgtattt 52200attagcagca taagaatgga ctaatacacc atattgtcaa agtttgcaaa gtgaatataa 52260attacttgta cttgtaaatt aaaaaaaaat aagtagaata attaagagtt tacaagtagt 52320taaatttgta atagaaatgc taaaattaat gtttaaaatg aaacactctc ttatctacat 52380aggttgttta aaggaatctg ggtcatacat gtggatatat gtgttcatgg gtaatatgct 52440tcgtggaata ggggagactc ccatagtacc attggggctt tcttacattg atgatttcgc 52500taaagaagga cattcttctt tgtatttagg taatgtacac aaaatattaa attgtatgat 52560cactttccct ttgtctactt ttgaaatagt agagttacta aacttattat tttacctatt 52620agaacatata tttgggtata tgtattgtat catatttctt ttaaaaacat ggtgaataag 52680aaccatgcat tcttggcatc tagtaaaatt gctttataat attttcaggt atattgaatg 52740caatagcaat gattggtcca atcattggct ttaccctggg atctctgttt tctaaaatgt 52800acgtggatat tggatatgta gatctaagta agtacaacca gaacaaggta ccatgataac 52860gtctttctaa gcacacatgc gaaaaacatt ttttcaaata actgaattca ctctttcaat 52920agtcctttgc ttaatataat tagaaagtta caagtaggaa ataaatgtat tactaatcag 52980aataaatata aaatccagct cctatttata ctatctttat aactaagtgt aaaatgagag 53040aatgtaaaca aatttatttt catgagcttg gtccaaaata accaaatgta aaatgtctcc 53100ctcccaaact gactgtccag tcaagtaaat tttatttttc agttgatggt ggcttggatg 53160ttgatgtgta caacttaaag tttgctttgc taaagtcttc ttgtggctgc tgcattgatt 53220tatggctgga gtcatttgag agacttcact gtgtatttta tggtcatttt ccctggtcct 53280agcagagggc ttggcgtatg gcaatgttca gtaagtactt gttgaacaaa ggaataaagc 53340agaggacaca taaataaaat ctatgatttt cttcttcatt ctcagagcat actttccttc 53400ttatctcata gatgaaagag atgccatgtt ataaaaactg tctcaacttc aggccctttt 53460ccctaaaaat attcttgcac catatctatc tttatcttct ttttcttttt tgcagctcag 53520tggaaaatat atacatctgt atccaatgtt gatagatcta gctggagctt agattctccc 53580ttcccgcttc tttatctcca tcttctcttt tattcagcaa acacacccaa gtatttccca 53640tctttatatg tagatacagt tttttatacc cccacacaac tttccagctg aatccttttt 53700ttattcctct ttagaaccaa gcacctagga aaatatcagc taaattagct aagatatctc 53760accttctcac ctcccatcca cttctaaatc cagtataatc tgcttctgtt attagtgaaa 53820cacaatcaat ttctacctac tttactatag atttgtaaat gggtatattt ctatcatttg 53880cgttaattga tatttccagt gcttcttcat ccattttccc tccttagata tcttattagt 53940acctaaagca caatatgtca aaatctgatc tcatcacctt acctccaacc ccactgtatt 54000ccctatattc ctccttttga tgaatatcca taccttattc aattattgac tgagttactg 54060tgccctgtaa tctcacattt ctctgcattt acacttggta aaacttttcc ctctttttca 54120tttgcatagt tcttgaagcc tcttccaaaa tgtggatcct cttagagaag ccttacttca 54180ccactttcca ttagtctcaa attaatagcc aagagcatgc ctttattgta acccttctca 54240caatgagcta ttaatatttg tgtgcttact tgccatctct ttaccacatg acagaatggc 54300atgttcttag caaataataa ttagttaagt ttgtgaataa ataaatatga ttttccacct 54360cattaggcct tcaatagatc attccaaaga gatcaaagga ttcatttcca agatgggata 54420gacatcacag tgggccagca acagccaaaa acttgaaagt gtttgctaat ctaaaactat 54480aaagaaaata cttgataaaa tgttttacat gttcaatttt agacatatgc cttagagtag 54540ctacacatta tgtacattat ttctactcat tcaactccag tttcatcact gctttatcac 54600gaagagtaca gaaatacgtg gtaaatgtcc ttaggttaat tattttataa gctctctaaa 54660taagaaatta ttacattatt tgagaattca tcaccataca atttctaaca ttgaatgttc 54720agatatcatt atatcttctc ttattcagtg atgagtatga gcttcactta caaagtatac 54780tttggcaaac tccaatgcct aaaggagctg aagacataaa aataaatgag taaagagtgc 54840caggaacagg aatttagggt gtgatggtta gaataggaga attcttttgg ttgtgaactg 54900ctctccccat gcatccaaaa gcacttgtgt tcctcagctc tggcctattc ttttaatgca 54960caaatttagg ccctgcattg gcaaggactt ctgattggtt tccaagaaaa tccaaacacc 55020aaaatttttg tgtagaattt ttcaattttt aagactgtga gtgagccaag aaaaactttt 55080tctcacgtcc tatctagcgc gattatgacc cttagttact atgtgtagaa cagtgaaaga 55140acagaaaaaa aagtcatcaa aattacattt gtcacaggtg atgaataaat actttgcatg 55200tagatggagt cactgattta accaatcatt tcctgaagtc tgagttgttg attatgacat 55260ggtatgatca tataaatcaa atttaaaccc agatctgtgc atacttgaaa ataattattt 55320ctaggtagtt tgttatcaag tcaatgttat cttatattag tgagttttct tatagattag 55380agtaatggca ccatttaatc gtgccacaaa cttctgtggt gtgtgtttct gtatgcatat 55440gcttttttat ttcttattat ttttctttta ttatggtaag aacaattaaa atgacatcta 55500ccttcttaac aggttttgaa acatacagtg gacccatgaa caataggttt aaattatgct 55560cgtccactta tgcacagact tttttcaata aatatattga aaaaatttgg ggagatttgt 55620gaaaatttga gaaaatttat agatgaattg catagtgtag aagtaaagga aaccctaaga 55680aaaaggtata tcatgagtgc ataaagtatg tttagatact ccactatttt atcatttact 55740accataaaat atacacaaat ctattataag aaattaaact tattagaggg tacaagatgg 55800ccaactagac acactcagga agcaccactt ccactgagga agcccaaaat attgaataaa 55860ctaacatact tcgagcatat cttttgagag aaaacactga aagtcaatag agaggtgaca 55920cagacactga ggctgaagag agagaaagct ggaaacccag tgcagggttg ttgaacacca 55980gagatagttt ccagccctga gtggctccta gctaaggggt gagtaaagtg gcagtgggac 56040agcctactct cactgttgac atctgggatc ctacctacaa gagaacccac gacccccaga 56100gacattggaa caggcagggg catctgccca gagagtaggc agaaatagaa ctacagccag 56160ccttgaaccc agggggtttt gcatgttggg tagctgcagc agaacgcagc cataggcgcc 56220caacatccaa ggctctcttt cttccaccaa gtagctctca actcacctga cttctgagcg 56280aagagacagc ggggccaact ttcctgtgag ctgggacaca tctgtattgt aggcccttct 56340gcccgccagt ccctcccagt actcctgcct ggccacacct gcaagaatat gtgcacagca 56400cagcctccac tgctcagcct gagggttttt tcaaggaccc ccacctgagt acttcctcag 56460tatccttgga gcacttcaga tcccccagtg tagctactgc ctgaaccaga ggggccagac 56520agtggagaca caggctagtc ccaaaacccc agggctgcag tgcatagctt gggagtgtga 56580gctgagattg gtgcccagca ctcaagcaga ggaagaattc tgaatctcag aacactgaga 56640ggggtgagat gcacgggttc atgggccagt gcagaatgag acatgcctca tttcataggc 56700ccagtccagg aaggctgtgt cctgtctgcc agctgctgcc tctgcctaag ggagctccat 56760ggctcagaac agtttcctaa caaaagaaat gcaagtgtgg caccagtgac cagagcggga 56820gattgggggg gtgtccccta tggcccaggc acaggcctgt taagggggtc atctctcttg 56880cccgctgcca caagcactgt tgtaaacaca ctgaaaaaca aaagagttat gtccccgagt 56940aacagcttat ctgccagcca ttactcttaa gcaccattta ctggatcaca gctcaattta 57000aaacatctgc ctatatattt gagactgtac ctcactctgt tacccaggct agagcgcaga 57060gaagcaatcg tagctcactg cagcctcaag ctcctaggct caagccattc tcccacctca 57120gccttctgag tagctgggac tacaggcaca caccactaca cttggctaat atgtgttatt 57180ttctgtaaag acagggtttt ccatgttgcc caggctgatc tcaaacttct ggcctcaagt 57240gatcctccca ccttagcctg gcaaagtgct ggaattacag gcttgagcca ctgtgcctga 57300cttcaaaaat agtttgtcag tatacattgc atatgaaact gagagcaaga atctagctat 57360aaataaaaat attgtgcaga gtcttatccc agaaattaaa ccaactgacc atactcaact 57420tataccacag ttaaaggaac accattcctt caagatgaaa aagaatcaac aagaaatctg 57480gcaattcaaa aagtaagaat gtaccttaac cttcaaatgg gtgcatttga gctctccagc 57540gatggttctt aaccacattg gaatgactaa aatgacagac aggcaattcg gaatctggat 57600ggcaagaaag ctcattgaga ttcaggaaag tgctgaaaca caatttaagg aattcaataa 57660ttccagtaga atgatccaaa agctgaaaga cataatagcc attaaaaaaa cactacttct 57720ggaattaaaa aaaatactac atggatttga taatacatcc agacctttag caacagaaca 57780taccaaagag agaaaagaat ctcagagctt aaaaaccagt ttttataatc cactccatca 57840gacaaaaaga aagaaagaaa aaaaaacata aaaatgaaga aaacttctag gaatttggtt 57900tccttctgta aagaaaccaa gcctatgatt cattggaatt cctgagagag aaaaagagag 57960agtaaacaac ttgtaaaacg tatttgcaga tatagtccat gaaaatatcc tcaaacttgc 58020tagagagatt gatatgcaaa ttcctaaatt acagagaacc cctttgagat gctataaaga 58080tgacaatccc caaggcatct actcattaga ttccccaaag tccacatgaa agaaataaat 58140attttaagat ttttttgggg ggcagctaga gagatggatc aagtcactgt caaggggaac 58200cccatcaatc ttgcagaaca cctttgagca aaaaccatac aagccagaag agattgggga 58260cctattttca gcacccttaa agaaaagaaa tttcaaccaa aaatttaata tcccaccaaa 58320ttaattttgt aagtgaaaga gaactaaact ccttctcata caagcaaaca ttgaggaaat 58380ttcttatcac taaaccagcc ttataacagg tctctagaag agtgctaaac atggaaacaa 58440aagattaata cttgccacaa caaatactca cttaaatagg tagcccagac acataaagca 58500actatacaac caagtctatg aaacaaccag ctaacaacat gatgccatga tcaaaatctc 58560acgtatcaat aataaccctg aatgtaaaca ggctaaatgc cccaagtaaa agacactgag 58620tgacaagctt cataagtaga caaaacttag ccttctgttg tctttaaaag acacatctta 58680catgtacaat acccacagga tcaaagtaaa ggaacggaaa gagatctatc catgcaaaca 58740gaaaacaaaa cagggcagta atcactattc ttatatcaga taaaacagac attaaaccaa 58800aaaccatcaa gaaggacaaa gaagggtatt acataaggat aaagtgttcc attaaacgag 58860aagacttaac tattctaaat atatatgcag tcaaaagtgg aggacccaga tttacaaaaa 58920agattcttag agacctaagg aaactaaaaa cagacagcca caccatgata gtggaagact 58980tcaacaactc actgacagtg ttagatatcg aagcagaaaa ttaaaatgta aattttggac 59040ttaaactcaa ctctcaacca actggatcca aaaacatcct acagaatact ccacccagca 59100ctatcagaat atgctttctt ctcatctgca tatagattgt attctaaaat caatcatatg 59160ctcagtcata aagtctcaat acattcaaaa aattaaaaga ttttgagtac attcttgaac 59220aaaagtgcaa taaaaataga aatcaatacc aaaaagattt cttaaaacca cccaaaagta 59280tggtaattca acaacttttc ctgaataatt cttggtttaa gaatgaaagt aaaaccgttt 59340ttgacattaa ataaaataga gacacacctc actaaaatct ttgggatcta tctaaagcag 59400tgttaagagg aagtttacaa tgctaaaggc cttcatcaag aaggcagaga gatttcaaat 59460taacaattta acattgcact tacactaact agaaaaaaaa aggacaaccc caaagcaaac 59520tgaaaataaa taacgaaaat cagaatgaaa ttgtgatgca aaatgtatac aaaagataaa 59580taaaaccaag agtttgttat tcaaaagaat acaaaaagat taatagactg ttaactagat 59640taacaaggaa aaaaaggaga cccaattaag cacaatcgga aatgacaaag atcacattac 59700aactcccata gaaatgcatt acaaatgccc ctctgcacac aaattagaaa atctagagga 59760agtagagtca ttcttggaaa caacctccaa agattaaacc agaaaaaaag tgaaaacctg 59820aacagaccga taacaagtta tcaaattgaa ttagtaataa aaaacctact gaccaaaaaa 59880aaagccctgg accagatgga ttctcagcca aattctacta attctaattt tattctaaca 59940taaaagttcg cttttttaaa gttaaacttc aaatttaagc acagaaacac atatgtacct 60000catattatct catctacagt caagagaagt gaaaacaaat gtgaagatgt actattaaag 60060cataacttta tacaattgac tgtaatatat acgttactgc tgtaataatt tcatagcacc 60120tcctgtaatt gtagtaataa ggttgtgttg aaagcacctg cttaaaacac catgtgacac 60180taattatctc cacatgaaca gttcctctct ccaataaatt gcggattgca gcaaaatctg 60240attgtgattc ttgtgcgttt ttatactgtt tagtgcaata ctgtcaactt tgaataacac 60300cgttggagcc atatgaattg ccactagtga tgctgaaact gctcctaaga aactgagaaa 60360agtcacgaca ttacaagaaa aagttgtatt gcttgatata taatgcagat tgaggtcttc 60420agctgcccat tgtttcaata caaatgaatc cagcataaag atcattgtaa aaaacaaaaa 60480aagggaaaaa aaaaggaaat tcatgatggc attgctgagt ctatgccagc aggcacaaaa 60540tcttgcactt ttagtaatat accgtcttat ctcatattga aaatgaaatt gttatatggc 60600tgcaaacttt tataagaaag gcataaccac agactttaat gtgatttgag aaaaagtgaa 60660gttattatat gaccatttaa agcaaaggaa ggtgagggat ctaaaactgg agaaactaat 60720gcaagcaaag gatggtttga taattttaga aaatgatttg ggtttaaaaa ttttcaaaat 60780aacagaagca gcagcttctg ccaaatgaga gaaagtgaac aagttttcag attccactaa 60840gaaaatcatt gagaaagcat atctgcatga gcaggttttt aatgcagatg aaagtgtcct 60900atcctgggga aaagaaagcc acgaaggacg tttattaata aagaagagaa gtgagcacca 60960ggatttaagg caggaaggga tgaggtaagt ctactattct gtacaaataa ggtcaggctt 61020attatcaaaa ctgctagtat ctacaaagtt gataagtccc aaaccttgaa ggcaaaagat 61080aaaaatcaac tgctagtctt ccagtcatac aaaaggaagg tctgaacaat tagtactctt 61140tttcagaatt gtttccatca atgccttgtt cctgaagaca ggaagtagct tgacagtaag 61200ggactgcctt tacagttctt ttcatatcag tcgatgcccc tggtcaccta gaaagcccat 61260aagttcaaca tcaaaggcat tgtagtgatc tatttcttcc accacaacat ctctaattca 61320gcctctagat catggagtca taagaaactt taaaggatca ttacagatga tactctaacg 61380aaaggattat cagtgctatc aaagaaaatc ctgataggca gaacatcata aaagactaga 61440agaattacac catttaagat gctattgtta tagggaaaaa aaaaagtgaa agtcattaag 61500tgcaaaacaa tacatttcta ccagagaaaa ttttgttcag atgttgtgca taaattcata 61560ggattaacaa catggccaat caagaaaatt atgaaagaga ttatggatat ggaagaaaaa 61620gtgaggagta aagaatttca agatatcggt attggagaaa ttcaagagct aattcatacc 61680tcatcaggga agttaacaga agatgacctg atggagatga gtgcctgcga actagtgtca 61740gatgatgggg aaggagacat agaagcagca gtgccagaaa caaattgtta ttaggcaatc 61800tagcagaagg attctgataa ttcaagactg tttttggctt cttttataac agggactctt 61860gtctaatgtg ggcactgaaa ctaaagcatg tgttggaaga aggattagtt ccatttagaa 61920aaatttttag agaaatgaca aaaccacaaa gtcaaataga aattatggcg tatttatgaa 61980atagttactg aatgtacttg cctcttttgc cttccctcta cctcctccac ctcttccacc 62040tcttctaccc tagtgaaagc aagaccagtg cctcccattc cttctcctcc tcagcctact 62100caatgtgaag agatgagaaa gatcttatga tggtccactt caacttaata gtaaatatgt 62160tttatcttcc ctgtgatttt ctttataaca ttttttctct agcttacttt atattaagaa 62220tactatatat aatacatata acatacaaaa catgtgttaa tcaactgttt atgttattgg 62280taaggattct gatcaacagt agctggtatg atttggatct gtgttcccgc caaagtcatg 62340tagaattgta atccccaatg acggaggtgg ggcctggtgg gaggtgattg ggtgataaag 62400gtagtttctc atgaatagtt taacaccatc ccccttgatg ctgatctcat gatactgagt 62460gaattctcat gagatttatt tgctcaaaag tgtgtaatac ctcccccctc tcttcttcct 62520gtagagactg cagaactgca taactgaaac tttataccca ttgactaaca actccctgct 62580tccccttccc cttaatcact ggcaataacc attctactct ttgcttctgt gagtgttact 62640gttttatgtt cctcacatga atgtaatcat gtagtatatg tccttctgta actggttcat 62700tttgcctaat gtcctcaaag ttcatccaag ttatcacata ttgcagaata tccttctttt 62760taaagactga ataatattcc attgtatgtc tatacaatat tttctttatc catttatccc 62820tcagcagaca tgaggttgtt tttacagcta gctattatga atagtgctgc aatgaacgtg 62880caaatgcaaa tggtctcttc aagataatga tttcaattct tttatatatg tacccagaag 62940tgggattgct gggtcatatg agagttctgt atttaatttt tgaggaatct ttataatacc 63000ttttatactg gctgtacctt tttgtattct accagcagtg taccgtgttc aaatatctcc 63060acattcttgc aaacactttc tttcttaaat gatagccatt ctacaggtgt aaggtgtagg 63120aaaagagtgg agttgtgctt ttgatttgca tttccctgat atgcaatgtt gaaaatcttt 63180ttattgacct gttgttcatt tgtgtgtctt ctttggagaa atttctattc aggtatgtag 63240cctaattgtt ttttcaaatt aatttttttt ttttgagtca ctctcactct gtcacccagg 63300ctggagtgca gttgtgtgat ctcagctcac tgcaatctct gcctgccagg ttccagtgat 63360tatccagcct cagcctccag agtatctggg attacaggtg cctccaccac acctggctaa 63420tttttgtatt tttagtagag atgggatttc accatgttgg cctggctggt ctcaaactcc 63480tgacctcagg tgatccaatt tgtcttggcc tcccaaagtg ctgggattac aggttatcag 63540ccactgactg acatatataa aattgtattt ttatcatgta cactctaatg ttttgaaata 63600catatataag tggaatagtt aaatttagct aattaacaaa tgcattatct tacatagtta 63660cttttgtagt ggaaacactt aacatctact ctctcagcat atttcaaaaa tacaacatat 63720tgtggttaag aatagtcacc ctgctgcata ataaatctct gcaatttttt cctcctaatt 63780gtaattatgt atgctttgac cagtatctcc tcatgtggga gatcagtcag agtggtggaa 63840gaagctatag ggaaggaagc aggcctttag aaaggtcaga aggctctgca aaacttcagg 63900ggagactaag ctgaagatag ctgttctctt accctgaggc agagcacaag aaataggtat 63960aaggaagtat aggggaattt atctaaatag gcttgtctac ccatgttgtc cagaaactga 64020cctttgacca tccgtacacg tgactgttcc cagtaagggg gaacaataat gttaattaca 64080cacagattgt gttggctcca gcctttcggc attatgtctg tactaaataa aagtgagcag 64140ctccagcttg ttgggactgc tactcactct ttggcagtcc cctagccact ctttcaccac 64200atacctgtgt ctgagtactc ctttcatctg ttggtaggcc agggtctacc aggatggacc 64260aggcatcctc aactccactg ttctcccaac cacctggctt ctggtagcca ccattctact 64320cactaataac taattaattt ttatttcaat agcttttggg gtagatgttg tttttcgtta 64380catgggtgaa ttctataatg ataaattttg atattttaca tacctgagta atgtacattg 64440tacccaatat gtagtttttt tatccctcag tccccttcca tctttcccct tctgagcctc 64500ctaaatccac cacatcaatc tgtatgtctt tgtatcttca tggcttagct cccaatgata 64560agtgagaaca tacagtattt ggttttccat tcctgagtta cttcacttag aataatgtcc 64620tccagttcca tccaagttcc tgcaaaattt ttcatcgtta ttattttttt gctattgagt 64680tgtaggattt ccccgtgtgc tttagaaatt aacccctttt catatataaa tgatttataa 64740tattttattt tattctgcat atttcttttt taccccattt attgtctctg ttctgttcca 64800ttggtctata tttctgtctt tatgctggta ccatattata ttaattacta tagctttaaa 64860atacattttg taattaggaa atatgaggca gctttattct ttctcaatgc ttttttggct 64920atttgatgtc cttcttggtt ccatatgtat tttagaattg tttgttatat ttttgtaaaa 64980atactattgg gcttttgata ggtattgtat tgaatcttta catatatttg ggtagtatgg 65040acatttacta ttaataagtc cttcaattat taacacagaa tgtctttcta attatttatg 65100gcttctttat ttcctcagtg tcttgaagta tttcatgcac aagtctttca ccttcttaaa 65160tttatttttg tgttttattc tttatgattt tagtgtaaat ggaattgctt tcctaatgtc 65220ttttcaaata gtacttggtt aattcataga aatataagta atatcttata attattttgt 65280atcctgcaac tttacagaat gtgtttattc aattctaaca ggtgtgtgtg tgtgtgcatg 65340tgtcatcttt agggttttct atatacaaaa tcatgccatc tgcaagtaga ggcaatttta 65400cttctttctt tcaagtttga atgtctttta tttctttttc ttggttaatt gctctggcat

65460aaaatggcag gactgtgttg aatagaagtg atgagaatgg ccattcttcc tttgttcctg 65520aaagctttct gtttttcact cttgaattta atgctagctg tgagcttttt aaatatgcac 65580ttcattttgt tgaggcaatt tttatctatt cctagcttgt tgaaagtttt tatcacaaaa 65640cattgttgga ttttatcaaa tgctgtttaa catctgcata tttgatcatg tagattttgt 65700cctttttttg ttaatgtgtt acattacgct tggtgatatt tgttaaactt agcatttcag 65760gtataaatcc cccttgaata tagtgtagta tcctttttat atgctattaa atttggttta 65820ctagtattgt ttgaggattt tctcctctgt cttcatcaga tatattggtt tgtagttttc 65880ttccttttgg tgtctttgtc tggctttggt atcagaataa tgctggcctt ataaaattag 65940tttgaagatg ttctcttctc ttcaattttt ggcaagagat tggaatggat tgccattaat 66000attttcttta gctatttagt aacacgcacc agtaaagcca tctggtccta agttttttgt 66060tgagaagtat ttgattatta attcaatatt tttactggtt gtaaatctct ttatattttc 66120tatattttct gtgttttatg tctccaggaa tttatttttt ctttcttatc taatttttga 66180tgtataattt ctcatagtaa tctcttatga ttgttttatt tttctagcat caattaaatg 66240tctctacttt cagctcttat tttgtttgtt tgagtctttt ctcttttgct tagtctagtt 66300taaagtttgt caattttgcc tctctttcaa aaagatcaac acttagttgt gttgatattt 66360tttctaatgt ttttttttcc atattcttta ttgtatttat ttcttctcta atcttttttt 66420ctcctgctaa ctttggcctt agtttgtttt tctttttata attttgtgag gtgtaaaata 66480ggttgttagt ttaagataat tctttacttt ttactagcat aattatgtga tatttatcag 66540tgtgtactga gagcaaacaa tgccagatgc tactagtgac cataaattag agaaataacc 66600tatgtttttt ggatatggaa atgaaattta ccctacaaat gtagatattt tttactgaac 66660acttcctctt actactgttc ttgctgcatc tcacatttta gaatgttttg tttttgattc 66720tcttcgtatc taaatatttt ctaatttccc ttttgatttc tttgacaatt taattattga 66780aaagtttgtt agtatccata tttttaaaat tttctacttt tctttttgat actaatttcc 66840agttttattc cattgtagtt agaaaagata attggtatga ttttaatttt aaatttatca 66900agacctgttg catgatgtaa catgtggtct atcttagaaa atattccatt tctatttgaa 66960aagaatatac attctgtttt tattgagtga agtattctct atgtgtctgt tacgttcaat 67020tggtctataa tgttgttgaa gtcctctgtt tcctcattga ttttctctct agtcattcta 67080tttataattg aaagtgagat attatgaagt cagcctacta tggagggcta actgtaatac 67140actattttat ataagagact ggagcatcct tggattttgg tatccatagg gagtcctaga 67200accattgttc acagatacca agagatgatt ttattgtatt tctctatatt tctcttttca 67260gttctgtcca tgtttgcttt atagcttttg ggtctttgag attgggtgaa tatattgggt 67320tgtatattct tggtgaatta acttaaaaaa tcattttata atgtcctttt tgcaacttga 67380gacagttttt tacttaaact ctttttcttt ctttgacaaa tagttaggtt gcaaattttc 67440caaacttgta tgctctgctt cccctttaaa tataactttc aactttaggt catttctttg 67500ctctcatatc tgagcattgc atgttagaag cagccaacct atatccttaa tgctttactg 67560cttagaaatt tcttccatca gatgttctaa gtcattgctc ttttttttta ttttggagac 67620agagtctcac tctgtggccc aggctggagt gcagtggtgc gatctcggct cactacaagc 67680tccacctccc aggttcacac tattctcctg tttctgcctc ccaagtagct gggactacag 67740gtgcccacca cgatgcctgg ctaatttttt tgtattttta gtagagatgg ggtttcaccg 67800tgttagccag gttggtctcg atctcctgac cttgtgatcc acccaccttg gcctcccaaa 67860gtgctgggat tacaggcgtg agccaccgtg cccggccaag tcatcaccct ttatttcaga 67920cttccacaga tcccctaggg tatgaacaaa atgcagccaa gtactttgcc cgacaccatg 67980cccggcttat tttgtacttt attagtggag acggggtttc tccatgttgg tcaggctggt 68040ctcaaactcc cgacctcaga tgatccaccc gtctcagcct cccaaagtgc tgggatgaca 68100ggcgtgagcc accgcgcctg gcctatttta ttttctatag cctcataaca gaggtgagac 68160tagtgatttt agagccacac ttcctggctt ctgtttttat tattttaatt atttattatt 68220attattatta attttgtttt tttggggggg ttgttttgtt ttgctaaggc ataacaagag 68280tgacttttgc tctagctccc aataactgtc atttctattt gagacctttt cagcatgaac 68340ttcattgtcc atgtcacgat ctgcattttg gtcataatca tttatcagtt tccaagaagt 68400ttcaaacttt ccttcatttt cttatcttct tctgagtcct ccaagctctt gtaagctctg 68460ctcattacct agttccaaag tcaagtccac attttcaggt atccttatag caatgtccca 68520cttcttggta acaattttct gtgttaggcc attctggcat tcttacacaa gaatgcatga 68580gactggctaa tttatcaagt aaagaggttt aattggctta tgattctgca agctgtacag 68640gcatggcact ggcattatct cagattctga ggagacccca aggagctttt actcctggca 68700gaagttaaag caggagcagg cacatcacat gttgagagaa agagcaaggg ggaggcaagg 68760tgccacacac tttttaagca atcagatctt ctcctgagaa ctcatacact attgcaagga 68820cagcaccaag caatgaagga tcaaccccca tgacccaaac acctcccacc aggccctacc 68880tccaacattg gatattacat ttcagcagga gatttgaaca agacaaatac ccaaaccata 68940tcagcctcca agtcttcatg gactggtatt gtataggaga aaactttctt cattcaaccc 69000cagcagagcg tctgtgggcc tctcaaattt tgattctttt ttaaactgct atctttttgt 69060taggaacttt cagaatctag agtatgtagg gtctcatgag cacttttaga cagtggacag 69120agaagcccgt cacttggtca actcccagaa aattttgaat atttcacatg ctatccaatt 69180ttttccttcc caaggagaat ttgaaaactg aggtgttttc tttgtttttt gtttgtttgt 69240ttgtttttct tttctttttt acctcctcac tctgcataga tctgggagca gggaggagct 69300gtagcaagtg ctcatgtgct aatttaagcc accatttttg tgctctttgt agcccattgg 69360aagcaagcat atgcctagcc ccaagatagg caagacaatg accagctgct ggagttggac 69420acagaaaaga tgaaatgtta ggtttgtggt cgaaatattt ccctccccat agagaagctg 69480gagttaagtt tttgtttcta atttttttta acttggtcat tctgccctaa gctatgggcc 69540aggagctatg ggaatgctta catactagtt caagctgcct tctttatttt ccgtagcctc 69600caaaggtctg gtatatgctg agtcctgtca acacttcaag ataggtgata tagaagacag 69660tcgcaagggt agtacctgaa aagttacagt tttggatgtg cagtctcact ctgtctctcc 69720acagggataa gctggagatg cagttttctt acattcagtc tatgttgagc cagggaatag 69780agctattgca agtgttcata ggcacttgca aatttctagt tcctcttgaa tgcatggtat 69840tataatgagg agaggaacag caaagaggtg tctccaattt tcttaaaagt gtcaatgtag 69900ctaatattgc acttccctgg ggtacaatgg cctgtcaact agcttctgga ttttccacta 69960atggaattga tcgctgtata attgttgaat aaaatattgt tgaaagaaaa aagggtccag 70020tccttcctat taggctatct tgctgataac tcatattggc tttttttatt acttagattg 70080tttattttat acctgttaaa agagtgcatt tacacttgag atatagcatt tacataatac 70140tcttattcat gatttaaaga aaaatatgac tgaaataaaa tggttaaatt atccttaact 70200tttagagtct aactcttcag ggttactttt aaactcatat tttcactgta ttttcttatc 70260ctctgtgctg tcaggagagt tggaaatgct tatttcaggc atggtgggaa gcccctttat 70320tgactcagta gatttcttgc aaactgctaa aatttcattg ctgacccttt cttgatttta 70380ttagcttgtg ccaatagaca ttttcagaca acaatgagac gtcatagttc ttccacaggt 70440agtaattaaa cagtctgcaa gcttaaatgt ccagtgatag aaactgtcca gtcatgtaat 70500cagaaaagcc atcaagtgca cacaagctca ggcaatgaca acaatatcat gactgattcc 70560tagacagtat ctgttgcatt atgtcatcaa atgttagact gatcctagtc tcagagatga 70620caaaaaatta aaagaaaaaa atcgtgtctt ggaattgagg aaatgtagtt tactttcttc 70680ataccattat ttccctgaac ctattgtatt tcaaaatgat ttttgactgg cttctataat 70740tatttattct aggcactatc aggataactc ctactgattc tcgatgggtt ggagcttggt 70800ggcttaattt ccttgtgtct ggactattct ccattatttc ttccatacca ttctttttct 70860tgccccaaac tccaaataaa ccacaaaaag aaagaaaagc ttcactgtct ttgcatgtgc 70920tggaaacaaa tgatgaaaag gatcaaacag ctaatttgac caatcaagga aaaaatatta 70980ccaaaaatgt gactggtaag tatttaacat tcattgtcaa tttggagttg ttaatctcaa 71040tgaaaaggaa gaatgagtat tccaaaataa taaagcatac ccaactcatc tggagttggc 71100tttcttttgc actaaattta gataaattat ttttctaaaa ctcctattaa agttaacata 71160tatgtcttga gcacataaca agtggaagag aattaggttt gtacttttta gcagggagaa 71220accaacaaaa gtttacaaac atccattttt tatgagccaa atagtaaata ttaattttag 71280tattatatgg tctaaactgg gagagttcaa agaattataa tatttcattc cttcatttat 71340tcaacaagta gtaccaggaa ctgtactatg ccctggtaat aaaacattac ctctattttt 71400caagaaccta gtgggtgatg ctgagaaata tatagacaat agcaatatag tgccttaagt 71460attatggtga aattaaactt aactattatc aggtgtagag atggattaag gagaaggaag 71520tcgggagaag tttctcccta tgtaattaga gtaatattta ttttggtaat tatctatcta 71580tctatcttat ctaaatattc aaaataaagt ggaagcaaag gtggtagtta agataattag 71640actaagtaat gtaaattagg atgcatcagc atttgacagt gcctcctctt ttgaatataa 71700accctgggac taatggagaa ccattgagag tcaataaaca aagagaatga cttggcagta 71760gccagagcaa gatatgtgaa tcagtgaggt gttgacagca gttttcagat ttgggagaaa 71820tggtgaaata gccaaagcaa tgcaacactt aaaccctcag catctttttc aagttttctt 71880taaagtaaga tgacaaattc tccagtgtag cctaggttct tcctttcatc aggtctttta 71940cttattactt tattgctatt ttctcctttc tatcacacta acccaagagc agtggtgttc 72000tggtactctt tatattggct catagcagag gactgttaag tttcagctac attggtaggt 72060tgaaattgtt catggcaaga gaattaccat gatttattac catggaaatt gggatatact 72120acaagtagaa gtttgttttc ctaagaatca gatgttaaac atttatgttt ttaaaattta 72180acattcacac taaaagtact ataccaataa ttttcatttt gtatatgatg tttctactgt 72240accaaatcaa atctttaaaa aatagtagat tgtctaaacc tataaggagc ggggttgact 72300gtgatccaaa cagaacagag aggataatga agttgtaaaa ataggacaat tgtagacata 72360atctctatta tgaacagttt ttgtaggtgt gaccctaaga aagaggatct taagtatgta 72420tctattagga atggataaaa taagaatata tagtcagaaa aaatattgaa tttattccat 72480atgctcttga atagaactaa aactgattag aatgaaaaga tgatttcagt tcattacaaa 72540aacagtgtgt aaacaatgag aacttttcaa aagtggagga aattgcttcc taaggtactt 72600agtttaatgc cacttaagtt gtttattgat ccacttatta atgatatata gtagatcatg 72660actatacaga agtttacact ggatgacatt gaatttctca tcctcaaaaa tgcaacgctt 72720gtgtgaatgt atatactcca tttctgttga agaaaggcca caactcactt ataatactta 72780caaatcaggg atggtttttc atgactgggg agacctgtgg agagaaatgt ggcacttttg 72840cccaagaatt ttaaatgttg tttattccca ctatacattt tcttatctct tctttttttc 72900ttttctgttt cttttctcta actccttcta ctccttattt caagcagatg caactgtttc 72960gtagctgaca ttaaatggat gtcttagttc tgaccatatc taatgaaaat ctttagagat 73020ttaaatagag aaaaatattt caaagtccgt atcatccaac tctcagtaac catatcttgg 73080ctctgtcttg atgaactctg atacttccta ctgtttttct aagtagttcc ttctactttt 73140aagtcctatt acagctagtt gacctggtga tcacagatcc aaatgacata atttctacca 73200tgaacagaag ttagaagttt gttaccacag ctgtttgtag ggataggtgg ttgtattatt 73260actattataa tactacttgg gacacaatat tatcccctgg ctgctttcct tgtatcttaa 73320gacagagggt taataatatt gccaaattta ctgagaaagt atgttatggt agaagagctg 73380tatactagag aaacaggagg tctgagtcct catactaaat taatctttaa gaattttgaa 73440cctcaatggt cttatttctg tgagttttga attatgctgt ctttacattt ccatttaata 73500gttatatttt taatataata cttatatcat taagtactaa taaataagaa acatcatatg 73560tcttattcac tttttgtttg tttgtttttg ggtttttttg tttgtttgtt tgtttgtttg 73620tttgagatgg agtcttgttg ctctattgcc taggctggag tgcagtgtca ccatctcagc 73680tcactgcaac cttcgcctcc ctaattcaag caattctcct gcctcagcct cccaagtagc 73740taagattaca ggtgtgtgcc atcgtgctgg ccaatgtttg tatttttagt agagttgggg 73800tttcaccatg ttggccaggc tggtctcgaa ttcctgaccc caggtgatcc atctgcctcg 73860gcctcccaaa gtgctaggat tacaggagtg agccactgtg cccggccttc acttttgttt 73920tttgaacaat tagcatattg tctggtaccc agttgaaaac ctaacatttg ctgaatgaat 73980gaataagtga attaatatgt ttgcaatagt attgtaaagt acccaggata accaaatatt 74040aagtgaagaa agcaagttac aaaacagcac ttacgtatga ccctatttga gggtaaaata 74100aactaaacta ataaatatta atattcgtat ggaaaatatt gaaagaatat atttaaaagc 74160tgtgaacagc ctgtggtatt gcaggctatt ctcactcttt gtgttatgtg tttatagaat 74220tttaaatctt acatgactta cgttcacaaa ttttagatat aaatgtatat ttaagttgca 74280ttcaaatatt ttctttattt ttacaatttt acaggttttt tccagtcttt taaaagcatc 74340cttactaatc ccctgtatgt tatgtttgtg cttttgacgt tgttacaagt aagcagctat 74400attggtgctt ttacttatgt cttcaaatac gtagagcaac agtatggtca gccttcatct 74460aaggctaaca tcttattggg taagacatat tttttacttg tgtgcttaat aagtgaaata 74520atactaaata ctgtattcca agtggtattt tattgtgaaa gtgattttgt attttagtaa 74580tacaggataa gtataatttt cttgtattct ttctcaaatg ttattaaaca tataaaactt 74640gtgatgtcac tattgctctg catttgaagt tgcatcttat tttagatgag ttcctgaaaa 74700aaatgttgca aataaatgga caatttagag gtagtatctg tataattgga tcttataatt 74760tagtgctaag atctgagaca aacccttttg taattataat cattataatt ctataattta 74820tggactttga aatcaagact cagttactta caaaaatatg acactaatag ttccaaaaag 74880agtatcgatt taaatacatc aaaatatgca taattcaaaa caaatatatt ttacagagta 74940ttttttgcta caatatctat tttcaatggc acatttagat gtgcttatta aggaaagttt 75000ccttgtatta ttcttcccac aactctagta ttgtagacac attatagaaa ttcaatataa 75060atatatgatg aattaaacaa cttatcatgt ggtatgtaac taggtcataa gtaaacaaga 75120aaatgaatgt actgaagcag gagaccaagc ttccagataa tctctttgtt gatcttaaga 75180taaaagttta aaatcgaaaa ataatgtttt gactcccagt aacctagcct gagctttttc 75240ctagagaaga cttcatcttt gttaactctt attagacaaa gatatggaaa agttatagga 75300gggattaaac attattaatc ctgtatgtag agcgatttgt cagttcaggt tctgtatgtt 75360ttttaataaa tgacaaagat atattaattt ttatgttgtt aagctctggg cagatttagt 75420gtgagttact gagggttaga actctatctg agagaggcaa aaggctttag atgaagttcc 75480ataggcagaa agatggtgtt ttgttgttgt ttatttccag aaaaacaaaa ttgcctcata 75540gaaattatct gctccaacaa atatcctcag ccacactgcc ttttgctatt gaggaaacca 75600aactgtcatc attggcagga acaaattaca cagatcccct accaccatac tgctatatca 75660ttcttctttt taaaaagtaa taagattggc attctactat aaagatacat gcacacatat 75720gtttattgca gcactatttg caatagcaaa gacttggaac caacccaaat gaccaccaat 75780catagactgg ataaagaaaa tgtggcacat gtgtaccatg gaatactatg cagccataaa 75840aaagaatgag tttatgtcct ttgcagggac atggatgaag ctggaaacca tcattctcag 75900caaactaaca caggaacaga aaaccaaaca ctgcatgttc ccactcataa gtgggagttg 75960aacaatgaga acacatggac acagggaggg gaacatcaca caccggggac tgttgagggg 76020tgggaagcaa ggggaggaag aacattagga caaataccta atgcattcag gggttaaaac 76080ctagatgaca gtttgatagg tgcagcaaac caccatggca catgtatatg tatgtaacaa 76140acatgcacat tctgcacatg tatcccagaa cttaaagtaa aattttaaaa agaagcaata 76200atattgaata aatttgattg acatacattg tgtttcatct ataaagacat atcagaaaac 76260tcatatatga ttacaacttt ttttcttttt tttctaggag tcataaccat acctattttt 76320gcaagtggaa tgtttttagg aggatatatc attaaaaaat tcaaactgaa caccgttgga 76380attgccaaat tctcatgttt tactgctgtg atgtcattgt ccttttacct attatatttt 76440ttcatactct gtgaaaacaa atcagttgcc ggactaacca tgacctatga tgggtttgta 76500tatatcacta tatcaattgc ataatatgtt aaccatcaaa ttaagagtct ctgtataagt 76560aatataaggc agaaaacaat tttaactaaa ctttctttaa gttaagagaa atttcaattt 76620taaaattttt aaaatatctg tttcttaaga cctcaaacac attcttttat tcctccacta 76680aagagaagca acataggttg taataataat aactattatt tatgtggtac ttacaattag 76740tagtgggtac ttttatcatt attttatgaa tgggaaaagt aaggcttaga gaaatacatg 76800gattacacag ctagcattat taagattcta actcaaattt gagtttttta agtccaaaac 76860tcttagtctt aaccaccact gtaatcttgg atggatcata agagttacat aaatggcatt 76920agccaaaagt gactaaacaa cttttatcta cagttcatat cgatgttcaa caactatctt 76980aacaaaagaa cacttttaat gttgtactga attttctttt ttgcaagcta atattgtttt 77040tttctgatat tatctacatt ggaagtagca ttaagaaata ttctatatat aattgcatat 77100tagacattga agaatcttta cttttccatg attaccatgt atagcaaagt atttttagtg 77160caacagtctc cacctcaaat caagggcaag aatcctatgc agttttctga taatttcctg 77220aatatagcca acaatttaag cttaggaagg ttcacattca agcaacaagc agagatgctc 77280agatcacaat tcagtaacca tgttctttag tgctgcttac tactggtgct gagctttcaa 77340agtctggatc ccatgaggtg ttggttttaa cttgtcaaat attcccacat tttcttctat 77400aaacattgtg ctattcttgg aggcttgcca aggttatctg aaattgtttc cctgcacact 77460gctaattctg aactgttatt ggtatctcct atccaccatc aactactgta gtaaattaaa 77520atacattgtc ctagaatact gaattttaga ggtaaaagaa ccttagagat gatgcaatcc 77580aacccttgta ttatactttc ctttattatt gaagagtcag aaaaaatgta acatgttgaa 77640gtcacacaat gtctttagac tctagactga tcctatgtca cacccttagt tcaaaagcct 77700tcttggttgt aaggacaggc cagtttcttg acaacaaggt tagtcactgt acaaagtata 77760caaaagatgg cagcagagtt aaacagaatt tgtttcattt aataaaattt tattaagcct 77820ttccttaaag gtaaatatta aggatatttg taggatacat cagttccctc atgggactca 77880taatctaatg ataaataata taattaatgg attcaacatt cataaaatcc tgcgactggg 77940ataagttttt ttttaagtat gaattattgc agaggtctcg gaatgtgttc tgaatatctc 78000taaggatccc tgagacttta tcaaggggtg cacaacttca aaactatttt tataataata 78060ctaagacatt atttgccttt ttattctcat gctatcctga cagtatagtg atattttcta 78120atgctccaag gtatgttatt aattcattaa tctgactgct aaaatatgtg tgcttatgta 78180cttttgtgta ttaaaatttt cttagtatta ctttctaata tagtacatgt caagaggtac 78240aacttaattt aacaaaatcc ctttggaaca agccctcaat cttttataag agtgtgaagg 78300acttctgaga accaattttt tttccaaaaa aaaaaaaaac cctgtgaggt tggcattatt 78360atctatgact tacaaatggc aaaactgatt ttagaaagaa gtgccagaat taatataaac 78420acagatgtga ctgattgcaa tatctggact gggtcattgt cttagtccat tcaggctgca 78480aagttctagg tagcttatta atacacagaa attaattttt caagattcta aaggctggaa 78540catgtaagac caaggtgatg gcacttttgg tgtctaggaa gggcccattt cttaatttat 78600agacggtacc ttctcattgt gtccaggcat ggtggatggg gcaggcaaag ggtcagtaat 78660tccattcatg agtactcatc ctcatgacct tatcactttc tagaggcctg acttcataaa 78720gtcttcatat acgagattag ttttcaatct atgaatttgg gggccacaaa cattctgact 78780atagtagtca taaaccattc tacttaacca ctccaagtag tatttcctca agcagaatat 78840gctttttaat aaaattattg ataatgtagt ttctgaagta tgaatcttag tttttcattt 78900aaattatgtg ctcattcaaa gataacacat caatcctcaa ttattatcaa attaaacatt 78960tgaaagaaaa taatttttta aatgtttaag cagaaatgaa ttatacaaaa aatatatttt 79020ataattttag ctatgttata atcatatttt ataatttata accatttcat aaaggaaatc 79080agtataaagt atactatagt tttatttcaa aaatatactg agcttttcta gcctttttca 79140actgattcta ttcttgattt ttcattttgt agaggttctg ctttaagcat gtctgttttt 79200ttcttacata ttaaaataga gatttttaaa ttcaacctag ttaaatagca ttcgtagact 79260cacaagactt tacagtgagc tgaaaggaat gtcagtctaa tgtcatcacc ttactgaaga 79320gaaactcagt ctcagaaaaa agatgtaact tatctaatgt gaagtttctt catagaatta 79380taacaacttc ttgtctaagt cctacttaac atctttggtt tatttttaca ttttgctttt 79440tctaggtcac aagtcatgta ttggcaaaga tggagagcgt aaaataaata agcattaaaa 79500aaaactttgc catttcgtca tcatcaaagc aaatttcttc atataaagaa aaattcttta 79560tctacttttt ttccctcttt ctctgctttc actttacttc ttccttctcc tccccttctt 79620tgtctttttc ttctctctct ctctttttga tatatgtcta tcatatattt ccagaaataa 79680tccagtgaca tctcatagag atgtaccact ttcttattgc aactcagact gcaattgtga 79740tgaaagtcaa tgggaaccag tctgtggaaa caatggaata acttacatct caccctgtct 79800agcaggttgc aaatcttcaa gtggcaataa aaagcctata gtgagtatta gtttttactt 79860tcctctcctt attcaaaagc acagattaga ttgaacaatt ttttaccaaa tatttctgta 79920actaaggact ccattaaaaa gataaaagag aaagtttcca gtattatctg ttattgtgat 79980gggtgtgatg tataaacaaa gttttatata aaagtctgct tagggcacaa tcaggttttt 80040ctgttacttg aattctaatt ggagatcacc ccactttttt cctttgagat tgtaagacta 80100tgacctttta gaatttgaat gcatttagaa tatctaagaa gcacctcatt tgactaaagc 80160ctataatttt cattaagttg gaattacttt atccctcaga attcaggaaa atgagttaac 80220ccattgtcag cacttcctat cttactaaga caacagtcaa tatgcaatgt tatatacaga 80280ttctgatctg tttagctctg ggatcactac cctttttact ttttaagaaa ttaatcaagg 80340cttcatgctc acttgactgc cctattcttg attttctatt ttgatttttc caaagctggc 80400acttctaccc aagataatgt agtatcctgc tcacctaatg tcaatatgtc ccatagaaat 80460gtcatttatt ccgtcctgca aaacctttct ttccatgtga actacagttt ttctctaatc

80520tcctgggtag ctacctgtca ctgggaatgg gttatggtgt ttcccatacc tacaatccac 80580tcaacatctc acaaagttgt gtaatgtttt cctaggaact tttactatta ccaacattac 80640taaaacagtc aactataatt attgctctct gccacaccct tctgtgtttg atttttaaac 80700attctccatc tactcttgcc catggatcta cctaccaatt ataataagga atggcatgta 80760gaattttaaa gaataaagca tcctggactt tttgaagaaa ggccacaact ttaataaact 80820tgcacaaata tggcccaaag actacttaaa agcccacatc ttagtcatgg caacaatgaa 80880tcttttgtgc agttgtttcc ttttcctttg ctgtttattt ttattttgct gttttttaaa 80940aaaataattt aactcttatt ttaggtaaag gggatacaaa tgaatttgtg ttagatgggt 81000atattgtgat aagctaaagt ttagggtaca atcattccca tcccccaggt agtgagcata 81060atacccaata agtggctttt tagtacttgc tgttttttat ctctccactc tagtagtctg 81120taatatgtat ttttcctgtc cttatattcg tgtggaccca gtgattagct tccacttata 81180agtgagaaca tgtggcatct ggttttctgt tcctatgtta attcacttaa gataatgacc 81240tccagctgca tccaggttgc tgcaagggac attatttcat ccttcttttg gccatgtagt 81300attccattgt ctatatgtac cacatttctt tatctaattc actgttgacg ggcacccagg 81360ttgagaccgt gtctttgcta ttgtgaatag agctgtgatg accatagaag tatataagta 81420gatgtgtttt tggtagaaga atttattttc ctttgggtat atacccggta gtgggattgc 81480tgagttgaat ggtagttctg tttaagttct ttgggaaatc tcgaaactac tttacacagt 81540gactgaacta atttacattc ctaccaacat aggataagca ttccctttct tctgcagcct 81600tgccagcgtc tgttttttta atgttttgaa ccagtcagcc cttctgactg gtgtgagatg 81660gtatctcctt gggattttga tttgcatttt tttgatgatt agtgatgtta aacattttta 81720tgtgtttgtt agctgcttgt atgtcttctt ttgagaagtg tctgttcatg tcctttgtct 81780actttttaat attgtttttg ttttttgctt gttgaattgt tcaagtttct tatagattct 81840ggatattagt cctgtgttag atgcatggtt tgcaaaggtt ttctcccatt ccatagattg 81900tcttttcact ctgttgatta tttttgttgt gcagaagctc attagtttaa ttatatccca 81960cttgtccatt ttttttgttg caattgcttt tgagaactta gtcacaaatt ttttgccaag 82020gccaatatcc agaatctttt cttggttttc ttcagtggtt tttatagttt taggttttac 82080atttcagtct gtaatacatt ttgattaaat tttttatatg aaaagaaggg gtccagtttc 82140atttctctgc atagttagcc agttattcca gcaccattta ctgaataatg agtactttcc 82200ccattgcatt ctttttgcta acttcattga agatcagatg gttttaggtg tgtggctttg 82260cttctgggtt ctctattctg ttcctttagt ctaggtgtct gtttttgaac cagtactatg 82320ctgtttggtt actgtggcct tgcagtatag tttgatatca ggtaatggga tgcctctcac 82380tttgttcttt atgcttagga ttgctttgac tattcagtct cttttttcct atggaatttt 82440acaatagttt tattctaatt cagtgaaaaa tcatgccggt tgtttgataa gaataccatt 82500gaatctgtag attgctttgg gcagtataga cagtttaatg ataatttttc taccaatcca 82560tgagagtaga atgtttttcc acttgtttgt gtcacctata atttctttca tcagggtttg 82620tatttatcct agtagagatc tttcacttcc ttggtttaaa tgtattccta ggtatttaat 82680ttattgtagt tattctaaat ggaattgcat tattgatttg ggtatcagtt taactgttat 82740cggtgtatag aaatgctact aatttttttc cattgatttt gtattctgaa actttattag 82800agtatgttgt cagttctagg aggcttttgg cagagtattt agggtttttt tttaattaat 82860taatttattt atttttaatt atactttaag ttttagggta catgtgcaca ttgtgcaggt 82920tagttacata tgtatacatg tgccatgctg gtgcactgaa cccactaact cgtcatctag 82980cattaggtat atctcccaat gctatccctc ccccctcctc ccaccccaca acagtcccca 83040gagtgtgata ttccccttcc tgtgtccatg tgatctcatt gttcaattcc cacctatgag 83100tgagaatatg cggtgtttgg ttttttgttc ttgcaacagt ttactgagaa tgatgttttc 83160cagtttcatc catgtcccta caaaggacat gaactcatca ttttttatgg ctgcatagta 83220ttccatggtg tatatgtgcc acattttctt aatccagtct atcactgttg gacatttggg 83280tgggttccaa gtctttgcta ttgtgaataa tgccacaata aacatacgtg tgcatgtgtc 83340tttatagcag catgatttac agtcatttgg gtatataccc agtaatggga tggctgggtc 83400aaatggtatt tccagttcta gatctctgag gaatcgccac actgacttcc acaatggtta 83460aactagttta cagtcccacc aacagtgtaa aagtgttcct atttctccac atcctctcca 83520gcacctgttg tttcctgact ttttaatgat tgccattcta actggtgtga gatggtatct 83580cattgtggtt ttgatttgca tttctctgat ggccagtgat gatgagcatt ttttcatgtg 83640ttttttggct gcataagtgt cttcttttga gaagtgtctg ttcatgtcct tcgcccactt 83700tttgatgggg ttttttgttt ttttcttgta aatctgttgg agttaattgt agattctgga 83760tattagccct ttgtcagatg agtaggttgt gaaaattttc tcccattttg taggttgcct 83820gttcactctg atggtagttt tttttgctgt gcagaagctc tttagtttaa ttagatccca 83880tttgtcaatt ttgtcttttg ttgccattgc ttttggtgtt ttagacatga attccttgcc 83940catgcctatg tcctgaatgg taatgcctag gttttcttct agggttttta tggttttagg 84000tctaacgttt aagtctttaa tccatcttga attgattttt gtataaggtg taaggaaggg 84060atccagtttc agctttctac atatggctag ccagttttcc cagcaccatt tattaaatag 84120ggaatccttt ccccattgct tgtttttctc aggtttgtca aagatcagat agttgtagat 84180atgcggcatt atttctgagg gctctgttct gttccattga tctatatctc tgttttggta 84240ccagtaccat gctgttttgg ttactgtagc cttgtagtat agtttgaagt caggtagtgt 84300gatgatgcct ccagctttgt tcttttggct taggattgac ttggcgatgt gggctctttt 84360ttggttccat atgaacttta aagtattttc caattctgtg aagaaagtca ttggtagctt 84420gatggggatg acattgaatc tgtaaattac cttgggcagt atggccattt tcacgatatt 84480gattcttcct acccatgagc atggaatgtt cttccatttg tttgtatcct cttttatttc 84540cttgagcagt ggtttgtagt tctccttgaa gaggtccttc acatcgcttg taagttggat 84600tcctaggtat tttattctct ttaaagcaat tgtgaatggg agttcactca tgatttggct 84660ctctgtttgt ctgttgttgg tgtataggaa tgcttgtgat ttttgtacat tgattttgta 84720tcctgagact ttgctgaagt tgcttatcag tttaaggaga ttttgggctg agacaatggg 84780gttttctaga tatacaatca tgtcatctgc aaacagggac aatttgactt cctcttttcc 84840taattgaata ccatttattt ccttctcctg cctaattgcc ctggccagaa cttccaacac 84900tctgttgaat aggagtggtg agagagggca tccctgtttt gtgccagttt tcaaacggaa 84960tgcttccagt ttttgcccat tcagtatgat attggctgtg ggtttgtcat agatagctct 85020tattattttg aaatacgtcc catcaatacc taatttattg agagttttta gcatgaagtg 85080ttgttgcatt ttgtcaaagg ctttttctgc atctattgag ataatcatgt ggtttttgtc 85140tttggctctg tttatatgct ggattacatt tattgatttg tgtatattga accagccttg 85200catcccaggg atgaagccca cttgatcatg gtggataagc ttttggatgt gctgctggat 85260tcattttgcc agtattttat tgaggatttt tgcatcaatg ttcatcaagg atattggtct 85320aagattctct ttttttgttg tgtctctgcc tggctttggt atcagaatga tgctggcctc 85380ataaaatgag ttagggagga ttccctcttt ttctattgac tggaatagtt tcagaaggaa 85440tggtaccagt tcctccttgt acctctggta gaattcagct gtgaatccat ctggtcctgg 85500actctttttg gttggtaagc tactgattat tgccacaatt tcagatcctg ttattggtct 85560attcagagat tcaacatctt cctgatttag tcttcggaga gtgtatatgt caaggaattt 85620atccatttct tctagatttt ctagtttatt tgcgtagagg tgtttgtagt attctctgat 85680ggtagtttgt atttctgtgg gatcggtggt gatatcccct ttatcgtttt ttattgtgtc 85740tattagattc ttctctcttt ttttctttat tagtcttgct agcggtctat caattttgtt 85800gatcctttca aaaaaccagc tcctggattc actaattttt tgaaggtttt tttttgtgtc 85860tctatttcct tcagttctgc tctgatttta gttatttctt gccttctgct agcttttgaa 85920tgtgtttgct cttgcttttc tagttctttt aattgtgatg ttagggtgtc aattttggat 85980ctttcctgct ttctcttgtg ggcatttagt gctataaatt tccctctaca cactgctttg 86040aatgcgtccc agagattctg gtatgtcgtg tctttgttct cgttggtttc aaagaacatc 86100tttatttctg ccttcatttc gttatgtacc cagtagtcat tcaggagcag gttgttcagt 86160ttccatgtag ttgagcggtt ttgagtgaga ttcttaatcc tgagttctag tttgattgca 86220ctgtggtctg agagatagtt tgttataatt tctgttcttt tccatttgct gaggagagct 86280ttacttccca gtatgtggtc agttttggaa taggtgtggt gtggtgctga aaaaaatgta 86340tattctgttg atttggggtg gagagttctg tagatgtcta ttaggtccgc ttggtgcaga 86400gctgagttca attcctgggt atccttgttg actttctgtc tcattgatct gtctaatgtt 86460gacagtgggg tgttaaagtc tcccattatt aatgtgtggg agtctaagtc tctttgtagg 86520tcactcagga cttgctttat gaatcttggt gctcctgtat tgggtgcata tatatttagg 86580atagttagct cttcttgttg aattgatccc tttaccatta tgtaatggcc ttctttgtct 86640cttttgatct ttgttgtttt aaagtctgtt ttatcagaga ctaggattgc aacccctaac 86700tttttttgtt ttccatttgc ttggtagatc ttcctccatc cttttatttt gagcctatgt 86760gtgtctctgc acgtgagatg ggtctcctga atacagcaca ctgatgggtc ttgactcttt 86820atccaatttg ccagtctgtg tcttttaatt ggagcattta gtccatttac atttaaagtt 86880aatattgtta tgtgtgaatt tgatcctgtc tttatgatgt tagctggtta ttttgctctt 86940tagttgacgc agtttcttcc tagtcttgat ggtctttaca ttttgccatg attttgcagt 87000ggctggtacc agttgttcct ttccatgttt agcgcttcct tcaggagctc ttgtagggca 87060ggcctggtgg tgacagaatc tctcagcatt tgcttgtctg taaagtattt tatttctcct 87120tcgcttatga agcttagttt ggctggatat gaaattctgg gttgaaaatt cttgtcttta 87180agaatgttga atattggccc ccactctctt ctggcttata gggtttctgc cgagagatcc 87240gctgttagtc tgatgggctt ccctttgagg gtaacccgac ctttctctct ggctgccctt 87300aacatttttt ccttcatttc aactttggtg aatctgacaa ttatgtgtct tggagttgct 87360cttctcaagg agtatctttg tggcattctc tgtatttcct gaatctgaac gttggcctgc 87420cttgctagat tggggaagtt ctcctggata atatcctgca gagtgttttc caacttggtt 87480ccattctccc catcactttc aggtacacca atcagacgta gatttggtct tttcacatag 87540tcccatattt cttggaggct ttgctcgttt ctttttattc ttttttctct aaacttccct 87600tctcacttca tttcattcat ttcatcttcc attgctgata ccctttcttc cagttgatcg 87660catcggctcc tgaggcttct gcattctcca cgtagttctc gagccttggt tttcagctcc 87720atcagctcct ttaagcactt ctctgtattg gttattctag ttatacattc ttctaaattt 87780ttttcaaagt tttcaacttc tttgcctttg gtttgaatgt cctcctgtag ctcagagtaa 87840tttgatcgtc tgaagccttc tctcagctcg tcaaagtcat tctccatcca gctttgttcc 87900attgctggtg aggaactgca ttcctttgga ggaggagagg tgctctgctt tctatagttt 87960ccagtttttc tgttctgttt tttccccatc tttgtggttt tatgtacttt tggtctttga 88020tgatggtgat gtacagatgg gttttcggtg tggatgtcgt ttctgtttgt tagttttcct 88080tctaacagac aggaccctca gctgcaggtc tgttggaata ccctgccgtg tgaggtgtca 88140gtgtgcccct gctggggcgt gcctcccagt taggctgctc aggggtcagg ggtcagggac 88200ccacttgagg aggcagtgtg cccgttctca gatctccagc tgcgtgccgg gagaaccact 88260gctctcttca aagctgtcag acagggacat ttaagtctgc agaggttact gctgtctttt 88320tgtttgtctg tgccctgccc ccagaggtgg agcctacaga ggcaggcagg cctccttgag 88380ctgtggtggg ctccgcccac ttcgagcttc caggccgctt tgtttttcct aatcaagcct 88440gggcaatggc gggcgcccct cccccagcct cgctgccgcc ttgcagtttg atctcagact 88500gctgtgctag caatcagcga gactccatgg gcgtaggacc ctccaagaca ggtgcgggat 88560gtaatctcgt ggtgcgccgt tttttaagcc cctcggaaaa gcgcagtatt cgggtgggag 88620tgacccgatt ttccaggtgc tgtccgtcac ccctttcttt gactgggaaa gggaactccc 88680tgaccccttg cgcttcccaa gccaggcaat gcctcgccct gcttcggctc acgcacggtg 88740cgcgcaccca ctgacctgcg cccactgtct ggcactccct agtgagatga acccggtacc 88800tcagatggaa atgcagaaat cacccgtctt ctgcgtcgct cacgctggga gctgtagacc 88860ggagctgttc ctattcggcc atcttggctc ctccaaccag ggtttttgag atatagaatc 88920atatcatagt gcagagagat aatgtgagtt catttcctat ttgtcagtgt tttatttctg 88980tctctttcct gattgatctg tctaggattt ccagtactat gttgaatagg agtggtgaga 89040gtgggcattc atgctttgct cctgttctta agaagaatgc ttccagcttt tgcacattat 89100atatgaagtt ggctgtggtt ttatcataga tggctcttat tattttgagc tatgttcctt 89160caatgcccag tttgttgaag aactttatca taaaaggatg gtggatttta ttgaaagctt 89220tttctgcatc tggtgaaatg ctcatatact gtttatccta aattccattt atgtagtgaa 89280tcacatttat tgattgtgta tactggacca tccttacatc tcaaaaataa agcctacttg 89340gtcatgatga attcactttt tgatgtgctg ctggattcag tttgctagtg ttttgttgag 89400gaattttgca cctatatgca tctatattca tctatattca ccagggatat tggcctgttg 89460gtttgttttt gatgttgttg ttgtttttgt gtcttgctat attttggtac caggatgatt 89520ctggcttcaa aaaaatcagt taagaaagag tccttctttc tcaatttttc agaataattt 89580agtacagtgg gtactcactc ttttttgtat ttccagtaga atttggctat gaatgcattt 89640ggtctagggc ttttattgat aggcaggttt tttcagtact gattcaaatt tggaactcta 89700tattagtgtt cagggtttca attactcttt gttcgtcttg gatggttgtt ggatggttca 89760ttttggatgg ttggataaga atgacccagt taatacatgc tccctctttg cacactagcg 89820aaggcctgaa agtgatagaa tattagaacc ctaaaaagaa ttgtgtctac cacaagacat 89880aatcttcatt atactggcaa tgactatgcc atttggggac tattgcaaag tttttattat 89940ttatttattt gtgtatttat ttatttatta ctaaatcctc aataatgaac catcacttct 90000taaaatagtg ttctttgtac caaagcttag ttttattgac caatacactt gttccataaa 90060aaattcctct atattattcc tagtgaaaaa aaatagtaag aactgtaagt ttggcagaac 90120tgtagatgta tagatttaaa ttcttctaca attcttcctt caataattga tctttagcat 90180taatagattc aacgtgaggt tcccttaaac tttagcctag atttagaaca gaatttatta 90240aagccacctg tctatataaa ctgttcaact gattaaaaat ctgaaatcac ttgtttctac 90300attttccact tctgtgctct aaacactagt ggggcattct gttgtgttta acctctctgg 90360taataatatc atctgtcatt gtatccttgg attttgttta tgcctgctaa attaaaattt 90420tagcatctct acctgtctct atttttcctg gactcagtgc cattttcatg ggtgactcca 90480gttaaatttt gattactccc aaactgctaa attatctgaa ttctttggat aattcctcct 90540cagggcatgt ctctgaaact tagagattgt ccaaaagagt atgtgctctg cagagggtaa 90600aagggaatgg aaaataatta ttaaagagaa tctatagtga tgagaaaatt gtatacagag 90660ttctaggcac taatttcttt gtttcttagt tttaaaatta agaatgaact aaatgtcaat 90720catgaattac attgtcttat atagaaagaa atccacaaaa ctattttacc ttttatctct 90780taagcaactg tatttttaga atcttcttaa actgtaaata tattagtttg aacaagtgag 90840acttcactaa atataatgca atgtatttgc agcactgtta ggtcttgcaa atttcttatg 90900tcatatttta tacacaacgc ttaaggtgtt ttacaactgc agttgtttgg aagtaactgg 90960tctccagaac agaaattact cagcccattt gggtgaatgc ccaagagatg atgcttgtac 91020aaggaaattt tacttttttg ttgcaataca agtcttgaat ttatttttct ctgcacttgg 91080aggcacctca catgtcatgc tgattgttaa gtaagtatga cttttaaaaa cattttcata 91140tgcatgagac tataaacaca cctaatgata tgcatatttt tacataatat actgggaatt 91200caaattcata tttcatcaaa ttttaatttt ctgagaattc attttattaa aattactatg 91260aactctcaag gctgtaatta ataattttgc ctctaattct tccattaaaa gtccagattc 91320catacgtttc ttctcttact aagaatctga agacacagac tgacaattct ctcagttgta 91380aaagaatcgc cctaggatcc taaaagaact tgttgaattt tgagttgcct tacatcctaa 91440tgagagatgc cttgcatctc tcagggtaaa tctattgatt tcactaaaat aaagcatttg 91500aaaactagat ataaaatatg ctccatttga taacattcca aaacttttaa tcgactcaca 91560gcatgacttt tataataccc ttgtagaaaa ataaaaaaat acacaggaag aattagttcc 91620tttcttggct cattagaaaa gatacaatgc ttggtgaata ttacatggta aatgaaacca 91680ataagatact tgttgtcata cagctttcaa aattacagga aagactggtg tgagataaat 91740aatcttaaaa tcaaagcaca tatttataaa ttgttctgag tcctcatcag gaaaaagatt 91800tccctaaaaa gaaagattca aaaggaaagt taatttagga ttgaggtggg gggctgtgaa 91860gaagaggatt cagagtacat ctcaaaataa gtaacattta ttctaaaggt ctaaagaaaa 91920agccaaatga aagggtttcc aggagagggt cttggtgctg acgccttaat acaggaaaga 91980gctggtgtgt ttgagaaatg aaaagaagct ggcagattga aacatactga atgagaggtt 92040gtgacacatg ataagattgg agagttagga agggtgcagg taatgcatgc cctactggcc 92100aagttgattc aatcacctaa aacttgtaac atgtaaataa ttgcttttag atcttaaaaa 92160tatacatgtg taagtatagt gacctgggtt aacattcaat tgtactttta aaacttacat 92220tgttgatcat aagttcactg tcagccaaca gcatgacatg gtagagatga aaaaaaaaag 92280catttttaac atttgttaac attagtatca acctgtaaat tgaatttaca gttgtttaat 92340tttgaccctg actgcaaatc ttatcaaatt atttatacta aatatgccac agatatagct 92400ccatcttaat ataaaatgtt gtctactcaa aaggagaagt ctttcatatt tgccaaatta 92460aattcattaa catattaaaa ataaccttaa aattaaataa tagtctgcat atcaacaggt 92520tttagctttt tattttaaac tcatgagttt gaaaaaacac tgttccatca tcgatgataa 92580caatatcata tctgtttcag aaattgatta aatcagcatt acaacttgtc aaaaatattt 92640aactcttgct agcctttgat tttattgaaa taagcatttt gtgaatatga ctacagaata 92700aaaatataaa tttcagtttg ttaatagttt tctaatgctt aacactatga agctattttt 92760taaacttgat taagtaggca gaaggacatc catttattca atatgtattc attttttatg 92820tcaggcatag ttgtatgcac tgaggatgca actgtgaaca aaagtgatag aactttataa 92880gcttttagta tgggtgggga atgaaggaat gaatgtgtgt agcagaaaac acagtaaaca 92940aataagtgag taaacatcta aaatagagta agtgtgaagc actagaaaga taaataaatc 93000acagttaaga aaatagaaaa aaatgagaaa ataggcaaga gatactagtt cagatatggt 93060gctttggaag tcctttgagt aaagacctga atgaagagat agaaaataaa ggtacaagcc 93120atgctaaatg gagacatagg aggaacaatc caggcaaggt agaagaaagg tcagcgtcct 93180ggtgtgaagt atagttgaca tgtacaaggt ccaaaaacgt gtgtaaggag gagagaggtg 93240acaagtgcag caagagagct agcctagttc agatcctatg ggtcacagga aagactttga 93300aatatattct aaatgtgttg aaagcccaag gggatttaag cattagtatt tgcaaagatg 93360ccttacataa ctagaagatc actctggctg tgggtagaaa gtgtgttttg tgaaaacaat 93420agtgaagtca gggaaaacag aaggcttgaa ttgttcttct caagatggaa gcttgattga 93480gaatgctgat aataggaaaa tatgaagtaa atgaaatgag taaatgaaac aaatatgagt 93540ctcagttgtt ttgctttatt ttattatatt tatttattta tttttgagag acagtcttgc 93600tctgtcaccc aggctggagt gcagtagcac aaccttggat tgctgcaacc ctccgcctcc 93660caggttcaaa cgatgctcct gcctcaacct cctaagtagc tggaattaca ggtgcacgcc 93720accgtgcctg actaattttt gtatttttag taggacctgg ttttaccacg ttggccaggc 93780tggtctcaaa ctcctgacct caagtgatct gctagcctct gcctctcaaa gtgctgggat 93840tacaggcctg agccacagca cctggccttt gttttatttt ttaatgcaaa gccagtaggg 93900tttgctgaga cattgaatgt ggcatgtgag aaagataatt taaggataat cccaaagttc 93960tggcttgagt tctggaagga tggtggtact attgaacaaa atgggaaaga ctaagaaagg 94020gtagattggg aaagtgaaaa agcaagaatt tgttctatct ctataaagct gagcagcctg 94080ttcaatatct agcaatgtca tatatgcaat ccaacaggag aaaccttgat gccagagcca 94140taaattttag agtcagcaac gtacagatgg tatttatttt tatttttact tatttattta 94200tttagagaca aggtctcatt ttgttgtcca ggctgaagta taatggcatg attatagctc 94260actgtaacct tgaatgcctg tattcaagca atcccccaag gcggtattaa aatccatgga 94320actaatgaga tcttctaggg actgagtaca gatagaaaca agatcctagg atcagttctc 94380aatcactcta atttaaagat cactaatagg agaaaccaat aaagaaaact gaggaggttt 94440catgagaaaa actaggaaag agcgttgtcc tcaaactaat aaagcatatg tcaaaaagag 94500cataagtaac tgtgtcaagg gctgctgaga gttcacagga gttgaacctg ggaggcggag 94560gctgcagtga gccaagatcg ctccactgca ctccagcctg ggagacagag caagactggt 94620ctaaaaaaaa aaaaaaagaa aagaaaacca caaaccaata tccctgatga acatatgaaa 94680aaattatcaa taaaacacta gcaaatcaaa tccgatggca cataagaaaa attttataac 94740atgatcaagt tgtttttatt ctagggatga agggttggtt caacatatat aaatcaataa 94800atgtgatttg ccacatagaa taaactaaaa accaaaacca tttgataaga caaaattaaa 94860aacaaaaacc atatgatcat ctcaatagat gcagaaaaat tatttgataa aatttaacat 94920ctttcatgac aaaaatcctc aacaatctgg gcatcaaagg aacatacctc aaaataataa 94980aagctatgta tgacaaaccc actgccaact tcatactgaa aggaaaaaag ttgaaagcat 95040tctcctgaga cctgaaacaa gacaagtgtg tctattttca ctactcttac tgcacatagt 95100atgggaagtc ctagctagag caatcaggca atagaaagaa agaaaaggta tccaaattag 95160aaaagaggaa ctcaaataaa ctctgttcac tgatgatatg caacaataac aacaaaaata 95220gactaatggg acttaaacta aaaatttcct gcacagcaat ggaaataatc aacagagtaa 95280acagacaacc tacaggaagg gaaaaaatat ttacaaacaa tacatctgac aaagggctaa 95340tatccttaat ctataagaaa tacaaaaaaa ctcatcaaga aaaaaattat taaaaatagg 95400gtaaatgata cgaccagcat gtttcaaaag acaaacagtc aacaaacaac aaacatatga 95460caaaatgctc aatatcacta atcatcagag aaatgaaaat taaagctaca gtgagattcc 95520attttatacc agtcagaacg gccattacta aaaagtcaaa aagcaagata ctggtaagaa

95580tgttgaggaa aaggaatgct tatatactgt tgagaatata aattagtaca acctttatga 95640aaaacaatgt ggagattttt caagtatctg aaaatagaag taccatttga cccagcaatc 95700caactattgg atatctacca aaaggaaagt aaatcatttt atgaaaaaga ctcatgctct 95760ttcacactta ttataacact gactagacca caaaaaatca gtatcttcag aggcataata 95820aagtctgttc taaccacttc ctcataggat tttcataagt accatatgag aaaatatttt 95880aagccatctt gaaatcatga tgcattgaat aaataaggga ataattatta ttattgctca 95940agtgtttgcc ttttaaaaca attaaaatat aattttatat aatggggcca ttcaactgtg 96000agcttaattc tatcatggag aaaaacaaca caggagaagg tttaatgttg tttcgttttg 96060atattttaat gatatttaat gtttctttgc ctttgtcttg tttcagaatt gttcaacctg 96120aattgaaatc acttgcactg ggtttccact caatggttat acgagcacta ggtatgatga 96180aaaaaaaaaa aaaaaaaaaa aaaaatatat atatatatat atatatatat atatacacac 96240acacatacat atattaaatt taagttataa atattaatgt caaggattaa agactgtaat 96300gaatctttaa ttatgatagt aaataaaatt agtatccttt ctatttctgt gataaataaa 96360aacaataaga gacagagtaa aattgagtga tggacctaaa ggagaattcg attgttaatt 96420atacataaag tcaatctgtt aagactaagg aattattgta tttgtattac actctttcaa 96480acacaaagat agatggtcct ccaaattttt cttttttttc agaaaaataa gaatatttcc 96540tcccagtagg cagagtgaag ggcctaactt ctaaactgtg gcatgattta ggcaaggcct 96600aaagctagct tgggaagcgt gggaatctgg tcagagaatc tggccaggct atggccaaat 96660tacaatgaag aaattgtcta agaagcgtat ttgatgataa agtcacaaat cctcaaagtt 96720aaaaaagaag aaatataaag ggaatagaag agaggaaatg agatgctata gtattctgtt 96780ggttttcttc cctccgttcc gttttgtgtg tctctaatct cccagactct gtacattctg 96840gcaggtttct accttcagtt tcaatggaga tacctctctg ctagaacctg ggtgacaaaa 96900gcttaaagta acatctgggt tgttagtact ccttctcata tgtagaaatg agactatgag 96960aatggagtaa aatttttttt agcaatagaa aataggaaaa aaaatgagtt tcaccattct 97020aattctgagt atcctatttc gatgtatcca atctgtggca cgatggaacc taaatgcacc 97080tatggaaaaa atacacattt agtacaaaac tttcaattca taaacaattg tcttgaatac 97140aataaacgtg taaattgtgg aaggcctata tatttacctg aaaaagtcat ttagaaaata 97200ggttatgagt tttaaaattg tagtgattag gacaaagttt attacttaaa acaatccatt 97260acgtttgttc aaatcagtgg cattatgtgg ggaaaataaa ctgttagcat atatttttca 97320tttttcaaag ggtggctgtg atttttgaaa cctgaaaatt tctcactcat ttcctcagta 97380ccgggttttc tcagatacat tggcctcagt cccttgtcat tttaatattt ctcactctca 97440aaaaattgag actgaggaaa actaaatgga attagtaaaa ttgtgatata tcaatcacta 97500tcattttatc catggcaaaa taaattctga aaattattca ccacaataca aaaaaaaaca 97560aagtaaagtt atgaacactt tagttgcacc atcttaagga cagttctcta ctggcgtgtc 97620cctaaaattc ttcatcaaat tacctttgcc tagaaccagg agtgaatctc agagttcatt 97680aaaacagcag tggaagcaga tggacactta ttatataaac aacatatctg tctgtgaaaa 97740gccttgcatt ctgctaaatc atgagctaca aataaaaatt aactaagaaa aagaccactg 97800aaaacttatc attgtgatca gaacactaac acaaacaaaa ttcagtacca caagccctaa 97860cttagcctaa gctgcttcag gaggtattta caaatgcaca aaatcaattg tagaaaatca 97920ctggactgtg agctctaatg acatcaataa gtgggaagta gatgtctgag cccagaaaaa 97980agtacaacct gccaaaagct aagcactctc tgaagctcag cctatactta tctggggagg 98040gagttctgat gaagcactca cttttaaatt ctcttaaaat aatgttaaaa aaaaaaaaag 98100tctgctttta cagcaattga gccaagatct ttttcctttc cccataaaat tgtaattcta 98160ctccatttca ggtttctttg cctaagaaaa atcccatatt aaccaacata acttccaagt 98220tttactaaca acattctcct ttttaccatt caggcttaag ttaattgtta tcataagaag 98280aacagagtat atatgcatgt atgtagggag ggtacgagta ggtaaaaggt gtcaatgaca 98340ttactacatg atttgggtct ttgagatttc taataatctt tattattggg tagatgcaga 98400acaaaataat aaacgaatcc tccaaatttt tgaactttta tttaatcaaa atatatcaat 98460gtggaatatc atgcagttac atttaaaata tgttccctaa actgacatct tctcttctcc 98520tattacagga ggaattctag ctccaatata ttttggggct ctgattgata caacgtgtat 98580aaagtggtcc accaacaact gtggcacacg tgggtcatgt aggacatata attccacatc 98640attttcgtaa gttgtcataa atatatttca ttattttttc tttgactata ttaattccta 98700aaaaatatca ttttcattat ataataatat taataatgat agccaccatt taatgaaaac 98760tgactttgca tgcagtatgg tatcaagcaa tctcgtatct cattttagta ctcatagaaa 98820ctataggaaa tggatatttt cttctattct gttatatacg aagaaactgt gattcaagga 98880taataaccaa cttgtcaaaa atcagagata atagaaaatg gctaggattt gtatgtgaat 98940cttttttgtt tccaaaactc tcctcatgtc agtatatata aggataaata tacacatgta 99000aatatagaca cagacatata tatatgcatg tgtgtgtatt cgattgcctc tgacttctct 99060agaaagaaac agaatgacta gctggggctc tggtcatatg tcaattaaga aaaaacggga 99120aaatatgttt ctatattact ctattcgtgg ggagagatat tccgtaagtg acatgaagat 99180aactgcatgg gcatctggaa aaacaaaaag ctacaattat actttacctc tttaaaaaaa 99240aactaatttc aaattcatat attgacaaat tatacacttt gaaatgtgaa actacatgta 99300ttaaaactca tagtataatt tctttcaatt atctacgaag cagaaactaa gtatgaccca 99360aatgcccaaa accataatag aaaaaaagac aaaatattta taaaatctgc atcattaaac 99420tttgaaaagg aaatttcaaa gtgaaagtat aaattaggag aataatttgc aacttgtaac 99480acagacacag gcaaatatcc cgaatatata cggaactctt aaacatcagc aaaaaaacca 99540tccaatgctg gcaaggatgc aaaacaacag gaatttcctt taatttttct ttcattgctg 99600gtggatatgt aaaaaatagt acagccatgg tagaagacag tctggaagtt tcttacaaag 99660aaaaacacag gcttatgata ctgttaagta atcatgcacc taggtattta cctaagttag 99720atgaaaacat gaccccacaa aaacctgcac ttgcatatga aaaaatggaa gcaaacaaga 99780tgtctttcaa taggtgaatg gatagccaaa ctggggtata ttcatacaat agaaaattat 99840tcagcaataa aaagaagtga cctatcaact cacaaaaaga caagaaagaa attaaatgca 99900tgtagctaag tgaaagaagg cagtctaaag aagcttctgg gcctggtgca gtggcccatg 99960cctgtaatct aggcactttg ggaggccaag gtgggaggat tcatgaggcc aggatttcaa 100020gaccagcctg gacaacatga caaaaccctg tctctactaa aaatacaaaa attagccagt 100080cacggtggtg cacatctgta atttcagcta cttgggaggc taaagcacaa gaatcccttg 100140aacccaggag gcggaggttg cagtaagcca agctcatggc actgctctcc ggcctggctg 100200acagagcgag actctgtctc aaaaaaagaa aaaaaaagaa cattaaaaaa aattaaagaa 100260gcttctgact gtattattct aactgtatga ccttttgtaa aagggccaaa ctatgaagac 100320aatgaaacat cagtggttgc taggagctca gtggggagaa gataaggatg agtaggtgga 100380gcacagggca ttttaagggt ggtgaaatga ttttatatga tattatcatg ttggatacat 100440gatgttatgt atttgtcaaa cctatggacc catacccata caacatacaa accacataaa 100500aagcaaactc taatctaaaa tatgaattta ataataatgc attcatattg gttcatcaat 100560tgtaacaaag ttacacacta atacaaactg ttaatgatag gggaaactgt atgtgtgggg 100620cggggagtat atgggacttc atactttctg tacagttttt ctgtaaatct aaaatttctg 100680taaaaagtat gttctattaa aaaaaatcaa gtatctccca aagaaaaaat cacgaatggc 100740tattaaatat ataaaaagat gctcaaatta attgataatg acaggattgc aattaaaact 100800cacccaaatt gtcaaccatc aaaaatgtta agtagacatt gtcttggcaa aagtacagaa 100860ctttgagcca gcagcaaact tctagaaatt tatcctacag ataactatac tcccaaatag 100920ataaaatggc acatatataa gattacatac atgtgtatgg caacattgtt tatgatggca 100980aaatattgga agcaacttaa atatctcttg ataagggagt aattagataa atagttctac 101040ctgcaggaaa atgaatagtc tgatgtcttg aaaaaagaag aaaaaattat ttgtttacta 101100atatggaacc ttcttcaaga catattttta tatgaaaaaa aagaaccatg aagaatgtgt 101160atggagcatg ctatcattta tatgaaagtg gaggtttatt agttcaggat acatctctgg 101220agtaaagacc taggatcaaa tttaccaaac agactctctt ccatttaatg tgtaaattca 101280ctatctaaaa tccccagcag ataaaatgat ccaacttttt ccagaattgt accccacaga 101340cattctcaca aatttattta aatattaatg acagaaaatg tctcacaaaa tgggagaaag 101400aaatgaaaag aaattacaaa tgaaaacttc ataaatttat cttaatgact ttatttaaga 101460atgtgttcat tttttattga aatcatcatg tatttccagg acacctggca agatgctcct 101520cagaatttcc ccaaagcaat gaccacaact tcaagtatta atgtaacatt ttgagatggc 101580tttataatgg tttgagtata aaaagaccct aaaactattt tttaagccat actagttcct 101640ttttgttcag tgaaggttta gttagaacta aaatggaatt taaaaatatt ttatgttaat 101700tgatttatta atgcattctt cttgttgaac aactggtata gtatccaaat ttttaatata 101760ctgcaaagac cattgtgata acattatata gtgtatatgt gtactatata tatttaatat 101820gcatatatat gcatatataa gacagacata ttatatatat gttattcttg tgtactttaa 101880tttatgctca tcccaagact ttaagattta aagggtcggt ctttgtacat ccccacatat 101940ttatcatttt cttttctctg atttcttctt gcatgtcaga ttctatctag ggtcattttc 102000cttctgatta aagtcgattt ttaaaaatgt ctttcagtga gctctttagt ggcaaattgc 102060caatttaaat ttctctggaa ggaactttag ttcaactgta tacttaaaag aaatgtacaa 102120ggtatagaat tctaaattga caactatttt ctcttgtcag attgaagata ttactctatt 102180gtcttctaag ttccatttta ctcttgataa gtaagctgtt gtctgttttc ttgttccttt 102240aaggtaacct cactcctctg tggattcttt aaatatcttg tcttaatccc tggaatctgt 102300aattacacta tgttcaggtt gcagatggaa taagtttgct aattagctga actcaagata 102360agaaaattat ttggttgggc ccaatataac cacaaatatc ctaaaaaata aaaagaggag 102420gtcagaagga tgtgatgtga gaaagactca gtctattgtt gctgggtttg aagatggaag 102480aaaggggcca ggagccgagg aatgtaggtg gcctctagaa gtgagaaaaa gcgaaggaac 102540agcttatttc ctggaggtcc cagaaaggaa tacagccctg ctgatacctt gattttagcc 102600aactaagaca agtattaggc ttctaactgc caggaaatgc tccgggctta gctcacacac 102660ccttttcttt cataaagttc acaccattcc aaccagctgg aaatgaccaa ccctctttgg 102720gacttaccac attgtagcta actcatggcc cttatcactt tccttttggt cacttgtgtt 102780ctttgcttga ttgtgtaaag tggaatttaa aaaaaaaaaa agagcagtgc atttaccaat 102840gaatacataa aaagttaaat tgttacctta agaatttttt aaataaactc aattttagag 102900agttttagga tcacagtaaa attgaggaga aattacagag atttcccaca taccacctgc 102960cccacacatg catagcctat cctaccatca atgtctccca acaaagggtg atacagttgt 103020tacaaatgat gaaacaacat taacacatct ttatctccca gagtccacag tttacattag 103080gtttcactct tgacattgta cttttatggg tttggacaaa tgcataatga catatatcca 103140ccattacagt attatacaaa gtagtttctc taccctaaaa atcctctgct ctgcctattc 103200attccttcct cctctaaaac ccctggagac cactgtgctt tttactgttt tcatagtttt 103260gcgttttcca gaatcataca gtatgtagca tttttagact agcttattta acttaatcac 103320atgcatttaa atttcctcca ggtgtttcaa ttgcttgata gctcatttct ttttattgct 103380gaataatatt ccattgtcta gatgtataac agattattta tatattcacc tactgagggc 103440atcttgatgg cttccaagtt tcatgtttct ttgatgatat atatgaagat gtttgattct 103500gttatattaa ccctggatcc tgtgtcctga aaccttgcaa taattgctta ttagttccaa 103560gtgtgttttt gtctgttatt ttaaactttc tacttagaca attatgtcat attgcaaaca 103620aagacaattt ctttcttttc aatctatata catttcattt tcttttcttt ttaaaaatta 103680cattaattac gactcccagt accatgttga aaaacagtgg tgagagggga cgtttttgac 103740ttgttcctga ccttagtggg aagactttga gtttctcact attaagtatg aagttagatg 103800tagggttttg gcagatattt ttgatcaagt tgaggaggtt ctcccctatt ccaagtttaa 103860tgggagtttt tattataaat gagtgtttga ttttgcaaat tcacttttct agatctattg 103920atgtgatcat gtcattttat tattcttctt tagcctgtta atgtaatgaa ctgtaagaat 103980tcattttgaa tgttgaacca gtcttggaaa cctgagggaa atcccactta gtcatgatgt 104040atactatatt tatacattgt tggattcaat ctgatatttt ttgagaattt ttgcgtctat 104100gttcatgaga gaagttgctc tgtagtattc tttttttttt tttttttttt tttggagaca 104160tagttttgct cttgttaccc aggctggagg gcaatggtgc gatcatggct caccgcaacc 104220tccgcttccc aggttcaagc gattctcctg cctcagcctc ccgagtagct gggattacag 104280gcatgcacca ccatacccgg ctaattttgt acttttagta gagacaaggt ttctccacgt 104340tggtcaggct ggtctcgaac tcctgacctc aggtgatccg cccacctcgg cctctcaaag 104400tgctggcatt gcaggtgtga gtcaccatgc ccagccctct gtagtattct tttcttgtaa 104460tgtctttgtc tgattttgtt attaggataa tgctagcctc acagaatgaa ataggaagta 104520cttctgctgc tgctatcatc tgaagaagat tgtaatgatt tggtataatt tcttacttaa 104580gtgtttgata gaattcacca atgaacctat cttaatttga tgctttcttt tttattatta 104640ttattatact ttaagttcta gggtacatgt gcacaatgtg ctggtttgtt acataggtat 104700acatgtgcca tgttggtgta ctgcacccat taactactca tttacattag gtatatctct 104760cagtgctatc cctcccccct ccccccaccc cacgacaggc cccagtgtgt gatgttcccc 104820ttcctgtgtc caagtgttct cactgttcaa ttcccaccta tgagtgaaaa catgtggcat 104880ttggtttttt tgtccttgtg atagtttgct gagaatgatg gtttccagct tcatccatgt 104940ccctacaaag gacatgaact catccttttt tatggctgca tagtattcca tggtttatat 105000gtgctacatt ttcttaatcc agtctatcac tgatggacat ttgggttggt tccaagtctt 105060tgctattgtg aatagtgcag caataaacaa acttggcttt ttggctaata tcaagtatag 105120tatctgttct tttcagttta gtttgatgct ttctgtttta gaaggttatt aaatatggat 105180tcatttttag agagttctat cctccttcaa tgcctggggt tccatgagga aatcagagct 105240ttttcccaaa aatggtacct cctatttttc ccaaggactc ctcgtctgtt agaaatgaac 105300ttagttcctt tcatgtggtc atcaagaggg gcaaaaagac agactgagga aataattcac 105360tcaagtgaga aaaataaata aataaaaact tctcaaaaaa acaagatcca agaagagaaa 105420aagcacaaag gtcttgtata tagatatata cacacacaga cacacacaca tatatataca 105480tatatgtata tatgtgtgta tatatgtata tgctatatat acatgtatat atgtgtatgt 105540atatatacac acaaacgtat atgtgtgtct gtaaagagag agggagagcg agagagagta 105600tgggagagca cttggatatc catttttaat taagctgact tttagctata gtgcccttta 105660aaaaaaatcc tttatatctc ttattatctg actttagcaa ggccaaacag ccagtatttc 105720tggcttttga acttctttag aaatagtaat ctcctaggtg aaataaataa gccttaactg 105780aggttgtaac ttaaccatga gtgtatgagg tattttcaaa taggtggtaa gcagttttta 105840caagatctag aatcttcaaa ggtaactcac agaaacgaaa attcaagaag ggaagccaga 105900agttggtcat ggaggagcag agaatcaaca aatggaaaaa gccacaagaa tatcaaatca 105960gaaagcattc attccctggg ccaagaattg agtcccaggc caccattgtg aaaagacaaa 106020ctcttagctt ctgagctata gcattggata gtcttcatta cctttcccag aaggattcca 106080gtgcaaccga tttcaagctt gcaaaggctt ttaactgctc gagataattt ttagagctaa 106140ctatgacatt aactacaaaa ttcctgtcct ctagatggca gagaccaaga gtaagtactg 106200ccacatagtt acaagatcaa gctcccacgg acataaaaca agatgagagg gaaacctcat 106260ccagtatagg tttcaggaac acacagcaaa gtttgtaacc gaccagccca agaggctggc 106320ttaaaaagta ggcttatagg aatcctaagc ctactttcta cattctttcc tatgacaccc 106380ctctccatta cagaacaaca ctaaaagaca aattcttagc acaaagtaca ccagatttgc 106440taaagcctaa gactagtctc aaaaattcat ttttctatta atcagaccac acacacacag 106500agagagagag agagagacag aaagacagag agacagagag acagagaaag acagagacag 106560agacagagag acagagacca gaagcttggc tggtaacaaa ttcttacccc ttttgccagc 106620ataccacgtt tctgggttcc ctttctctgc agcttccaga agaatgaagt ggcttttgat 106680gaccctgctc attgcaccat agctttgggg gccaagccac tttacaaaag aaaattatcc 106740ttttctgttt tataaaacta taggcaaaag cttctcattt ttgcaagatg ctgcccaatg 106800ggctgcatga ggaaccaaat taacattttc caccccagcc tagcaaaata cacataacaa 106860aacagacatt tgtcacctca ttcagcaccc aatattgacc tggcgaggct caaactttct 106920ttcattggtc cctatcatct ctgatccact caagatgtgg agggctaaac tccaactgag 106980aattcaggtc tctgggcaag atgaagaagt ggacagtcac cccgactcag gcctttttga 107040gcttccttca ggactcactg aatgtgacca gacaaataat gagggttttc tgagttaggt 107100gtcctagact tccatcagta gttcctttag aggtctcctc cacatataca aatacacaca 107160acaaagacaa gacagacaga aggccttcca aaccacgact tctaaccaag aattccgagt 107220cttcctccca aacgaacctt ctattctcca cctgagaatt ctccctaaaa tcttcttgat 107280tgaagagaaa tctcctgaac caagacttcc tactaattag agctaaccaa cacctccaaa 107340ggagctgaac tgagacctca aaaaaaaaac aaacaaacaa aaaaaaaaaa acaagagccc 107400caaaggagcc aaaccaaggc ccctaaagaa gccaaatcat gatccccaaa ggagccaaac 107460caactgggag aagaaaggag gagttggcag tgcctagaat actcaccaaa ttagtttgga 107520gacagacatc atttccagga actatttctc cattgcaatt aaatccatgc acattgggtc 107580agcagcaccc tgccagtaga gacagtgcca gagtcagccc acagtccaag agaactaggc 107640agccacttgg gctggcctct ggatccatca ccagagcagg gctactgaac catgggcagg 107700taggcacaaa ggcaatccca gatgagaccc ctagtgtgta accacctaac gggttcacct 107760tgcccactgc ctagacagag cttatttatc aagaaagatc ttacttatca aaacagagaa 107820attgcaataa agagtaattc atgcagagcc agctgtgcag tacaccagag ttttgttatt 107880attcaaatca gtctctctga gaatttgagg actggagttt ttaaagataa tttggtgggt 107940aggggggcca gtgagtcaag agttctgatt ggtcaggtga gagatgaaat catagggagt 108000tgatactgtc ctctcgtgct gagtcacttc ctgggagggg gccacaggat gagataggcc 108060agtttatcaa tctgggtggt gtgagctcat ctgtgaagtt caggatctgc aaaatatatc 108120aagtattgat cttaggtttt acaatagtgc tgttatcctc aggagcaatt tggttagagt 108180cagaatcttg tagcctccag atgcattact cctaaatcat aatttctaat cttttggcta 108240attcgttagt cctacaaagg tagtctgttt cccaggcaag aagctggttt gttttgggaa 108300aggactgtta ctgtcttggt tttaaactcg aagctataaa ctaaatttct cccagaatta 108360gttcggctta cacccagaaa tcaacaagaa cagcttggag gatagaagca agatggagtt 108420ggttaggtca gctctctttc agtctcggtt atagttttgc agtgaaaatt tcataagcat 108480ttagtgcaat aaactttcca ctttatgctg ttgaagctat atcctagagg ttttaaaata 108540ctttgtctcg attttcattt gtttaaaaca aaaaaattgt gttctgctct aattttgtta 108600tttacccaaa agtaattcag gaccaagtta tacagatttc ttgtaattgt gtagtttcaa 108660gagttgctct tgatactgat ttctattttt attctgctgt ggttcatgaa gatgtttgtt 108720ataactctga ttttttaaaa aatttattgt gacttatgac ttagaatgtg gttagtttta 108780gagaatgttt tatgaacaga taaaaaatgc attttctctg atttttgggt gaagtattct 108840ctagatatct attagatcca cttggtaaag agtctacttc aagtcgaatt tttttttttt 108900ttttttagct tttggccttg atgatgtgcc tgcctagtgc tgtcagtctg gtgtcgaagc 108960ttattactca ttgtattact ttctatctct ttgcttaggt ctggtagtat ttattttata 109020aatatgattg cttcagtatt gagtgtgtat atatttagat tagttaaatc ttgttgaatt 109080aaatgcttta tcattatgta atgcacttac ttggtttttt ttaaactgtt gtttgtttaa 109140ggtctgtttt atttgataca aagagaggaa tttcagctta tttttgcttt ccatttgaaa 109200gatagatctt tcttcattct tttactttaa gtctatgggt gtccttacat acgagatgga 109260ttccttaagg gcagcagaag gttgcctttt tttttttaat ccactttgct actctatgtc 109320ttttatatga agcatttagg caatttacat tcaaagttaa tattgatatg tgagattttg 109380tacctctcat actgttgtta gctagttgct ttatagttgc aattgtgtag ttacttaata 109440ggatctgtag gctttgtaat tatgggtgct tttatagtag caagtattgg tctgtttttt 109500cctgttttga actcctttga gcattttttc taaaactgat ctggtggtga catatttcct 109560tagtgtttac tggtctggga aatattttat ttctacttta ttcacaaatc ttcatttggg 109620aagttatgaa gttcttggct gtcattatta tttttctttt gtaagtctaa caataggccc 109680ccagtctctt ctagcttgta atgtatctgc tgggaagttc acctttagtc taatggtatt 109740tccttcataa ataatttggc ccttttctct agctgccgtt aggatttgtt ttttcatgtt 109800gaacttaggc aatctgatga ctatattcat atagtatctg aatggttgtt ttgtatagta 109860tctcatacta tagtatgttt tgtatagtat ctcatacact gttgcaccca caacagtgta 109920cagtggagag agtgggaaat taccctctat ccagattcat tcctgagtgt tggtactgcc 109980tccttcagta attggtgctg tgcccatgtt ctctttgtcc caggggaagc tatagtgggc 110040tacagtcccc actcttttag gggaagaaca cattgagggt tagatctcca gaggtcctgc 110100tgtctcccca aagtccactg acccctgtgc ctaccaaagt cagagcagtt tgttggacat 110160gtttgccagg aattgggtgg catggtgact caaagatgga gaatcctcag gcagggcggt 110220ggcataccat agatgcacca acagtatggc acatctttcc tttagataga aaggtggtgc 110280agctgtacct gtgcaggctg gccacctagt tgtctatccc tggggagttc ccaaattgcc 110340accaatagca ttaccctgca tcaagagggc agaggaaatt cctaacaatt tggtggtcag 110400cagattatca gagatgtgag gggagcagag aagcactttc agctaaattt tcacagggtt 110460ctctgggggt tgattattac caggctttta ccgcttttct ttactacacc acagctgctt 110520cttatgggca ctataacagt tcctggctct ctttctcagt tttttatttg gtacttcttt 110580attcaccagt aactttgatc ttctttctga ggagaactgt aatttgatgt ccctggtcag

110640ccatcttgaa aagaacttga cttatttttt tatcagtggc agcatgatat atcttcctcc 110700atctaattac ttttaatcta tacatctata agtagatctc ttagagacta catatagttt 110760gtttcttctt tttaatcctt taacaaactc agtcttttaa ttggtggatt tagatcattg 110820acattaaaag tgactactga tgttgtgaga ccaatgttga ttataatttt actattgtct 110880atttgttata cttgttcttt gatcctattt ttgtcttcta ttcttttttc ttctgttgtg 110940ttcttaacta aatagtctat atgactctga ttttatatga ctatataatc ataacttttt 111000atgttacctt tctttatgta tatcaagttt ctgacctata tgagtctctc taaaaagctt 111060ctcttaacat ttcttacaag gaagatgtac tggaaaaaca tttcttcaat tgttgtttgt 111120ctgagaatgt gtttatttct actttacttt taaaagaatt tcacagagta cagaatttta 111180agttggtgat ttttttctct taagacttta aatatttcac tccactctct tcttgcttgc 111240atggtttctg aagagaagtc tattttctcc cctatagata aaatttgttt ttccttctgg 111300ttagtttcag gataaagttt tctttatctt tgactttctg taatttgaaa ataacacacc 111360tacacgtagt ttttctggtc aataataact tatttgtata tttaaaaata acttaggaag 111420tgtagttgaa ttgtttgtaa ctcaaaggac aaatccttag cattttctga gtttcctgaa 111480tctgtgatat agtgtctgac attaatttaa gagaaattct tagtaatttt tttttttttg 111540agatggagtc tcactctgtt gcccaggctg gagtgcaatg gcatgatctt ggctcactgc 111600aacccccgcc tcccgagttc aagtgattct cctgcctcag cctcctgagt agctgggata 111660acaggcaccc gccaccacgc ccagctagtt tttgtatttt tggtatagac ggggtttcac 111720catgttggtc aggctggtct ctaactcctg acctcgtgat ctgcctgcct cagtctccca 111780aagtgctggg attacaggca tgatccactg cacctggcca gtaattattt tttaaaaatg 111840tttcttttgc tccttttctc tttgttttcc ttctaacctt tccattacac ccacttatat 111900aattgtctca aaatttttat atgatttcaa ttgatttact ttttagtctt gtttctcttt 111960gcttttcagt tttggaggtt ttcattgata tatcctcaaa ttagagagtc ttcatcagtt 112020gtgttctatc tactaataag cccatcaaag gcattcttta tttctgctac agaatttttt 112080atttttagca ttttcttggg ttcttaaaat ttttattttt atacttacat tgtccatctg 112140ttattgaatg ctgtctacct tattgattag aacacttaac atattaatca tagttgtttt 112200aaattccatt ttgaaaattt ccacgtcccg gacatatcta ggtctggttt aaagcttact 112260tattcctttc aatctatgtt ttttttttca cttttggtat gactggcaat ttttttcatt 112320acagttaagc ataatgcatt aggtaaaagg aactgctttg ataagccttt attaatatgg 112380tgtaaggtgc tggagaaggg gtagcattct acaggcctac atttaggttt tattatttta 112440gttataatcc agtaacctct ggattataaa tttcaaacat acttctcagt ttctcctccc 112500agctgtaggt ggggcaggat ggcttaacag ggcttgagtt gtatattttt ctcgttttat 112560gaagaaggcc agaggcaact agagtatagt ttctatggct tcataaccct attacaataa 112620taaaatatct atcgttatgc cccaataaaa agaattatta gaattattgt cttaatattt 112680tatttataat tttttttctt taggatctgg atactggaga aaatgtttta agttattaca 112740cacaatttaa actgatttat tgttttattt tctctatttc tacagaaggg tctacttggg 112800cttgtcttca atgttaagag tctcatcact tgttttatat attatattaa tttatgccat 112860gaagaaaaaa tatcaagaga aagatatcaa tgcatcagaa aatggaagtg tcatggatga 112920agcaaactta gaatccttaa ataaaaataa acattttgtc ccttctgctg gggcagatag 112980tgaaacacat tgttaagggg agaaaaaaag ccacttctgc ttctgtgttt ccaaacagca 113040ttgcattgat tcagtaagat gttatttttg aggagttcct ggtcctttca ctaagaattt 113100ccacatcttt tatggtggaa gtataaataa gcctatgaac ttataataaa acaaactgta 113160ggtagaaaaa atgagagtac tcattgttac attatagcta catatttgtg gttaaggtta 113220gactatatga tccatacaaa ttaaagtgag agacatggtt actgtgtaat aaaagaaaaa 113280atacttgttc aggtaattct aattcttaat aaaacaaatg agtatcatac aggtagaggt 113340taaaaaggag gagctagatt catatcctaa gtaaagagaa atgcctagtg tctattttat 113400taaacaaaca aacacagagt ttgaactata atactaaggc ctgaagtcta gcttggatat 113460atgctacaat aatatctgtt actcacataa aattatatat ttcacagact ttatcaatgt 113520ataattaaca attatcttgt ttaagtaaat ttagaataca tttaagtatt gtggaagaaa 113580taaagacatt ccaatatttg caagctgtga ttgtcaaaca acatattaca ttatgtgtta 113640agtttccagt gggcccacgg taatgtatta ggaaaaattg actttgacta atgtagccac 113700tctcatactt atcttagcta gatttcctag atcatttgcc gcaccttcta cgtcagcact 113760tgcttcttca ctttgtactt agataatgaa accagcttct ttttttaaac cccgtgaaac 113820aaattctaca gctttttttc ttttgcagct ttcccacgtc tcttagtcat catagaatga 113880cagagagtta tgtccttgct ctagattaga tttggcctaa gggaacattg tggctgcttt 113940gttcttcaat ccaggctact gaagttttct ccatgttagc cataagtctg tttcactttg 114000ttattatttg tgtgttcact gaagtaggac tcttaattat cttcaagtac tttatttttg 114060cattcacaac ttggctaact gctgaatgca agatgcttag ttttgactta ccttggctct 114120tgatatgcct tcctcactaa acttaatcat ttctaaaatt tgacttaaaa tgagagatat 114180gtgactcttt ctttcactca aacacctaga ggtcattgta aggttattat ttggcttaat 114240ttctatgttg ttctgtctca ggacatagga aggcccaagg ggatggagag agatgtagca 114300atagctggtt ggtggagcat tcagaacaca cacaacttta ttgattaagt tccacgtatt 114360atatgggtat ggatagtggc aagtcaaatc aattacaata gtaacatcaa agatcactaa 114420ccacaggtca ctatcacaga tacaataaca atgaataagt ctgaaatatt gtgagaatta 114480gtaaaatgtg acacagagac ataaagtgag cacatatttt tgaaaaaatg atgtcaatag 114540acttgtttga tgcaggattg ccacaaactt ccaatttgaa aacaaaaaac aaacaaaaaa 114600aacaccaaaa tatgtgaagt gcaataaagt gaagttcaat aaaatgaagt atgccaggaa 114660taaaaactag caggatcaca ggatcaacct ctacttaaaa gtattagaaa tatggaggta 114720aatagaagaa atagctaaaa agagttgtaa atgcttgcct ctggaaagca gtaataataa 114780gcagagaaaa actcattttc aatatgagat ttttgatata atcttatttt tacaactttg 114840tgcataaatg gctttggtaa aaattaaaaa tcaatcatca gactggtatg tctcttatta 114900atcaacaata aacaataata ttgataccca ggtactacac tgagagcctt gggtgagcct 114960ccaagtcttg ctggcttcag ataccagaaa gatcacaggg gttaatgcac taagcagact 115020cttgaggtcc ctgattccag gacttgactc tgggatagca tttctgaacc tgccctcggc 115080cagaggggag cccattgttc tgaagtttga atcccacctc aggcagaatt caatagaagc 115140tgattaaagt gcccttgggc cttaaggaaa cattggcagt agtctagcag tactccctgt 115200gggcctgaag tgttgtggct atgggttgag gctcctttgt atttggaaat gcgagggaag 115260agtgggaaag acggtcttgt ggtttgcgtg ccacctcagc cacaatatga tagaacacca 115320ggtagacttt acgagttttg gctctagtct ctgactcctg gatggcatct ctggacccac 115380atgggacctg ggggacctcg ccaccctgaa aggaaggaca caggccttgc tggcttttct 115440gcctgctgat tgtagagccc catggccttg agcaaacatt ggcagtagtc agggagtaat 115500tacagcagac cttgggcaag actcataaat gtgctggctt caggtgtaac ccaatgtagt 115560catagttctg gatgccacag aggtgcttac gccactccaa acc 11560373691PRTHomo sapiens 73Met Asp Gln Asn Gln His Leu Asn Lys Thr Ala Glu Ala Gln Pro Ser 1 5 10 15 Glu Asn Lys Lys Thr Arg Tyr Cys Asn Gly Leu Lys Met Phe Leu Ala 20 25 30 Ala Leu Ser Leu Ser Phe Ile Ala Lys Thr Leu Gly Ala Ile Ile Met 35 40 45 Lys Ser Ser Ile Ile His Ile Glu Arg Arg Phe Glu Ile Ser Ser Ser 50 55 60 Leu Val Gly Phe Ile Asp Gly Ser Phe Glu Ile Gly Asn Leu Leu Val 65 70 75 80 Ile Val Phe Val Ser Tyr Phe Gly Ser Lys Leu His Arg Pro Lys Leu 85 90 95 Ile Gly Ile Gly Cys Phe Ile Met Gly Ile Gly Gly Val Leu Thr Ala 100 105 110 Leu Pro His Phe Phe Met Gly Tyr Tyr Arg Tyr Ser Lys Glu Thr Asn 115 120 125 Ile Asn Ser Ser Glu Asn Ser Thr Ser Thr Leu Ser Thr Cys Leu Ile 130 135 140 Asn Gln Ile Leu Ser Leu Asn Arg Ala Ser Pro Glu Ile Val Gly Lys 145 150 155 160 Gly Cys Leu Lys Glu Ser Gly Ser Tyr Met Trp Ile Tyr Val Phe Met 165 170 175 Gly Asn Met Leu Arg Gly Ile Gly Glu Thr Pro Ile Val Pro Leu Gly 180 185 190 Leu Ser Tyr Ile Asp Asp Phe Ala Lys Glu Gly His Ser Ser Leu Tyr 195 200 205 Leu Gly Ile Leu Asn Ala Ile Ala Met Ile Gly Pro Ile Ile Gly Phe 210 215 220 Thr Leu Gly Ser Leu Phe Ser Lys Met Tyr Val Asp Ile Gly Tyr Val 225 230 235 240 Asp Leu Ser Thr Ile Arg Ile Thr Pro Thr Asp Ser Arg Trp Val Gly 245 250 255 Ala Trp Trp Leu Asn Phe Leu Val Ser Gly Leu Phe Ser Ile Ile Ser 260 265 270 Ser Ile Pro Phe Phe Phe Leu Pro Gln Thr Pro Asn Lys Pro Gln Lys 275 280 285 Glu Arg Lys Ala Ser Leu Ser Leu His Val Leu Glu Thr Asn Asp Glu 290 295 300 Lys Asp Gln Thr Ala Asn Leu Thr Asn Gln Gly Lys Asn Ile Thr Lys 305 310 315 320 Asn Val Thr Gly Phe Phe Gln Ser Phe Lys Ser Ile Leu Thr Asn Pro 325 330 335 Leu Tyr Val Met Phe Val Leu Leu Thr Leu Leu Gln Val Ser Ser Tyr 340 345 350 Ile Gly Ala Phe Thr Tyr Val Phe Lys Tyr Val Glu Gln Gln Tyr Gly 355 360 365 Gln Pro Ser Ser Lys Ala Asn Ile Leu Leu Gly Val Ile Thr Ile Pro 370 375 380 Ile Phe Ala Ser Gly Met Phe Leu Gly Gly Tyr Ile Ile Lys Lys Phe 385 390 395 400 Lys Leu Asn Thr Val Gly Ile Ala Lys Phe Ser Cys Phe Thr Ala Val 405 410 415 Met Ser Leu Ser Phe Tyr Leu Leu Tyr Phe Phe Ile Leu Cys Glu Asn 420 425 430 Lys Ser Val Ala Gly Leu Thr Met Thr Tyr Asp Gly Asn Asn Pro Val 435 440 445 Thr Ser His Arg Asp Val Pro Leu Ser Tyr Cys Asn Ser Asp Cys Asn 450 455 460 Cys Asp Glu Ser Gln Trp Glu Pro Val Cys Gly Asn Asn Gly Ile Thr 465 470 475 480 Tyr Ile Ser Pro Cys Leu Ala Gly Cys Lys Ser Ser Ser Gly Asn Lys 485 490 495 Lys Pro Ile Val Phe Tyr Asn Cys Ser Cys Leu Glu Val Thr Gly Leu 500 505 510 Gln Asn Arg Asn Tyr Ser Ala His Leu Gly Glu Cys Pro Arg Asp Asp 515 520 525 Ala Cys Thr Arg Lys Phe Tyr Phe Phe Val Ala Ile Gln Val Leu Asn 530 535 540 Leu Phe Phe Ser Ala Leu Gly Gly Thr Ser His Val Met Leu Ile Val 545 550 555 560 Lys Ile Val Gln Pro Glu Leu Lys Ser Leu Ala Leu Gly Phe His Ser 565 570 575 Met Val Ile Arg Ala Leu Gly Gly Ile Leu Ala Pro Ile Tyr Phe Gly 580 585 590 Ala Leu Ile Asp Thr Thr Cys Ile Lys Trp Ser Thr Asn Asn Cys Gly 595 600 605 Thr Arg Gly Ser Cys Arg Thr Tyr Asn Ser Thr Ser Phe Ser Arg Val 610 615 620 Tyr Leu Gly Leu Ser Ser Met Leu Arg Val Ser Ser Leu Val Leu Tyr 625 630 635 640 Ile Ile Leu Ile Tyr Ala Met Lys Lys Lys Tyr Gln Glu Lys Asp Ile 645 650 655 Asn Ala Ser Glu Asn Gly Ser Val Met Asp Glu Ala Asn Leu Glu Ser 660 665 670 Leu Asn Lys Asn Lys His Phe Val Pro Ser Ala Gly Ala Asp Ser Glu 675 680 685 Thr His Cys 690

Claims

1. A method of determining a statin dosage, the method comprising the steps of: conducting an assay in a biological sample to identify the presence or absence of a SLCO1B1 biomarker and an Apolipoprotein E gene (ApoE) biomarker that are associated with statin efficacy; and determining a dosage of statin for the individual based upon the presence or absence of the SLCO1B1 and ApoE biomarkers, wherein the statin is selected from the group consisting of pravastatin, atorvastatin, and cerivastatin.

2. The method of claim 1, wherein the biomarkers are genetic polymorphisms.

3. The method of claim 2, wherein the polymorphisms comprise an rs4149056 C polymorphism at a SLCO1B1 locus and selected from the group consisting of an ApoE2 polymorphism, an APoE3 polymorphism, and an ApoE4 polymorphism at an ApoE locus.

4. The method of claim 2, wherein the polymorphisms comprise a C/T or a T/T genotype at SLCO1B1-056 and an ApoE genotype selected from the group consisting of ApoE2/E2, ApoE2/E3, and ApoE3/E3.

5. The method of claim 4, wherein the statin dosage is between about 20 and about 40 milligrams.

6. The method of claim 1, further comprising the step of measuring an amount of the biomarker.

7. The method of claim 6, wherein the level and the amount are weighted.

8. A method for identifying a patient's likelihood of responding to statin treatment, the method comprising the steps of: identifying a SLCO1B1 polymorphism and an ApoE polymorphism in a blood and/or plasma sample obtained from a patient, the SLCO1B1 and ApoE polymorpohisms being indicative of statin efficacy; characterizing the patient's likelihood of responding to statin treatment based upon the presence or absence of the SLCO1B1 and ApoE polymorphisms identified in the identifying step, wherein the statin treatment comprises a statin selected from the group consisting of pravastatin, atorvastatin, and cerivastatin.

9. The method of claim 8, further comprising categorizing the patient as a normal responder or a hypo-responder.

10. The method of claim 8, further comprising the step of obtaining a plasma lathosterol/cholesterol ratio in the sample and wherein the characterizing step is further based upon the plasma lathosterol/cholesterol ratio.

11. The method of claim 10, wherein the ratio and the polymorphisms contraindicate statin treatment.

12. The method of claim 11, wherein the ratio is less than about 215.

13. A diagnostic kit for determining a statin dosage for an individual, the diagnostic kit comprising: a first reagent for detecting the presence or absence of a SLCO1B1 biomarker in a biological sample from the individual; and a second reagent for detecting the presence or absence of an Apolipoprotein E gene (ApoE) biomarker in the biological sample.

14. The diagnostic kit of claim 13, wherein the biomarkers are genetic polymorphisms.

15. The diagnostic kit of claim 14, wherein the polymorphisms comprise an rs4149056 C polymorphism at a SLCO1B1 locus and selected from the group consisting of an ApoE2 polymorphism, an APoE3 polymorphism, and an ApoE4 polymorphism at an ApoE locus.

16. The diagnostic kit of claim 14, wherein the polymorphisms comprise a C/T or a T/T genotype at SLCO1B1-056 and an ApoE genotype selected from the group consisting of ApoE2/E2, ApoE2/E3, and ApoE3/E3.

Images