METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION

Abstract

Disclosed herein are antisense compounds and methods for decreasing apo(a) to treat, prevent, or ameliorate diseases, disorders or conditions related to apo(a) or Lp(a). Certain diseases, disorders or conditions related to apo(a) or Lp(a) include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The antisense compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.

Description

SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0177USC5SEQ_ST25.txt created Oct. 9, 2019, which is 424 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

[0002] Embodiments described herein provide methods, compounds, and compositions for reducing expression of apolipoprotein (a) mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate cardiovascular and/or metabolic diseases, disorders or conditions.

BACKGROUND

[0003] Lipoproteins are globular, micelle-like particles that consist of a non-polar core of acylglycerols and cholesteryl esters surrounded by an amphiphilic coating of protein, phospholipid and cholesterol. Lipoproteins have been classified into five broad categories on the basis of their functional and physical properties: chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons transport dietary lipids from intestine to tissues. VLDLs, IDLs and LDLs all transport triacylglycerols and cholesterol from the liver to tissues. HDLs transport endogenous cholesterol from tissues to the liver

[0004] Lipoprotein particles undergo continuous metabolic processing and have variable properties and compositions. Lipoprotein densities increase without increasing particle diameter because the density of their outer coatings is less than that of the inner core. The protein components of lipoproteins are known as apolipoproteins. At least nine apolipoproteins are distributed in significant amounts among the various human lipoproteins.

[0005] The lipoprotein(a) [Lp(a)] particle was identified nearly 50 years ago and is comprised of a highly unique LDL particle in which one apolipoprotein B (apoB) protein is linked via a disulfide bond to a single apolipoprotein(a) [apo(a)] protein. The apo(a) protein shares a high degree of homology with plasminogen particularly within the kringle IV type 2 repetitive domain. Levels of circulating Lp(a) are inversely proportional to the number of kringle IV type 2 variable repeats present in the molecule and, as both alleles are co-expressed within individuals, can display heterozygous plasma isoform profiles (Kraft et al., Eur J Hum Genet, 1996; 4(2): 74-87). It is thought that this kringle repeat domain in apo(a) may be responsible for its pro-thrombotic and anti-fibrinolytic properties, potentially enhancing atherosclerotic progression.

[0006] Apo(a) is transcriptionally regulated by IL-6 and in studies in rheumatoid arthritis patients treated with an IL-6 inhibitor (tocilizumab), plasma levels were reduced by 30% after 3 month treatment (Schultz et al., PLoS One 2010; 5:e14328).

[0007] Apo(a) has been shown to preferentially bind oxidized phospholipids and potentiate vascular inflammation (Bergmark et al., J Lipid Res 2008; 49:2230-2239; Tsimikas et al., Circulation. 2009; 119(13):1711-1719).

[0008] Further, studies suggest that the Lp(a) particle may also stimulate endothelial permeability, induce plasminogen activator inhibitor type-1 expression and activate macrophage interleukin-8 secretion (Koschinsky and Marcovina, Curr Opin Lipidol 2004; 15:167-174). Importantly, recent genetic association studies revealed that Lp(a) was an independent risk factor for myocardial infarction, stroke, peripheral vascular disease and abdominal aortic aneurysm (Rifai et al., Clin Chem 2004; 50:1364-71; Erqou et al., JAMA 2009; 302:412-23; Kamstrup et al., Circulation 2008; 117:176-84). Further, in the recent Precocious Coronary Artery Disease (PROCARDIS) study, Clarke et al. (Clarke et al., NEJM (2009)361; 2518-2528) described robust and independent associations between coronary heart disease and plasma Lp(a) concentrations. Additionally, Solfrizzi et al., suggested that increased serum Lp(a) may be linked to an increased risk for Alzheimer's Disease (AD) (Solfrizzi et al., J Neurol Neurosurg Psychiatry 2002, 72:732-736. Currently, in the clinic setting, examples of indirect apo(a) inhibitors for treating cardiovascular disease include aspirin, Niaspan, Mipomersen, Anacetrapib, Epirotirome and Lomitapide which reduce plasma Lp(a) levels by 18%, 39%, 32%, 36%, 43% and 17%, respectively. Additionally, Lp(a) apheresis has been used in the clinic to reduce apo(a) containing Lp(a) particles.

[0009] To date, therapeutic strategies to treat cardiovascular disease by directly targeting apo(a) levels have been limited. Ribozyme oligonucleotides (U.S. Pat. No. 5,877,022) and antisense oligonucleotides (WO 2005/000201; WO 2003/014397; U.S. Pat. No. 8,138,328; Merki et al., J Am Coll Cardiol 2011; 57:1611-1621) have been developed, but none of the compounds directly targeting apo(a) are currently used in the clinic.

[0010] Thus, there remains a clear unmet medical need for novel agents which can potently and selectively reduce apo(a) levels in patients at enhanced risk for cardiovascular events due to chronically elevated plasma Lp(a) levels.

SUMMARY

[0011] Provided herein are compositions and methods for modulating expression of apo(a) mRNA and protein. In certain embodiments, the apo(a) specific inhibitor decreases expression of apo(a) mRNA and protein.

[0012] In certain embodiments, the composition is an apo(a) specific inhibitor. In certain embodiments, the apo(a) specific inhibitor is a nucleic acid, protein, or small molecule. In certain embodiments, the apo(a) specific inhibitor is an antisense oligonucleotide targeting apo(a). In certain embodiments, the apo(a) specific inhibitor is a modified oligonucleotide consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 3901 to 3920 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. In certain embodiments, the apo(a) specific inhibitor is a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 1-130, 133, 134. In certain embodiments, the apo(a) specific inhibitor is a modified oligonucleotide consisting of 20 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of SEQ ID NO: 58, wherein the modified oligonucleotide comprises: (a) a gap segment consisting of ten linked deoxynucleosides; (b) a 5' wing segment consisting of five linked nucleosides; (c) a 3' wing segment consisting of five linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.

[0013] Certain embodiments provide a composition comprising a compound described herein, or a salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0014] In certain embodiments, the modulation of apo(a) expression occurs in a cell or tissue. In certain embodiments, the modulations occur in a cell or tissue in an animal. In certain embodiments, the animal is a human. In certain embodiments, the modulation is a reduction in apo(a) mRNA level. In certain embodiments, the modulation is a reduction in apo(a) protein level. In certain embodiments, both apo(a) mRNA and protein levels are reduced. Such reduction may occur in a time-dependent or in a dose-dependent manner.

[0015] Certain embodiments provide compositions and methods for use in therapy. Certain embodiments provide compositions and methods for preventing, treating, delaying, slowing the progression and/or ameliorating apo(a) related diseases, disorders, and conditions. Certain embodiments provide compositions and methods for preventing, treating, delaying, slowing the progression and/or ameliorating Lp(a) related diseases, disorders, and conditions. In certain embodiments, such diseases, disorders, and conditions are inflammatory, cardiovascular and/or metabolic diseases, disorders, and conditions. In certain embodiments, the compositions and methods for therapy include administering an apo(a) specific inhibitor to an individual in need thereof. In certain embodiments, the apo(a) specific inhibitor is a nucleic acid. In certain embodiments, the nucleic acid is an antisense compound. In certain embodiments, the antisense compound is a modified oligonucleotide.

DETAILED DESCRIPTION

[0016] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "or" means "and/or", unless stated otherwise. Additionally, as used herein, the use of "and" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms, such as "includes" and "included", is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0017] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this disclosure, including, but not limited to, patents, patent applications, published patent applications, articles, books, treatises, and GENBANK Accession Numbers and associated sequence information obtainable through databases such as National Center for Biotechnology Information (NCBI) and other data referred to throughout in the disclosure are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

[0018] Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis.

[0019] Unless otherwise indicated, the following terms have the following meanings:

[0020] "2'-O-methoxyethyl" (also 2'-MOE, MOE, 2'-O(CH.sub.2).sub.2--OCH.sub.3 and 2'-O-(2-methoxyethyl)) refers to an O-methoxy-ethyl modification of the 2' position of a furanosyl ring. A 2'-O-methoxyethyl modified sugar is a modified sugar.

[0021] "2'-deoxyribonucleoside" means a nucleoside comprising 2'-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA).

[0022] "2'-MOE nucleoside" (also 2'-O-methoxyethyl nucleoside) means a nucleoside comprising a 2'-MOE modified sugar moiety. "2'-O-methoxyethyl nucleotide" means a nucleotide comprising a 2'-O-methoxyethyl modified sugar moiety.

[0023] "3'-fluoro-HNA" (also "F-HNA" or "3'-F-HNA") means the sugar moiety of a nucleoside having the following structure:

##STR00001##

[0024] wherein Bx is a nucleobase.

[0025] "3' target site" refers to the nucleotide of a target nucleic acid which is complementary to the 3'-most nucleotide of a particular antisense compound.

[0026] "5' target site" refers to the nucleotide of a target nucleic acid which is complementary to the 5'-most nucleotide of a particular antisense compound.

[0027] "5-methylcytosine" means a cytosine modified with a methyl group attached to the 5' position. A 5-methylcytosine is a modified nucleobase.

[0028] "About" means within .+-.10% of a value. For example, if it is stated, "a marker may be increased by about 50%", it is implied that the marker may be increased between 45%-55%.

[0029] "Active pharmaceutical agent" means the substance or substances in a pharmaceutical composition that provide a therapeutic benefit when administered to an individual. For example, in certain embodiments an antisense oligonucleotide targeted to apo(a) is an active pharmaceutical agent.

[0030] "Active target region" or "target region" means a region to which one or more active antisense compounds is targeted. "Active antisense compounds" means antisense compounds that reduce target nucleic acid levels or protein levels.

[0031] "Administered concomitantly" refers to the co-administration of two agents in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration. The effects of both agents need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive.

[0032] "Administering" or "administration" means providing a pharmaceutical agent to an individual, and includes, but is not limited to, administering by a medical professional and self-administering. Administration of a pharmaceutical agent to an individual can be continuous, chronic, short or intermittent. Administration can parenteral or non-parenteral.

[0033] "Agent" means an active substance that can provide a therapeutic benefit when administered to an animal. "First Agent" means a therapeutic compound of the invention. For example, a first agent can be an antisense oligonucleotide targeting apo(a). "Second agent" means a second therapeutic compound of the invention (e.g. a second antisense oligonucleotide targeting apo(a)) and/or a non-apo(a) therapeutic compound.

[0034] "Amelioration" or "ameliorate" or "ameliorating" refers to a lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. The severity of indicators can be determined by subjective or objective measures, which are known to those skilled in the art.

[0035] "Animal" refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

[0036] "Antibody" refers to a molecule characterized by reacting specifically with an antigen in some way, where the antibody and the antigen are each defined in terms of the other. Antibody can refer to a complete antibody molecule or any fragment or region thereof, such as the heavy chain, the light chain, Fab region, and Fc region.

[0037] "Antisense activity" means any detectable or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid.

[0038] "Antisense compound" means an oligomeric compound that is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, snoRNAs, miRNAs, and satellite repeats. As used herein, the term "antisense compound" encompasses pharmaceutically acceptable derivatives of the compounds described herein.

[0039] "Antisense inhibition" means reduction of target nucleic acid levels or target protein levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.

[0040] "Antisense oligonucleotide" means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid. As used herein, the term "antisense oligonucleotide" encompasses pharmaceutically acceptable derivatives of the compounds described herein.

[0041] "Apo(a)" means any nucleic acid or protein sequence encoding apo(a). For example, in certain embodiments, apo(a) includes a DNA sequence encoding apo(a), a RNA sequence transcribed from DNA encoding apo(a) (including genomic DNA comprising introns and exons), a mRNA sequence encoding apo(a), or a peptide sequence encoding apo(a).

[0042] "Apo(a) nucleic acid" means any nucleic acid encoding apo(a). For example, in certain embodiments, an apo(a) nucleic acid includes a DNA sequence encoding apo(a), a RNA sequence transcribed from DNA encoding apo(a) (including genomic DNA comprising introns and exons), and a mRNA sequence encoding apo(a).

[0043] "Apo(a) mRNA" means a mRNA encoding an apo(a) protein.

[0044] "Apo(a) protein" means any protein sequence encoding Apo(a).

[0045] "Apo(a) specific inhibitor" refers to any agent capable of specifically inhibiting the expression of an apo(a) nucleic acid and/or apo(a) protein. For example, apo(a) specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of apo(a) nucleic acid and/or apo(a) protein. In certain embodiments, by specifically modulating apo(a) nucleic acid expression and/or apo(a) protein expression, apo(a) specific inhibitors can affect other components of the lipid transport system including downstream components. Similarly, in certain embodiments, apo(a) specific inhibitors can affect other molecular processes in an animal.

[0046] "Atherosclerosis" means a hardening of the arteries affecting large and medium-sized arteries and is characterized by the presence of fatty deposits. The fatty deposits are called "atheromas" or "plaques," which consist mainly of cholesterol and other fats, calcium and scar tissue, and damage the lining of arteries.

[0047] "Bicyclic sugar" means a furanosyl ring modified by the bridging of two atoms. A bicyclic sugar is a modified sugar.

[0048] "Bicyclic nucleoside" (also BNA) means a nucleoside having a sugar moiety comprising a bridge connecting two carbon atoms of the sugar ring, thereby forming a bicyclic ring system. In certain embodiments, the bridge connects the 4'-carbon and the 2'-carbon of the sugar ring.

[0049] "Cap structure" or "terminal cap moiety" means chemical modifications, which have been incorporated at either terminus of an antisense compound.

[0050] "Cardiovascular disease" or "cardiovascular disorder" refers to a group of conditions related to the heart, blood vessels, or the circulation. Examples of cardiovascular diseases include, but are not limited to, aneurysm, angina, arrhythmia, atherosclerosis, cerebrovascular disease (stroke), coronary heart disease, hypertension, dyslipidemia, hyperlipidemia, hypertriglyceridemia and hypercholesterolemia.

[0051] "Chemically distinct region" refers to a region of an antisense compound that is in some way chemically different than another region of the same antisense compound. For example, a region having 2'-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2'-O-methoxyethyl modifications.

[0052] "Chimeric antisense compound" means an antisense compound that has at least two chemically distinct regions.

[0053] "Cholesterol" is a sterol molecule found in the cell membranes of all animal tissues. Cholesterol must be transported in an animal's blood plasma by lipoproteins including very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). "Plasma cholesterol" refers to the sum of all lipoproteins (VDL, IDL, LDL, HDL) esterified and/or non-esterified cholesterol present in the plasma or serum.

[0054] "Cholesterol absorption inhibitor" means an agent that inhibits the absorption of exogenous cholesterol obtained from diet.

[0055] "Co-administration" means administration of two or more agents to an individual. The two or more agents can be in a single pharmaceutical composition, or can be in separate pharmaceutical compositions. Each of the two or more agents can be administered through the same or different routes of administration. Co-administration encompasses parallel or sequential administration. "Complementarity" means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. In certain embodiments, complementarity between the first and second nucleic acid can be between two DNA strands, between two RNA strands, or between a DNA and an RNA strand. In certain embodiments, some of the nucleobases on one strand are matched to a complementary hydrogen bonding base on the other strand. In certain embodiments, all of the nucleobases on one strand are matched to a complementary hydrogen bonding base on the other strand. In certain embodiments, a first nucleic acid is an antisense compound and a second nucleic acid is a target nucleic acid. In certain such embodiments, an antisense oligonucleotide is a first nucleic acid and a target nucleic acid is a second nucleic acid.

[0056] "Constrained ethyl" or "cEt" refers to a bicyclic nucleoside having a furanosyl sugar that comprises a methyl(methyleneoxy) (4'-CH(CH.sub.3)--O-2') bridge between the 4' and the 2' carbon atoms.

[0057] "Constrained ethyl nucleoside" (also cEt nucleoside) means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH(CH.sub.3)--O-2' bridge.

[0058] "Contiguous nucleobases" means nucleobases immediately adjacent to each other.

[0059] "Cross-reactive" means an oligomeric compound targeting one nucleic acid sequence can hybridize to a different nucleic acid sequence. For example, in some instances an antisense oligonucleotide targeting human apo(a) can cross-react with an apo(a) from another species. Whether an oligomeric compound cross-reacts with a nucleic acid sequence other than its designated target depends on the degree of complementarity the compound has with the non-target nucleic acid sequence. The higher the complementarity between the oligomeric compound and the non-target nucleic acid, the more likely the oligomeric compound will cross-react with the nucleic acid.

[0060] "Cure" means a method that restores health or a prescribed treatment for an illness.

[0061] "Coronary heart disease (CHD)" means a narrowing of the small blood vessels that supply blood and oxygen to the heart, which is often a result of atherosclerosis.

[0062] "Deoxyribonucleotide" means a nucleotide having a hydrogen at the 2' position of the sugar portion of the nucleotide. Deoxyribonucleotides can be modified with any of a variety of substituents.

[0063] "Diabetes mellitus" or "diabetes" is a syndrome characterized by disordered metabolism and abnormally high blood sugar (hyperglycemia) resulting from insufficient levels of insulin or reduced insulin sensitivity. The characteristic symptoms are excessive urine production (polyuria) due to high blood glucose levels, excessive thirst and increased fluid intake (polydipsia) attempting to compensate for increased urination, blurred vision due to high blood glucose effects on the eye's optics, unexplained weight loss, and lethargy.

[0064] "Diabetic dyslipidemia" or "type 2 diabetes with dyslipidemia" means a condition characterized by Type 2 diabetes, reduced HDL-C, elevated triglycerides (TG), and elevated small, dense LDL particles.

[0065] "Diluent" means an ingredient in a composition that lacks pharmacological activity, but is pharmaceutically necessary or desirable. For example, the diluent in an injected composition can be a liquid, e.g. saline solution.

[0066] "Dyslipidemia" refers to a disorder of lipid and/or lipoprotein metabolism, including lipid and/or lipoprotein overproduction or deficiency. Dyslipidemias can be manifested by elevation of lipids such as chylomicron, cholesterol and triglycerides as well as lipoproteins such as low-density lipoprotein (LDL) cholesterol.

[0067] "Dosage unit" means a form in which a pharmaceutical agent is provided, e.g. pill, tablet, or other dosage unit known in the art. In certain embodiments, a dosage unit is a vial containing lyophilized antisense oligonucleotide. In certain embodiments, a dosage unit is a vial containing reconstituted antisense oligonucleotide.

[0068] "Dose" means a specified quantity of a pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose can be administered in one, two, or more boluses, tablets, or injections. For example, in certain embodiments where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single injection, therefore, two or more injections can be used to achieve the desired dose. In certain embodiments, the pharmaceutical agent is administered by infusion over an extended period of time or continuously. Doses can be stated as the amount of pharmaceutical agent per hour, day, week, or month. Doses can also be stated as mg/kg or g/kg.

[0069] "Effective amount" or "therapeutically effective amount" means the amount of active pharmaceutical agent sufficient to effectuate a desired physiological outcome in an individual in need of the agent. The effective amount can vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.

[0070] "Fully complementary" or "100% complementary" means each nucleobase of a nucleobase sequence of a first nucleic acid has a complementary nucleobase in a second nucleobase sequence of a second nucleic acid. In certain embodiments, a first nucleic acid is an antisense compound and a second nucleic acid is a target nucleic acid.

[0071] "Furanosyl" means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom.

[0072] "Gapmer" means a chimeric antisense compound in which an internal region having a plurality of nucleosides that support RNaseH cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising external regions. The internal region may be referred to as a "gap" and the external regions may be referred to as the "wings."

[0073] "Gap-widened" means a chimeric antisense compound having a gap segment of 12 or more contiguous 2'-deoxyribonucleosides positioned between and immediately adjacent to 5' and 3' wing segments having from one to six nucleosides.

[0074] "Glucose" is a monosaccharide used by cells as a source of energy and inflammatory intermediate. "Plasma glucose" refers to glucose present in the plasma.

[0075] "High density lipoprotein-C" or "HDL-C" means cholesterol associated with high density lipoprotein particles. Concentration of HDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. "Serum HDL-C" and "plasma HDL-C" mean HDL-C in serum and plasma, respectively.

[0076] "HMG-CoA reductase inhibitor" means an agent that acts through the inhibition of the enzyme HMG-CoA reductase, such as atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.

[0077] "Hybridization" means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include an antisense compound and a target nucleic acid.

[0078] "Hypercholesterolemia" means a condition characterized by elevated cholesterol or circulating (plasma) cholesterol, LDL-cholesterol and VLDL-cholesterol, as per the guidelines of the Expert Panel Report of the National Cholesterol Educational Program (NCEP) of Detection, Evaluation of Treatment of high cholesterol in adults (see, Arch. Int. Med. (1988) 148, 36-39).

[0079] "Hyperlipidemia" or "hyperlipemia" is a condition characterized by elevated serum lipids or circulating (plasma) lipids. This condition manifests an abnormally high concentration of fats. The lipid fractions in the circulating blood are cholesterol, low density lipoproteins, very low density lipoproteins, chylomicrons and triglycerides. The Fredrickson classification of hyperlipidemias is based on the pattern of TG and cholesterol-rich lipoprotein particles, as measured by electrophoresis or ultracentrifugation and is commonly used to characterize primary causes of hyperlipidemias such as hypertriglyceridemia (Fredrickson and Lee, Circulation, 1965, 31:321-327; Fredrickson et al., New Eng J Med, 1967, 276 (1): 34-42).

[0080] "Hypertriglyceridemia" means a condition characterized by elevated triglyceride levels. Its etiology includes primary (i.e. genetic causes) and secondary (other underlying causes such as diabetes, metabolic syndrome/insulin resistance, obesity, physical inactivity, cigarette smoking, excess alcohol and a diet very high in carbohydrates) factors or, most often, a combination of both (Yuan et al. CMAJ, 2007, 176:1113-1120).

[0081] "Identifying" or "selecting an animal with metabolic or cardiovascular disease" means identifying or selecting a subject prone to or having been diagnosed with a metabolic disease, a cardiovascular disease, or a metabolic syndrome; or, identifying or selecting a subject having any symptom of a metabolic disease, cardiovascular disease, or metabolic syndrome including, but not limited to, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypertension increased insulin resistance, decreased insulin sensitivity, above normal body weight, and/or above normal body fat content or any combination thereof. Such identification can be accomplished by any method, including but not limited to, standard clinical tests or assessments, such as measuring serum or circulating (plasma) cholesterol, measuring serum or circulating (plasma) blood-glucose, measuring serum or circulating (plasma) triglycerides, measuring blood-pressure, measuring body fat content, measuring body weight, and the like.

[0082] "Improved cardiovascular outcome" means a reduction in the occurrence of adverse cardiovascular events, or the risk thereof. Examples of adverse cardiovascular events include, without limitation, death, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest, and atrial dysrhythmia.

[0083] "Immediately adjacent" means there are no intervening elements between the immediately adjacent elements, for example, between regions, segments, nucleotides and/or nucleosides.

[0084] "Increasing HDL" or "raising HDL" means increasing the level of HDL in an animal after administration of at least one compound of the invention, compared to the HDL level in an animal not administered any compound.

[0085] "Individual" or "subject" or "animal" means a human or non-human animal selected for treatment or therapy.

[0086] "Individual in need thereof" refers to a human or non-human animal selected for treatment or therapy that is in need of such treatment or therapy.

[0087] "Induce", "inhibit", "potentiate", "elevate", "increase", "decrease", "reduce" or the like denote quantitative differences between two states. For example, "an amount effective to inhibit the activity or expression of apo(a)" means that the level of activity or expression of apo(a) in a treated sample will differ from the level of apo(a) activity or expression in an untreated sample. Such terms are applied to, for example, levels of expression, and levels of activity.

[0088] "Inflammatory condition" refers to a disease, disease state, syndrome, or other condition resulting in inflammation. For example, rheumatoid arthritis and liver fibrosis are inflammatory conditions. Other examples of inflammatory conditions include sepsis, myocardial ischemia/reperfusion injury, adult respiratory distress syndrome, nephritis, graft rejection, inflammatory bowel disease, multiple sclerosis, arteriosclerosis, atherosclerosis and vasculitis.

[0089] "Inhibiting the expression or activity" refers to a reduction or blockade of the expression or activity of a RNA or protein and does not necessarily indicate a total elimination of expression or activity.

[0090] "Insulin resistance" is defined as the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes.

[0091] "Insulin sensitivity" is a measure of how effectively an individual processes glucose. An individual having high insulin sensitivity effectively processes glucose whereas an individual with low insulin sensitivity does not effectively process glucose.

[0092] "Internucleoside linkage" refers to the chemical bond between nucleosides.

[0093] "Intravenous administration" means administration into a vein.

[0094] "Linked nucleosides" means adjacent nucleosides which are bonded together.

[0095] "Lipid-lowering" means a reduction in one or more lipids (e.g., LDL, VLDL) in a subject. "Lipid-raising" means an increase in a lipid (e.g., HDL) in a subject. Lipid-lowering or lipid-raising can occur with one or more doses over time.

[0096] "Lipid-lowering therapy" or "lipid lowering agent" means a therapeutic regimen provided to a subject to reduce one or more lipids in a subject. In certain embodiments, a lipid-lowering therapy is provided to reduce one or more of apo(a), CETP, apoB, total cholesterol, LDL-C, VLDL-C, IDL-C, non-HDL-C, triglycerides, small dense LDL particles, and Lp(a) in a subject. Examples of lipid-lowering therapy include, but are not limited to, apoB inhibitors, statins, fibrates and MTP inhibitors.

[0097] "Lipoprotein", such as VLDL, LDL and HDL, refers to a group of proteins found in the serum, plasma and lymph and are important for lipid transport. The chemical composition of each lipoprotein differs, for example, in that the HDL has a higher proportion of protein versus lipid, whereas the VLDL has a lower proportion of protein versus lipid.

[0098] "Lp(a)" comprises apo(a) and a LDL like particle containing apoB. The apo(a) is linked to the apoB by a disulfide bond.

[0099] "Low density lipoprotein-cholesterol (LDL-C)" means cholesterol carried in low density lipoprotein particles. Concentration of LDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. "Serum LDL-C" and "plasma LDL-C" mean LDL-C in the serum and plasma, respectively.

[0100] "Major risk factors" refers to factors that contribute to a high risk for a particular disease or condition. In certain embodiments, major risk factors for coronary heart disease include, without limitation, cigarette smoking, hypertension, high LDL, low HDL-C, family history of coronary heart disease, age, and other factors disclosed herein.

[0101] "Metabolic disorder" or "metabolic disease" refers to a condition characterized by an alteration or disturbance in metabolic function. "Metabolic" and "metabolism" are terms well known in the art and generally include the whole range of biochemical processes that occur within a living organism. Metabolic disorders include, but are not limited to, hyperglycemia, prediabetes, diabetes (type 1 and type 2), obesity, insulin resistance, metabolic syndrome and dyslipidemia due to type 2 diabetes.

[0102] "Metabolic syndrome" means a condition characterized by a clustering of lipid and non-lipid cardiovascular risk factors of metabolic origin. In certain embodiments, metabolic syndrome is identified by the presence of any 3 of the following factors: waist circumference of greater than 102 cm in men or greater than 88 cm in women; serum triglyceride of at least 150 mg/dL; HDL-C less than 40 mg/dL in men or less than 50 mg/dL in women; blood pressure of at least 130/85 mmHg; and fasting glucose of at least 110 mg/dL. These determinants can be readily measured in clinical practice (JAMA, 2001, 285: 2486-2497).

[0103] "Mismatch" or "non-complementary nucleobase" refers to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second or target nucleic acid.

[0104] "Mixed dyslipidemia" means a condition characterized by elevated cholesterol and elevated triglycerides.

[0105] "Modified internucleoside linkage" refers to a substitution or any change from a naturally occurring internucleoside bond (i.e. a phosphodiester internucleoside bond). For example, a phosphorothioate linkage is a modified internucleoside linkage.

[0106] "Modified nucleobase" refers to any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. For example, 5-methylcytosine is a modified nucleobase. An "unmodified nucleobase" means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U).

[0107] "Modified nucleoside" means a nucleoside having at least one modified sugar moiety, and/or modified nucleobase.

[0108] "Modified nucleotide" means a nucleotide having at least one modified sugar moiety, modified internucleoside linkage and/or modified nucleobase.

[0109] "Modified oligonucleotide" means an oligonucleotide comprising at least one modified nucleotide.

[0110] "Modified sugar" refers to a substitution or change from a natural sugar. For example, a 2'-O-methoxyethyl modified sugar is a modified sugar.

[0111] "MOE nucleoside" means a nucleoside comprising a 2'-substituted sugar moiety comprising MOE at the 2'-position.

[0112] "Motif" means the pattern of chemically distinct regions in an antisense compound.

[0113] "Naturally occurring internucleoside linkage" means a 3' to 5' phosphodiester linkage.

[0114] "Natural sugar moiety" means a sugar found in DNA (2'-H) or RNA (2'-OH).

[0115] "Nucleic acid" refers to molecules composed of monomeric nucleotides. A nucleic acid includes ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids (ssDNA), double-stranded nucleic acids (dsDNA), small interfering ribonucleic acids (siRNA), and microRNAs (miRNA). A nucleic acid may also comprise any combination of these elements in a single molecule.

[0116] "Nucleobase" means a heterocyclic moiety capable of pairing with a base of another nucleic acid.

[0117] "Nucleobase complementarity" refers to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the oligonucleotide and the target nucleic acid are considered to be complementary at that nucleobase pair.

[0118] "Nucleobase sequence" means the order of contiguous nucleobases independent of any sugar, linkage, or nucleobase modification.

[0119] "Nucleoside" means a nucleobase linked to a sugar.

[0120] "Nucleoside mimetic" includes those structures used to replace the sugar or the sugar and the base, and not necessarily the linkage at one or more positions of an oligomeric compound; for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo or tricyclo sugar mimetics such as non-furanose sugar units.

[0121] "Nucleotide" means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside.

[0122] "Nucleotide mimetic" includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by --N(H)--C(.dbd.O)--O-- or other non-phosphodiester linkage).

[0123] "Oligomeric compound" or "oligomer" means a polymer of linked monomeric subunits which is capable of hybridizing to a region of a nucleic acid molecule. In certain embodiments, oligomeric compounds are oligonucleosides. In certain embodiments, oligomeric compounds are oligonucleotides. In certain embodiments, oligomeric compounds are antisense compounds. In certain embodiments, oligomeric compounds are antisense oligonucleotides. In certain embodiments, oligomeric compounds are chimeric oligonucleotides.

[0124] "Oligonucleotide" means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another.

[0125] "Parenteral administration" means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration. Administration can be continuous, chronic, short or intermittent.

[0126] "Peptide" means a molecule formed by linking at least two amino acids by amide bonds. Peptide refers to polypeptides and proteins.

[0127] "Pharmaceutical agent" means a substance that provides a therapeutic benefit when administered to an individual. For example, in certain embodiments, an antisense oligonucleotide targeted to apo(a) is a pharmaceutical agent.

[0128] "Pharmaceutical composition" or "composition" means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition can comprise one or more active agents and a pharmaceutical carrier e.g., a sterile aqueous solution.

[0129] "Pharmaceutically acceptable carrier" means a medium or diluent that does not interfere with the structure of the compound. Certain of such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. Certain of such carriers enable pharmaceutical compositions to be formulated for injection, infusion or topical administration. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution.

[0130] "Pharmaceutically acceptable derivative" encompasses derivatives of the compounds described herein such as solvates, hydrates, esters, prodrugs, polymorphs, isomers, isotopically labelled variants, pharmaceutically acceptable salts and other derivatives known in the art.

[0131] "Pharmaceutically acceptable salts" means physiologically and pharmaceutically acceptable salts of antisense compounds, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. The term "pharmaceutically acceptable salt" or "salt" includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. "Pharmaceutically acceptable salts" of the compounds described herein may be prepared by methods well-known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002). Sodium salts of antisense oligonucleotides are useful and are well accepted for therapeutic administration to humans. Accordingly, in one embodiment the compounds described herein are in the form of a sodium salt.

[0132] "Phosphorothioate linkage" means a linkage between nucleosides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage (P.dbd.S) is a modified internucleoside linkage.

[0133] "Portion" means a defined number of contiguous (i.e. linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense compound.

[0134] "Prevent" or "preventing" refers to delaying or forestalling the onset or development of a disease, disorder, or condition for a period of time from minutes to indefinitely. Prevent also means reducing risk of developing a disease, disorder, or condition.

[0135] "Prodrug" means a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., a drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals or conditions.

[0136] "Raise" means to increase in amount. For example, to raise plasma HDL levels means to increase the amount of HDL in the plasma.

[0137] "Reduce" means to bring down to a smaller extent, size, amount, or number. For example, to reduce plasma triglyceride levels means to bring down the amount of triglyceride in the plasma.

[0138] "Region" or "target region" is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic. For example, a target region may encompass a 3' UTR, a 5' UTR, an exon, an intron, an exon/intron junction, a coding region, a translation initiation region, translation termination region, or other defined nucleic acid region. The structurally defined regions for apo(a) can be obtained by accession number from sequence databases such as NCBI and such information is incorporated herein by reference. In certain embodiments, a target region may encompass the sequence from a 5' target site of one target segment within the target region to a 3' target site of another target segment within the target region.

[0139] "Ribonucleotide" means a nucleotide having a hydroxy at the 2' position of the sugar portion of the nucleotide. Ribonucleotides can be modified with any of a variety of substituents.

[0140] "Second agent" or "second therapeutic agent" means an agent that can be used in combination with a "first agent". A second therapeutic agent can include, but is not limited to, antisense oligonucleotides targeting apo(a) or apoB. A second agent can also include anti-apo(a) antibodies, apo(a) peptide inhibitors, cholesterol lowering agents, lipid lowering agents, glucose lowering agents and anti-inflammatory agents.

[0141] "Segments" are defined as smaller, sub-portions of regions within a nucleic acid. For example, a "target segment" means the sequence of nucleotides of a target nucleic acid to which one or more antisense compounds is targeted. "5' target site" refers to the 5'-most nucleotide of a target segment. "3' target site" refers to the 3'-most nucleotide of a target segment. Alternatively, a "start site" can refer to the 5'-most nucleotide of a target segment and a "stop site" refers to the 3'-most nucleotide of a target segment. A target segment can also begin at the "start site" of one sequence and end at the "stop site" of another sequence.

[0142] "Shortened" or "truncated" versions of antisense oligonucleotides or target nucleic acids taught herein have one, two or more nucleosides deleted.

[0143] "Side effects" means physiological responses attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

[0144] "Single-stranded oligonucleotide" means an oligonucleotide which is not hybridized to a complementary strand.

[0145] "Specifically hybridizable" refers to an antisense compound having a sufficient degree of complementarity to a target nucleic acid to induce a desired effect while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e. under physiological conditions in the case of in vivo assays and therapeutic treatments.

[0146] "Statin" means an agent that inhibits the activity of HMG-CoA reductase.

[0147] "Subcutaneous administration" means administration just below the skin.

[0148] "Subject" means a human or non-human animal selected for treatment or therapy.

[0149] "Sugar moiety" means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside.

[0150] "Symptom of cardiovascular disease or disorder" means a phenomenon that arises from and accompanies the cardiovascular disease or disorder and serves as an indication of it. For example, angina; chest pain; shortness of breath; palpitations; weakness; dizziness; nausea; sweating; tachycardia; bradycardia; arrhythmia; atrial fibrillation; swelling in the lower extremities; cyanosis; fatigue; fainting; numbness of the face; numbness of the limbs; claudication or cramping of muscles; bloating of the abdomen; or fever are symptoms of cardiovascular disease or disorder.

[0151] "Targeting" or "targeted" means the process of design and selection of an antisense compound that will specifically hybridize to a target nucleic acid and induce a desired effect.

[0152] "Target nucleic acid," "target RNA," and "target RNA transcript" all refer to a nucleic acid capable of being targeted by antisense compounds.

[0153] "Therapeutically effective amount" means an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual.

[0154] "Therapeutic lifestyle change" means dietary and lifestyle changes intended to lower fat/adipose tissue mass and/or cholesterol. Such change can reduce the risk of developing heart disease, and may includes recommendations for dietary intake of total daily calories, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, carbohydrate, protein, cholesterol, insoluble fiber, as well as recommendations for physical activity.

[0155] "Treat" or "treating" refers to administering a compound described herein to effect an alteration or improvement of a disease, disorder, or condition.

[0156] "Triglyceride" or "TG" means a lipid or neutral fat consisting of glycerol combined with three fatty acid molecules.

[0157] "Type 2 diabetes," (also known as "type 2 diabetes mellitus", "diabetes mellitus, type 2", "non-insulin-dependent diabetes", "NIDDM", "obesity related diabetes", or "adult-onset diabetes") is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia.

[0158] "Unmodified nucleotide" means a nucleotide composed of naturally occurring nucleobases, sugar moieties, and internucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e. .beta.-D-ribonucleosides) or a DNA nucleotide (i.e. .beta.-D-deoxyribonucleoside).

[0159] "Wing segment" means one or a plurality of nucleosides modified to impart to an oligonucleotide properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

Certain Embodiments

[0160] Certain embodiments provide a compounds and methods for decreasing apo(a) mRNA and protein expression. In certain embodiments, the compound is an apo(a) specific inhibitor for treating, preventing, or ameliorating an apo(a) associated disease. In certain embodiments, the compound is an antisense oligonucleotide targeting apo(a).

[0161] Certain embodiments provide a compounds and methods for decreasing Lp(a) levels. In certain embodiments, the compound is an apo(a) specific inhibitor for treating, preventing, or ameliorating an Lp(a) associated disease. In certain embodiments, the compound is an antisense oligonucleotide targeting apo(a).

[0162] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 15 to 30, 18 to 24, 19 to 22, 13 to 25, 14 to 25, 15 to 25 linked nucleosides. In certain embodiments, the modified oligonucleotide comprises at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29 or 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 20 linked nucleosides.

[0163] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NOs: 1-4. Certain embodiments provide a compound comprising a modified oligonucleotide targeting an apo(a) segment comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of any of the target segments shown in Tables 3-13 and 28-30. In the tables, the "Start Site" refers to the 5'-most nucleotide of a target segment and "Stop Site" refers to the 3'-most nucleotide of a target segment. A target segment can range from the start site to the stop site of each sequence listed in the tables. Alternatively, the target segment can range from the start site of one sequence and end at the stop site of another sequence. For example, as shown in Table 5, a target segment can range from 3901-3920, the start site to the stop site of SEQ ID NO: 58. In another example, as shown in Table 5, a target segment can range from 3900-3923, the start site of SEQ ID NO: 57 to the stop site of SEQ ID NO: 61.

[0164] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to any of SEQ ID NOs: 1-4. Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to any of the target segments shown in Tables 3-13 and 28-30.

[0165] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to an equal length portion of nucleobases 3901 to 3920 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1.

[0166] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29 or 30 contiguous nucleobases complementary to an equal length portion of nucleobases 3900 to 3923 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1.

[0167] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 12-130, 133, 134. In certain embodiments, the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 12-130, 133, 134.

[0168] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 12-20, 22-33, 35-44, 47-50, 51, 53, 57-62, 65-66, 68, 70-79, 81, 85-86, 89-90, 92-94, 97, 105-110, 103-104, 133-134.

[0169] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 12-19, 26-30, 32, 35, 38-44, 46-47, 50, 57-58, 61, 64-66, 68, 72-74, 76-77, 92-94, 103-110.

[0170] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 111, 114-121, 123-129.

[0171] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 14, 17, 18, 26-28, 39, 71, 106-107.

[0172] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 14, 26-29, 39-40, 82.

[0173] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 14, 16-18.

[0174] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 26-27, 107.

[0175] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 28-29, 39-40, 47.

[0176] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 28, 93, 104, 134.

[0177] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a) consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, least 9, least 10, least 11, at least 12, least 13, at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 58.

[0178] In certain embodiments, the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 58.

[0179] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide is single-stranded.

[0180] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein at least one internucleoside linkage is a modified internucleoside linkage. In certain embodiments, each internucleoside linkage is a phosphorothioate internucleoside linkage.

[0181] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein at least one nucleoside comprises a modified nucleobase. In certain embodiments, the modified nucleobase is a 5-methylcytosine.

[0182] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide comprises at least one modified sugar. In certain embodiments, the modified sugar is a bicyclic sugar. In certain embodiments, the modified sugar comprises a 2'-O-methoxyethyl, a constrained ethyl, a 3'-fluoro-HNA or a 4'-(CH.sub.2).sub.n--O-2' bridge, wherein n is 1 or 2.

[0183] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and comprises: (a) a gap segment consisting of linked deoxynucleosides; (b) a 5' wing segment consisting of linked nucleosides; (c) a 3' wing segment consisting of linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

[0184] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises: (a) a gap segment consisting of ten linked deoxynucleosides; (b) a 5' wing segment consisting of five linked nucleosides; (c) a 3' wing segment consisting of five linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.

[0185] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of SEQ ID NOs: 12-130, 133, 134, wherein the modified oligonucleotide comprises: (a) a gap segment consisting of ten linked deoxynucleosides; (b) a 5' wing segment consisting of five linked nucleosides; (c) a 3' wing segment consisting of five linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.

[0186] Certain embodiments provide a compound comprising a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NO: 58, wherein the modified oligonucleotide comprises: (a) a gap segment consisting of ten linked deoxynucleosides; (b) a 5' wing segment consisting of five linked nucleosides; (c) a 3' wing segment consisting of five linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.

[0187] Certain embodiments provide a modified oligonucleotide targeting apo(a), wherein the modified oligonucleotide consists of 20 linked nucleosides with the nucleobase sequence of SEQ ID NO: 58, wherein the modified oligonucleotide comprises: (a) a gap segment consisting of ten linked deoxynucleosides; (b) a 5' wing segment consisting of five linked nucleosides; (c) a 3' wing segment consisting of five linked nucleosides; and wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.

[0188] In certain embodiments, the compound is in a salt form. In further embodiments, the compound further comprises of a pharmaceutically acceptable carrier or diluent. In certain embodiments, the compound comprising a modified oligonucleotide targeting apo(a), or a salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0189] Certain embodiments provide a composition comprising a compound as described herein, wherein the viscosity level of the compound is less than 40 centipoise (cP). In certain embodiments, the antisense compounds as described herein are efficacious by virtue of having a viscosity of less than 40 cP, less than 35 cP, less than 30 cP, less than 25 cP, less than 20 cP or less than 15 cP when measured by the parameters as described in Example 13.

[0190] Certain embodiments provide compositions and methods for use in therapy to treat an apo(a) related disease, disorder or condition. Certain embodiments provide compositions and methods for use in therapy to treat an Lp(a) related disease, disorder or condition. In certain embodiments, the composition is a compound comprising an apo(a) specific inhibitor. In certain embodiments, the apo(a) specific inhibitor is a nucleic acid. In certain embodiments, the nucleic acid is an antisense compound. In certain embodiments, the antisense compound is a modified oligonucleotide targeting apo(a). In certain embodiments, the modified oligonucleotide targeting apo(a), is used in treating, preventing, slowing progression, ameliorating a cardiovascular and/or metabolic disease, disorder or condition. In certain embodiments, the compositions and methods for therapy include administering an apo(a) specific inhibitor to an individual in need thereof.

[0191] Certain embodiments provide compositions and methods for reducing apo(a) levels. Certain embodiments provide compositions and methods for reducing Lp(a) levels. In certain embodiments, reducing apo(a) levels in a tissue, organ or subject improves the ratio of LDL to HDL or the ratio of TG to HDL.

[0192] Certain embodiments provide compositions and methods for preventing, treating, delaying, slowing the progression and/or ameliorating apo(a) related diseases, disorders, and conditions in a subject in need thereof. Certain embodiments provide compositions and methods for preventing, treating, delaying, slowing the progression and/or ameliorating Lp(a) related diseases, disorders, and conditions in a subject in need thereof. In certain embodiments, such diseases, disorders, and conditions include cardiovascular and/or metabolic diseases, disorders, and conditions. Certain such cardiovascular diseases, disorders or conditions include, but are not limited to, aneurysm (e.g., abdominal aortic aneurysm), angina, arrhythmia, atherosclerosis, cerebrovascular disease, coronary artery disease, coronary heart disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, myocardial infarction, peripheral vascular disease (e.g., peripheral artery disease, peripheral artery occlusive disease), retinal vascular occlusion, or stroke. Certain such metabolic diseases, disorders or conditions include, but are not limited to, hyperglycemia, prediabetes, diabetes (type I and type II), obesity, insulin resistance, metabolic syndrome and diabetic dyslipidemia. Certain such inflammatory diseases, disorders or conditions include, but are not limited to, coronary artery disease (CAD), Alzheimer's Disease and thromboembolic diseases, disorder or conditions Certain thromboembolic diseases, disorders or conditions include, but are not limited to, stroke, thrombosis (e.g., venous thromboembolism), myocardial infarction and peripheral vascular disease.

[0193] Certain embodiments provide a method of reducing at least one symptom of a cardiovascular disease, disorder or condition. In certain embodiments, the symptoms include, but are not limited to, angina, chest pain, shortness of breath, palpitations, weakness, dizziness, nausea, sweating, tachycardia, bradycardia, arrhythmia, atrial fibrillation, swelling in the lower extremities, cyanosis, fatigue, fainting, numbness of the face, numbness of the limbs, claudication or cramping of muscles, bloating of the abdomen, and fever.

[0194] In certain embodiments, the modulation of apo(a) or Lp(a) expression occurs in a cell, tissue or organ. In certain embodiments, the modulations occur in a cell, tissue or organ in an animal. In certain embodiments, the modulation is a reduction in apo(a) mRNA level. In certain embodiments, the modulation is a reduction in apo(a) protein level. In certain embodiments, both apo(a) mRNA and protein levels are reduced. In certain embodiments, the modulation is a reduction in Lp(a) level. Such reduction may occur in a time-dependent or in a dose-dependent manner.

[0195] In certain embodiments, the subject or animal is human.

[0196] In certain embodiments, the compound is parenterally administered. In further embodiments, the parenteral administration is subcutaneous.

[0197] In certain embodiments, the compound is co-administered with a second agent or therapy. In certain embodiments, the second agent is a glucose-lowering agent. In certain embodiments, the second agent is a LDL, TG or cholesterol lowering agent. In certain embodiments, the second agent is an anti-inflammatory agent. In certain embodiments, the second agent is an Alzheimer Disease drug. In certain embodiments, the second agent can be, but is not limited to, a non-steroidal anti-inflammatory drug (NSAID e.g., aspirin), niacin (e.g., Niaspan), nicotinic acid, an apoB inhibitor (e.g., Mipomersen), a CETP inhibitor (e.g., Anacetrapib), an apo(a) inhibitor, a thyroid hormone analog (e.g., Eprotirome), a HMG-CoA reductase inhibitor (e.g., a statin), a fibrate (e.g., Gemfibrozil) and an microsomal triglyceride transfer protein inhibitor (e.g., Lomitapide). The therapy can be, but is not limited to, Lp(a) apheresis. Agents or therapies can be co-administered or administered concomitantly. Agents or therapies can be sequentially or subsequently administered.

[0198] Certain embodiments provide use of a compound targeted to apo(a) for decreasing apo(a) levels in an animal. Certain embodiments provide use of a compound targeted to apo(a) for decreasing Lp(a) levels in an animal. Certain embodiments provide use of a compounds targeted to apo(a) for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with apo(a). Certain embodiments provide use of a compounds targeted to apo(a) for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with Lp(a).

[0199] Certain embodiments provide use of a compound targeted to apo(a) in the preparation of a medicament for decreasing apo(a) levels in an animal. Certain embodiments provide use of a compound targeted to apo(a) in the preparation of a medicament for decreasing Lp(a) levels in an animal. Certain embodiments provide use of a compound for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with apo(a). Certain embodiments provide use of a compound for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with Lp(a).

[0200] Certain embodiments provide a kit for treating, preventing, or ameliorating a disease, disorder or condition as described herein wherein the kit comprises: (i) an apo(a) specific inhibitor as described herein; and optionally (ii) a second agent or therapy as described herein.

[0201] A kit of the present invention can further include instructions for using the kit to treat, prevent, or ameliorate a disease, disorder or condition as described herein by combination therapy as described herein.

Antisense Compounds

[0202] Oligomeric compounds include, but are not limited to, oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics, antisense compounds, antisense oligonucleotides, ribozymes, microRNAs and siRNAs. An oligomeric compound may be "antisense" to a target nucleic acid, meaning that it is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding.

[0203] In certain embodiments, an antisense compound has a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted. In certain such embodiments, an antisense oligonucleotide has a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted.

[0204] In certain embodiments, an antisense compound targeted to an apo(a) nucleic acid is 12 to 30 subunits in length. In other words, such antisense compounds are from 12 to 30 linked subunits. In other embodiments, the antisense compound is 8 to 80, 10 to 80, 12 to 50, 15 to 30, 18 to 24, 19 to 22, 13 to 25, 14 to 25 or 15 to 25 linked subunits. In certain such embodiments, the antisense compounds are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits in length, or a range defined by any two of the above values. In certain such embodiments, the antisense compounds are 8 linked subunits in length. In some embodiments the antisense compound is an antisense oligonucleotide. In some embodiments, the linked subunits are nucleosides.

[0205] In certain embodiments, the antisense compound comprises a shortened or truncated modified oligonucleotide. The shortened or truncated modified oligonucleotide can have one or more nucleosides deleted from the 5' end (5' truncation), one or more nucleosides deleted from the 3' end (3' truncation) or one or more nucleosides deleted from the central portion. Alternatively, the deleted nucleosides can be dispersed throughout the modified oligonucleotide, for example, in an antisense compound having one nucleoside deleted from the 5' end and one nucleoside deleted from the 3' end.

[0206] When a single additional nucleoside is present in a lengthened oligonucleotide, the additional nucleoside can be located at the central portion, 5' or 3' end of the oligonucleotide. When two or more additional nucleosides are present, the added nucleosides can be adjacent to each other, for example, in an oligonucleotide having two nucleosides added to the central portion, to the 5' end (5' addition), or alternatively to the 3' end (3' addition), of the oligonucleotide. Alternatively, the added nucleosides can be dispersed throughout the antisense compound, for example, in an oligonucleotide having one nucleoside added to the 5' end and one subunit added to the 3' end.

[0207] It is possible to increase or decrease the length of an antisense compound, such as an antisense oligonucleotide, and/or introduce mismatch bases without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of antisense oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Antisense oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the antisense oligonucleotides were able to direct specific cleavage of the target mRNA, albeit to a lesser extent than the antisense oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase antisense oligonucleotides, including those with 1 or 3 mismatches.

[0208] Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo.

[0209] Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase antisense oligonucleotides, and 28 and 42 nucleobase antisense oligonucleotides comprised of the sequence of two or three of the tandem antisense oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase antisense oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase antisense oligonucleotides.

Antisense Compound Motifs

[0210] In certain embodiments, antisense compounds targeted to an apo(a) nucleic acid have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense compounds properties, such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

[0211] Chimeric antisense compounds typically contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense compound may optionally serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of a RNA:DNA duplex.

[0212] Antisense compounds having a gapmer motif are considered chimeric antisense compounds. In a gapmer an internal region having a plurality of nucleotides that supports RNase H cleavage is positioned between external regions having a plurality of nucleotides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment generally serves as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. In certain embodiments, the regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer may in some embodiments include .beta.-D-ribonucleosides, .beta.-D-deoxyribonucleosides, 2'-modified nucleosides (such 2'-modified nucleosides may include 2'-MOE, and 2'-O--CH.sub.3, among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a 4'-(CH2)n-O-2' bridge, where n=1 or n=2). Preferably, each distinct region comprises uniform sugar moieties. The wing-gap-wing motif is frequently described as "X-Y-Z", where "X" represents the length of the 5' wing region, "Y" represents the length of the gap region, and "Z" represents the length of the 3' wing region. As used herein, a gapmer described as "X-Y-Z" has a configuration such that the gap segment is positioned immediately adjacent to each of the 5' wing segment and the 3' wing segment. Thus, no intervening nucleotides exist between the 5' wing segment and gap segment, or the gap segment and the 3' wing segment. Any of the antisense compounds described herein can have a gapmer motif. In some embodiments, X and Z are the same; in other embodiments they are different. In a preferred embodiment, Y is between 8 and 15 nucleotides. X, Y or Z can be any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotides. Thus, gapmers include, but are not limited to, for example 5-10-5, 4-8-4, 4-12-3, 4-12-4, 3-14-3, 2-13-5, 2-12-2, 2-16-2, 1-18-1, 3-10-3, 2-10-2, 1-10-1, 2-8-2, 6-8-6, 5-8-5, 1-8-1, 2-6-2, 2-13-2, 1-8-2, 2-8-3, 3-10-2, 1-18-2 or 2-18-2.

[0213] In certain embodiments, the antisense compound as a "wingmer" motif, having a wing-gap or gap-wing configuration, i.e. an X-Y or Y-Z configuration as described above for the gapmer configuration. Thus, wingmer configurations include, but are not limited to, for example 5-10, 8-4, 4-12, 12-4, 3-14, 16-2, 18-1, 10-3, 2-10, 1-10, 8-2, 2-13 or 5-13.

[0214] In certain embodiments, antisense compounds targeted to an apo(a) nucleic acid possess a 5-10-5 gapmer motif.

[0215] In certain embodiments, an antisense compound targeted to an apo(a) nucleic acid has a gap-widened motif.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

[0216] Nucleotide sequences that encode the apo(a) target sequence include, without limitation, the following: GENBANK Accession No. NM_005577.2, incorporated herein as SEQ ID NO: 1; GENBANK Accession No. NT_007422.12 truncated from nucleotides 3230000 to 3380000, incorporated herein as SEQ ID NO: 2; GENBANK Accession No. NT_025741.15 truncated from nucleotides 65120000 to 65258000, designated herein as SEQ ID NO: 3; and GENBANK Accession No. NM_005577.1, incorporated herein as SEQ ID NO: 4.

[0217] It is understood that the sequence set forth in each SEQ ID NO in the Examples contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage or a nucleobase. Antisense compounds described by Isis Number (Isis No.) indicate a combination of nucleobase sequence and motif.

[0218] In certain embodiments, a "target region" is a structurally defined region of the target nucleic acid. For example, a target region can encompass a 3' UTR, a 5' UTR, an exon, an intron, an exon/intron junction, a coding region, a translation initiation region, a translation termination region, or other defined nucleic acid region. The structurally defined regions for apo(a) can be obtained by accession number from sequence databases such as NCBI and such information is incorporated herein by reference. In certain embodiments, a target region can encompass the sequence from a 5' target site of one target segment within the target region to a 3' target site of another target segment within the same target region.

[0219] In certain embodiments, a "target segment" is a smaller, sub-portion of a target region within a nucleic acid. For example, a target segment can be the sequence of nucleotides of a target nucleic acid to which one or more antisense compounds are targeted. "5' target site" refers to the 5'-most nucleotide of a target segment. "3' target site" refers to the 3'-most nucleotide of a target segment.

[0220] A target region can contain one or more target segments. Multiple target segments within a target region can be overlapping. Alternatively, they can be non-overlapping. In certain embodiments, target segments within a target region are separated by no more than about 300 nucleotides. In certain embodiments, target segments within a target region are separated by a number of nucleotides that is, is about, is no more than, is no more than about, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 nucleotides on the target nucleic acid, or is a range defined by any two of the preceding values. In certain embodiments, target segments within a target region are separated by no more than, or no more than about, 5 nucleotides on the target nucleic acid. In certain embodiments, target segments are contiguous. Contemplated are target regions defined by a range having a starting nucleic acid that is any of the 5' target sites or 3' target sites listed, herein.

[0221] Targeting includes determination of at least one target segment to which an antisense compound hybridizes, such that a desired effect occurs. In certain embodiments, the desired effect is a reduction in mRNA target nucleic acid levels. In certain embodiments, the desired effect is reduction of levels of protein encoded by the target nucleic acid or a phenotypic change associated with the target nucleic acid.

[0222] Suitable target segments can be found within a 5' UTR, a coding region, a 3' UTR, an intron, an exon, or an exon/intron junction. Target segments containing a start codon or a stop codon are also suitable target segments. A suitable target segment can specifically exclude a certain structurally defined region, such as the start codon or stop codon.

[0223] The determination of suitable target segments can include a comparison of the sequence of a target nucleic acid to other sequences throughout the genome. For example, the BLAST algorithm can be used to identify regions of similarity amongst different nucleic acids. This comparison can prevent the selection of antisense compound sequences that can hybridize in a non-specific manner to sequences other than a selected target nucleic acid (i.e., non-target or off-target sequences).

[0224] There can be variation in activity (e.g., as defined by percent reduction of target nucleic acid levels) of the antisense compounds within an active target region. In certain embodiments, reductions in apo(a) mRNA levels can be indicative of inhibition of apo(a) expression. Reductions in levels of an apo(a) protein can be indicative of inhibition of target mRNA expression. Further, phenotypic changes can be indicative of inhibition of apo(a) expression. For example, an increase in HDL levels, decrease in LDL levels, decrease in cholesterol levels or decrease in triglyceride levels, are among phenotypic changes that can be assessed for inhibition of apo(a) expression. Other phenotypic indications, e.g., symptoms associated with a cardiovascular disease, may also be assessed; for example, angina; chest pain; shortness of breath; palpitations; weakness; dizziness; nausea; sweating; tachycardia; bradycardia; arrhythmia; atrial fibrillation; swelling in the lower extremities; cyanosis; fatigue; fainting; numbness of the face; numbness of the limbs; claudication or cramping of muscles; bloating of the abdomen; or fever.

Hybridization

[0225] In some embodiments, hybridization occurs between an antisense compound disclosed herein and an apo(a) nucleic acid. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.

[0226] Hybridization can occur under varying conditions. Stringent conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized.

[0227] Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art (Sambrooke and Russell, Molecular Cloning: A Laboratory Manual, 3.sup.rd Ed., 2001). In certain embodiments, the antisense compounds provided herein are specifically hybridizable with an apo(a) nucleic acid.

Complementarity

[0228] An antisense compound and a target nucleic acid are complementary to each other when a sufficient number of nucleobases of the antisense compound can hydrogen bond with the corresponding nucleobases of the target nucleic acid, such that a desired effect will occur (e.g., antisense inhibition of a target nucleic acid, such as an apo(a) nucleic acid).

[0229] Noncomplementary nucleobases between an antisense compound and an apo(a) nucleic acid can be tolerated provided that the antisense compound remains able to specifically hybridize to a target nucleic acid. Moreover, an antisense compound can hybridize over one or more segments of an apo(a) nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

[0230] In certain embodiments, the antisense compounds provided herein, or a specified portion thereof, are, or are at least, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to an apo(a) nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of an antisense compound with a target nucleic acid can be determined using routine methods.

[0231] For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases can be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having 4 (four) noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

[0232] In certain embodiments, the antisense compounds provided herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, an antisense compound may be fully complementary to an apo(a) nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein, "fully complementary" means each nucleobase of an antisense compound is capable of precise base pairing with the corresponding nucleobases of a target nucleic acid. For example, a 20 nucleobase antisense compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the antisense compound. Fully complementary can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase antisense compound can be "fully complementary" to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase oligonucleotide is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the antisense compound. At the same time, the entire 30 nucleobase antisense compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the antisense compound are also complementary to the target sequence.

[0233] The location of a non-complementary nucleobase(s) can be at the 5' end or 3' end of the antisense compound. Alternatively, the non-complementary nucleobase(s) can be at an internal position of the antisense compound. When two or more non-complementary nucleobases are present, they can be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide.

[0234] In certain embodiments, antisense compounds that are, or are up to, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as an apo(a) nucleic acid, or specified portion thereof.

[0235] In certain embodiments, antisense compounds that are, or are up to, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as an apo(a) nucleic acid, or specified portion thereof.

[0236] The antisense compounds provided herein also include those which are complementary to a portion of a target nucleic acid. As used herein, "portion" refers to a defined number of contiguous (i.e. linked) nucleobases within a region or segment of a target nucleic acid. A "portion" can also refer to a defined number of contiguous nucleobases of an antisense compound. In certain embodiments, the antisense compounds are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 15 nucleobase portion of a target segment. Also contemplated are antisense compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, ora range defined by any two of these values.

Identity

[0237] The antisense compounds provided herein can also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific Isis number, or portion thereof. As used herein, an antisense compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the antisense compounds described herein as well as compounds having non-identical bases relative to the antisense compounds provided herein also are contemplated. The non-identical bases can be adjacent to each other or dispersed throughout the antisense compound. Percent identity of an antisense compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

[0238] In certain embodiments, the antisense compounds, or portions thereof, are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the antisense compounds or SEQ ID NOs, or a portion thereof, disclosed herein.

[0239] In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleobase portion is compared to an equal length portion of the target nucleic acid.

[0240] In certain embodiments, a portion of the antisense oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleobase portion is compared to an equal length portion of the target nucleic acid.

Modifications

[0241] A nucleoside is a base-sugar combination. The nucleobase (also known as base) portion of the nucleoside is normally a heterocyclic base moiety. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2', 3' or 5' hydroxyl moiety of the sugar. Oligonucleotides are formed through the covalent linkage of adjacent nucleosides to one another, to form a linear polymeric oligonucleotide. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside linkages of the oligonucleotide.

[0242] Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity.

[0243] Chemically modified nucleosides can also be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides.

Modified Internucleoside Linkages

[0244] The naturally occurring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodiester linkage. Antisense compounds having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over antisense compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.

[0245] Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known.

[0246] In certain embodiments, antisense compounds targeted to an apo(a) nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage.

Modified Sugar Moieties

[0247] Antisense compounds can optionally contain one or more nucleosides wherein the sugar group has been modified. Such sugar modified nucleosides may impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense compounds. In certain embodiments, nucleosides comprise chemically modified ribofuranose ring moieties. Examples of chemically modified ribofuranose rings include without limitation, addition of substitutent groups (including 5' and 2' substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or C(R.sub.1)(R.sub.2) (R, R.sub.1 and R.sub.2 are each independently H, C.sub.1-C.sub.12 alkyl or a protecting group) and combinations thereof. Examples of chemically modified sugars include 2'-F-5'-methyl substituted nucleoside (see PCT International Application WO 2008/101157 Published on Aug. 21, 2008 for other disclosed 5',2'-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2'-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5'-substitution of a BNA (see PCT International Application WO 2007/134181 Published on Nov. 22, 2007 wherein LNA is substituted with for example a 5'-methyl or a 5'-vinyl group).

[0248] Examples of nucleosides having modified sugar moieties include without limitation nucleosides comprising 5'-vinyl, 5'-methyl (R or S), 4'-S, 2'-F, 2'-OCH.sub.3, 2'-OCH.sub.2CH.sub.3, 2'-OCH.sub.2CH.sub.2F and 2'-O(CH.sub.2).sub.2OCH.sub.3 substituent groups. The substituent at the 2' position can also be selected from allyl, amino, azido, thio, O-allyl, O--C.sub.1-C.sub.10 alkyl, OCF.sub.3, OCH.sub.2F, O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2--O--N(R.sub.m)(R.sub.n), O--CH.sub.2--C(.dbd.O)--N(R.sub.m)(R.sub.n), and O--CH.sub.2--C(.dbd.O)--N(R.sub.l)--(CH.sub.2).sub.2--N(R.sub.m)(R.sub.n)- , where each R.sub.l, R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl.

[0249] As used herein, "bicyclic nucleosides" refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleosides include without limitation nucleosides comprising a bridge between the 4' and the 2' ribosyl ring atoms. In certain embodiments, antisense compounds provided herein include one or more bicyclic nucleosides comprising a 4' to 2' bridge. Examples of such 4' to 2' bridged bicyclic nucleosides, include but are not limited to one of the formulae: 4'-(CH.sub.2)--O-2' (LNA); 4'-(CH.sub.2)--S-2'; 4'-(CH.sub.2).sub.2--O-2' (ENA); 4'-CH(CH.sub.3)--O-2' and 4'-CH(CH.sub.2OCH.sub.3)--O-2' (and analogs thereof see U.S. Pat. No. 7,399,845, issued on Jul. 15, 2008); 4'-C(CH.sub.3)(CH.sub.3)--O-2' (and analogs thereof see published International Application WO/2009/006478, published Jan. 8, 2009); 4'-CH.sub.2--N(OCH.sub.3)-2' (and analogs thereof see published International Application WO/2008/150729, published Dec. 11, 2008); 4'-CH.sub.2--O--N(CH.sub.3)-2' (see published U.S. Patent Application US2004-0171570, published Sep. 2, 2004); 4'-CH.sub.2--N(R)--O-2', wherein R is H, C.sub.1-C.sub.12 alkyl, or a protecting group (see U.S. Pat. No. 7,427,672, issued on Sep. 23, 2008); 4'-CH.sub.2--C(H)(CH.sub.3)-2' (see Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH.sub.2--C--(.dbd.CH.sub.2)-2' (and analogs thereof see published International Application WO 2008/154401, published on Dec. 8, 2008).

[0250] Further reports related to bicyclic nucleosides can also be found in published literature (see for example: Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129(26) 8362-8379; Elayadi et al., Curr. Opinion Invest. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; and Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 7,034,133; 7,053,207; 7,399,845; 7,547,684; and 7,696,345; U.S. Patent Publication No. US2008-0039618; US2009-0012281; U.S. Patent Ser. Nos. 60/989,574; 61/026,995; 61/026,998; 61/056,564; 61/086,231; 61/097,787; and 61/099,844; Published PCT International applications WO 1994/014226; WO 2004/106356; WO 2005/021570; WO 2007/134181; WO 2008/150729; WO 2008/154401; and WO 2009/006478. Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example .alpha.-L-ribofuranose and .beta.-D-ribofuranose (see PCT international application PCT/DK98/00393, published on Mar. 25, 1999 as WO 99/14226).

[0251] In certain embodiments, bicyclic sugar moieties of BNA nucleosides include, but are not limited to, compounds having at least one bridge between the 4' and the 2' position of the pentofuranosyl sugar moiety wherein such bridges independently comprises 1 or from 2 to 4 linked groups independently selected from --[C(R.sub.a)(R.sub.b)].sub.n--, --C(R.sub.a).dbd.C(R.sub.b)--, --C(R.sub.a).dbd.N--, --C(.dbd.O)--, --C(.dbd.NR.sub.a)--, --C(.dbd.S)--, --O--, --Si(R.sub.a).sub.2--, --S(.dbd.O).sub.x--, and --N(R.sub.a)--;

[0252] wherein:

[0253] x is 0, 1, or 2;

[0254] n is 1, 2, 3, or 4;

[0255] each R.sub.a and R.sub.b is, independently, H, a protecting group, hydroxyl, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C.sub.5-C.sub.7 alicyclic radical, substituted C.sub.5-C.sub.7 alicyclic radical, halogen, OJ.sub.1, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, COOJ.sub.1, acyl (C(.dbd.O)--H), substituted acyl, CN, sulfonyl (S(.dbd.O).sub.2-J.sub.1), or sulfoxyl (S(.dbd.O)-J.sub.1); and

[0256] each J.sub.1 and J.sub.2 is, independently, H, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted C.sub.5-C.sub.20 aryl, acyl (C(.dbd.O)--H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C.sub.1-C.sub.12 aminoalkyl, substituted C.sub.1-C.sub.12 aminoalkyl or a protecting group.

[0257] In certain embodiments, the bridge of a bicyclic sugar moiety is --[C(R.sub.a)(R.sub.b)].sub.n--, --[C(R.sub.a)(R.sub.b)].sub.n--O--, --C(R.sub.aR.sub.b)--N(R)--O-- or --C(R.sub.aR.sub.b)--O--N(R)--. In certain embodiments, the bridge is 4'-CH.sub.2-2', 4'-(CH.sub.2).sub.2-2', 4'-(CH.sub.2).sub.3-2', 4'-CH.sub.2--O-2', 4'-(CH.sub.2).sub.2--O-2', 4'-CH.sub.2--O--N(R)-2' and 4'-CH.sub.2--N(R)--O-2'- wherein each R is, independently, H, a protecting group or C.sub.1-C.sub.12 alkyl.

[0258] In certain embodiments, bicyclic nucleosides are further defined by isomeric configuration. For example, a nucleoside comprising a 4'-2' methylene-oxy bridge, may be in the .alpha.-L configuration or in the .beta.-D configuration. Previously, .alpha.-L-methyleneoxy (4'-CH.sub.2--O-2') BNA's have been incorporated into antisense oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372).

[0259] In certain embodiments, bicyclic nucleosides include, but are not limited to, (A) .alpha.-L-methyleneoxy (4'-CH.sub.2--O-2') BNA, (B) .beta.-D-methyleneoxy (4'-CH.sub.2--O-2') BNA, (C) ethyleneoxy (4'-(CH.sub.2).sub.2--O-2') BNA, (D) aminooxy (4'-CH.sub.2--O--N(R)-2') BNA, (E) oxyamino (4'-CH.sub.2--N(R)--O-2') BNA, and (F) methyl(methyleneoxy) (4'-CH(CH.sub.3)--O-2') BNA, (G) methylene-thio (4'-CH.sub.2--S-2') BNA, (H) methylene-amino (4'-CH.sub.2--N(R)-2') BNA, (I) methyl carbocyclic (4'-CH.sub.2--CH(CH.sub.3)-2') BNA, and (J) propylene carbocyclic (4'-(CH.sub.2).sub.3-2') BNA as depicted below.

##STR00002## ##STR00003##

wherein Bx is the base moiety and R is independently H, a protecting group or C.sub.1-C.sub.12 alkyl.

[0260] In certain embodiments, bicyclic nucleosides are provided having Formula I:

##STR00004##

wherein:

[0261] Bx is a heterocyclic base moiety;

[0262] -Q.sub.a-Q.sub.b-Q.sub.c- is --CH.sub.2--N(R.sub.c)--CH.sub.2--, --C(.dbd.O)--N(R.sub.c)--CH.sub.2--, --CH.sub.2--O--N(R.sub.c)--, --CH.sub.2--N(R.sub.c)--O-- or --N(R.sub.c)--O--CH.sub.2;

[0263] R.sub.c is C.sub.1-C.sub.12 alkyl or an amino protecting group; and

[0264] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium.

[0265] In certain embodiments, bicyclic nucleosides are provided having Formula II:

##STR00005##

wherein:

[0266] Bx is a heterocyclic base moiety;

[0267] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

[0268] Z.sub.a is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thio.

[0269] In one embodiment, each of the substituted groups is, independently, mono or poly substituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ.sub.c, NJ.sub.cJ.sub.d, SJ.sub.c, N.sub.3, OC(.dbd.X)J.sub.c, and NJ.sub.eC(.dbd.X)NJ.sub.cJ.sub.d, wherein each J.sub.c, J.sub.d and J.sub.e is, independently, H, C.sub.1-C.sub.6 alkyl, or substituted C.sub.1-C.sub.6 alkyl and X is O or NJ.sub.c.

[0270] In certain embodiments, bicyclic nucleosides are provided having Formula III:

##STR00006##

wherein:

[0271] Bx is a heterocyclic base moiety;

[0272] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

[0273] Z.sub.b is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkynyl or substituted acyl (C(.dbd.O)--).

[0274] In certain embodiments, bicyclic nucleosides are provided having Formula IV:

##STR00007##

wherein:

[0275] Bx is a heterocyclic base moiety;

[0276] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

[0277] R.sub.d is C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl;

[0278] each q.sub.a, q.sub.b, q.sub.c and q.sub.d is, independently, H, halogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxyl, substituted C.sub.1-C.sub.6 alkoxyl, acyl, substituted acyl, C.sub.1-C.sub.6 aminoalkyl or substituted C.sub.1-C.sub.6 aminoalkyl;

[0279] In certain embodiments, bicyclic nucleosides are provided having Formula V:

##STR00008##

wherein:

[0280] Bx is a heterocyclic base moiety;

[0281] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

[0282] q.sub.a, q.sub.b, q.sub.e and q.sub.f are each, independently, hydrogen, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxy, substituted C.sub.1-C.sub.12 alkoxy, OJ.sub.j, SJ.sub.j, SOJ.sub.j, SO.sub.2J.sub.j, NJ.sub.jJ.sub.k, N.sub.3, CN, C(.dbd.O)OJ.sub.j, C(.dbd.O)NJ.sub.jJ.sub.k, C(.dbd.O)J.sub.j, O--C(.dbd.O)NJ.sub.jJ.sub.k, N(H)C(.dbd.NH)NJ.sub.jJ.sub.k, N(H)C(.dbd.O)NJ.sub.jJ.sub.k or N(H)C(.dbd.S)NJ.sub.jJ.sub.k;

[0283] or q.sub.e and q.sub.f together are .dbd.C(q.sub.g)(q.sub.h);

[0284] q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

[0285] The synthesis and preparation of the methyleneoxy (4'-CH.sub.2--O-2') BNA monomers adenine, cytosine, guanine, 5-methyl-cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition properties have been described (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). BNAs and preparation thereof are also described in WO 98/39352 and WO 99/14226.

[0286] Analogs of methyleneoxy (4'-CH.sub.2--O-2') BNA and 2'-thio-BNAs, have also been prepared (Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222). Preparation of locked nucleoside analogs comprising oligodeoxyribonucleotide duplexes as substrates for nucleic acid polymerases has also been described (Wengel et al., WO 99/14226). Furthermore, synthesis of 2'-amino-BNA, a novel comformationally restricted high-affinity oligonucleotide analog has been described in the art (Singh et al., J. Org. Chem., 1998, 63, 10035-10039). In addition, 2'-amino- and 2'-methylamino-BNA's have been prepared and the thermal stability of their duplexes with complementary RNA and DNA strands has been previously reported.

[0287] In certain embodiments, bicyclic nucleosides are provided having Formula VI:

##STR00009##

wherein:

[0288] Bx is a heterocyclic base moiety;

[0289] T.sub.a and T.sub.b are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium;

[0290] each q.sub.i, q.sub.j, q.sub.k and q.sub.l is, independently, H, halogen, C.sub.1-C.sub.12 alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.1-C.sub.12 alkoxyl, substituted C.sub.1-C.sub.12 alkoxyl, OJ.sub.j, SJ.sub.j, SOJ.sub.j, SO.sub.2J.sub.j, NJ.sub.jJ.sub.k, N.sub.3, CN, C(.dbd.O)OJ.sub.j, C(.dbd.O)NJ.sub.jJ.sub.k, C(.dbd.O)J.sub.j, O--C(.dbd.O)NJ.sub.jJ.sub.k, N(H)C(.dbd.NH)NJ.sub.jJ.sub.k, N(H)C(.dbd.O)NJ.sub.jJ.sub.k or N(H)C(.dbd.S)NJ.sub.jJ.sub.k; and

[0291] q.sub.i and q.sub.j or q.sub.l and q.sub.k together are .dbd.C(q.sub.g)(q.sub.h), wherein q.sub.g and q.sub.h are each, independently, H, halogen, C.sub.1-C.sub.12 alkyl or substituted C.sub.1-C.sub.12 alkyl.

[0292] One carbocyclic bicyclic nucleoside having a 4'-(CH.sub.2).sub.3-2' bridge and the alkenyl analog bridge 4'-CH.dbd.CH--CH.sub.2-2' have been described (Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443 and Albaek et al., J. Org. Chem., 2006, 71, 7731-7740). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (Srivastava et al., J. Am. Chem. Soc., 2007, 129(26), 8362-8379).

[0293] As used herein, "4'-2' bicyclic nucleoside" or "4' to 2' bicyclic nucleoside" refers to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2' carbon atom and the 4' carbon atom of the sugar ring.

[0294] As used herein, "monocyclic nucleosides" refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside may be modified or substituted at any position.

[0295] As used herein, "2'-modified sugar" means a furanosyl sugar modified at the 2' position. In certain embodiments, such modifications include substituents selected from: a halide, including, but not limited to substituted and unsubstituted alkoxy, substituted and unsubstituted thioalkyl, substituted and unsubstituted amino alkyl, substituted and unsubstituted alkyl, substituted and unsubstituted allyl, and substituted and unsubstituted alkynyl. In certain embodiments, 2' modifications are selected from substituents including, but not limited to: O[(CH.sub.2).sub.nO].sub.mCH.sub.3, O(CH.sub.2).sub.nNH.sub.2, O(CH.sub.2).sub.nCH.sub.3, O(CH.sub.2).sub.nF, O(CH.sub.2).sub.nONH.sub.2, OCH.sub.2C(.dbd.O)N(H)CH.sub.3, and O(CH.sub.2).sub.nON[(CH.sub.2).sub.nCH.sub.3].sub.2, where n and m are from 1 to about 10. Other 2'-substituent groups can also be selected from: C.sub.1-C.sub.12 alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH.sub.3, OCN, Cl, Br, CN, F, CF.sub.3, OCF.sub.3, SOCH.sub.3, SO.sub.2CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving pharmacokinetic properties, or a group for improving the pharmacodynamic properties of an antisense compound, and other substituents having similar properties. In certain embodiments, modified nucleosides comprise a 2'-MOE side chain (Baker et al., J. Biol. Chem., 1997, 272, 11944-12000). Such 2'-MOE substitution have been described as having improved binding affinity compared to unmodified nucleosides and to other modified nucleosides, such as 2'-O-methyl, O-propyl, and O-aminopropyl. Oligonucleotides having the 2'-MOE substituent also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin, Helv. Chim. Acta, 1995, 78, 486-504; Altmann et al., Chimia, 1996, 50, 168-176; Altmann et al., Biochem. Soc. Trans., 1996, 24, 630-637; and Altmann et al., Nucleosides Nucleotides, 1997, 16, 917-926).

[0296] As used herein, a "modified tetrahydropyran nucleoside" or "modified THP nucleoside" means a nucleoside having a six-membered tetrahydropyran "sugar" substituted in for the pentofuranosyl residue in normal nucleosides (a sugar surrogate). Modified THP nucleosides include, but are not limited to, what is referred to in the art as hexitol nucleic acid (HNA), anitol nucleic acid (ANA), mannitol nucleic acid (MNA) (see Leumann, Bioorg. Med. Chem., 2002, 10, 841-854), fluoro HNA (F-HNA) or those compounds having Formula VII:

##STR00010##

wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula VII:

[0297] Bx is a heterocyclic base moiety;

[0298] T.sub.a and T.sub.b are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound or one of T.sub.a and T.sub.b is an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound and the other of T.sub.a and T.sub.b is H, a hydroxyl protecting group, a linked conjugate group or a 5' or 3'-terminal group;

[0299] q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each independently, H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or substituted C.sub.2-C.sub.6 alkynyl; and each of R.sub.1 and R.sub.2 is selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkoxy, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, OC(.dbd.X)J.sub.1, OC(.dbd.X)NJ.sub.1J.sub.2, NJ.sub.3C(.dbd.X)NJ.sub.1J.sub.2 and CN, wherein X is O, S or NJ.sub.1 and each J.sub.1, J.sub.2 and J.sub.3 is, independently, H or C.sub.1-C.sub.6 alkyl.

[0300] In certain embodiments, the modified THP nucleosides of Formula VII are provided wherein q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is other than H. In certain embodiments, at least one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is methyl. In certain embodiments, THP nucleosides of Formula VII are provided wherein one of R.sub.1 and R.sub.2 is fluoro. In certain embodiments, R.sub.1 is fluoro and R.sub.2 is H; R.sub.1 is methoxy and R.sub.2 is H, and R.sub.1 is methoxyethoxy and R.sub.2 is H. In certain embodiments, R.sub.1 is H and R.sub.2 is fluoro; R.sub.1 is H and R.sub.2 is methoxy, and R.sub.1 is H and and R.sub.2 is methoxyethoxy.

[0301] As used herein, "2'-modified" or "2'-substituted" refers to a nucleoside comprising a sugar comprising a substituent at the 2' position other than H or OH. 2'-modified nucleosides, include, but are not limited to, bicyclic nucleosides wherein the bridge connecting two carbon atoms of the sugar ring connects the 2' carbon and another carbon of the sugar ring; and nucleosides with non-bridging 2'substituents, such as allyl, amino, azido, thio, O-allyl, O--C.sub.1-C.sub.10 alkyl, --OCF.sub.3, O--(CH.sub.2).sub.2--O--CH.sub.3, 2'-O(CH.sub.2).sub.2SCH.sub.3, O--(CH.sub.2).sub.2--O--N(R.sub.m)(R.sub.n), or O--CH.sub.2--C(.dbd.O)--N(R.sub.m)(R.sub.n), where each R.sub.m and R.sub.n is, independently, H or substituted or unsubstituted C.sub.1-C.sub.10 alkyl. 2'-modifed nucleosides may further comprise other modifications, for example at other positions of the sugar and/or at the nucleobase.

[0302] As used herein, "2'-F" refers to a nucleoside comprising a sugar comprising a fluoro group at the 2' position.

[0303] As used herein, "2'-OMe" or "2'-OCH.sub.3" or "2'-O-methyl" each refers to a nucleoside comprising a sugar comprising an --OCH.sub.3 group at the 2' position of the sugar ring.

[0304] As used herein, "MOE" or "2'-MOE" or "2'-OCH.sub.2CH.sub.2OCH.sub.3" or "2'-O-methoxyethyl" each refers to a nucleoside comprising a sugar comprising a --OCH.sub.2CH.sub.2OCH.sub.3 group at the 2' position of the sugar ring.

[0305] As used herein, "oligonucleotide" refers to a compound comprising a plurality of linked nucleosides. In certain embodiments, one or more of the plurality of nucleosides is modified. In certain embodiments, an oligonucleotide comprises one or more ribonucleosides (RNA) and/or deoxyribonucleosides (DNA).

[0306] Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds (see for example review article: Leumann, Bioorg. Med. Chem., 2002, 10, 841-854). Such ring systems can undergo various additional substitutions to enhance activity.

[0307] Methods for the preparations of modified sugars are well known to those skilled in the art.

[0308] In nucleotides having modified sugar moieties, the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target.

[0309] In certain embodiments, antisense compounds comprise one or more nucleosides having modified sugar moieties. In certain embodiments, the modified sugar moiety is 2'-MOE. In certain embodiments, the 2'-MOE modified nucleosides are arranged in a gapmer motif. In certain embodiments, the modified sugar moiety is a bicyclic nucleoside having a (4'-CH(CH.sub.3)--O-2') bridging group. In certain embodiments, the (4'-CH(CH.sub.3)--O-2') modified nucleosides are arranged throughout the wings of a gapmer motif. In certain embodiments, the modified sugar moiety is a cEt. In certain embodiments, the cEt modified nucleotides are arranged throughout the wings of a gapmer motif.

Modified Nucleobases

[0310] Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications may impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds. Modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). Certain nucleobase substitutions, including 5-methylcytosine substitutions, are particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid. For example, 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2.degree. C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278).

[0311] Additional modified nucleobases include 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (--C.ident.C--CH.sub.3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

[0312] Heterocyclic base moieties may include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Nucleobases that are particularly useful for increasing the binding affinity of antisense compounds include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.

[0313] In certain embodiments, antisense compounds targeted to an apo(a) nucleic acid comprise one or more modified nucleobases. In certain embodiments, gap-widened antisense oligonucleotides targeted to an apo(a) nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

Compositions and Methods for Formulating Pharmaceutical Compositions

[0314] Antisense oligonucleotides may be admixed with pharmaceutically acceptable active or inert substance for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

[0315] Antisense compound targeted to an apo(a) nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier.

[0316] In certain embodiments, the "pharmaceutical carrier" or "excipient" is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient can be liquid or solid and can be selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.).

[0317] Pharmaceutically acceptable organic or inorganic excipients, which do not deleteriously react with nucleic acids, suitable for parenteral or non-parenteral administration can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.

[0318] A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS). PBS is a diluent suitable for use in compositions to be delivered parenterally. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense compound targeted to an apo(a) nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is PBS. In certain embodiments, the antisense compound is an antisense oligonucleotide.

[0319] Pharmaceutical compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or an oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

[0320] A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense compound which are cleaved by endogenous nucleases within the body, to form the active antisense compound.

Conjugated Antisense Compounds

[0321] Antisense compounds can be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties. Additional conjugate groups include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes.

[0322] Antisense compounds can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense compounds to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the antisense compound having terminal nucleic acid from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5'-terminus (5'-cap), or at the 3'-terminus (3'-cap), or can be present on both termini. Cap structures are well known in the art and include, for example, inverted deoxy abasic caps. Further 3' and 5'-stabilizing groups that can be used to cap one or both ends of an antisense compound to impart nuclease stability include those disclosed in WO 03/004602, published on Jan. 16, 2003.

Cell Culture and Antisense Compounds Treatment

[0323] The effects of antisense compounds on the level, activity or expression of apo(a) nucleic acids can be tested in vitro in a variety of cell types. Cell types used for such analyses are available from commercial vendors (e.g. American Type Culture Collection, Manassas, Va.; Zen-Bio, Inc., Research Triangle Park, N.C.; Clonetics Corporation, Walkersville, Md.) and are cultured according to the vendor's instructions using commercially available reagents (e.g., Invitrogen Life Technologies, Carlsbad, Calif.). Illustrative cell types include, but are not limited to, HepG2 cells, Hep3B cells, Huh7 (hepatocellular carcinoma) cells, primary hepatocytes, A549 cells, GM04281 fibroblasts and LLC-MK2 cells.

In Vitro Testing of Antisense Oligonucleotides

[0324] Described herein are methods for treatment of cells with antisense oligonucleotides, which can be modified appropriately for treatment with other antisense compounds.

[0325] In general, cells are treated with antisense oligonucleotides when the cells reach approximately 60-80% confluence in culture.

[0326] One reagent commonly used to introduce antisense oligonucleotides into cultured cells includes the cationic lipid transfection reagent LIPOFECTIN.RTM. (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotides are mixed with LIPOFECTIN.RTM. in OPTI-MEM.RTM. 1 (Invitrogen, Carlsbad, Calif.) to achieve the desired final concentration of antisense oligonucleotide and a LIPOFECTIN.RTM. concentration that typically ranges 2 to 12 ug/mL per 100 nM antisense oligonucleotide.

[0327] Another reagent used to introduce antisense oligonucleotides into cultured cells includes LIPOFECTAMINE 2000.RTM. (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotide is mixed with LIPOFECTAMINE 2000.RTM. in OPTI-MEM.RTM. 1 reduced serum medium (Invitrogen, Carlsbad, Calif.) to achieve the desired concentration of antisense oligonucleotide and a LIPOFECTAMINE.RTM. concentration that typically ranges 2 to 12 ug/mL per 100 nM antisense oligonucleotide.

[0328] Another reagent used to introduce antisense oligonucleotides into cultured cells includes Cytofectin.RTM. (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotide is mixed with Cytofectin.RTM. in OPTI-MEM.RTM. 1 reduced serum medium (Invitrogen, Carlsbad, Calif.) to achieve the desired concentration of antisense oligonucleotide and a Cytofectin.RTM. concentration that typically ranges 2 to 12 ug/mL per 100 nM antisense oligonucleotide.

[0329] Another reagent used to introduce antisense oligonucleotides into cultured cells includes Oligofectamine.TM. (Invitrogen Life Technologies, Carlsbad, Calif.). Antisense oligonucleotide is mixed with Oligofectamine.TM. in Opti-MEM.TM.-1 reduced serum medium (Invitrogen Life Technologies, Carlsbad, Calif.) to achieve the desired concentration of oligonucleotide with an Oligofectamine.TM. to oligonucleotide ratio of approximately 0.2 to 0.8 .mu.L per 100 nM.

[0330] Another reagent used to introduce antisense oligonucleotides into cultured cells includes FuGENE 6 (Roche Diagnostics Corp., Indianapolis, Ind.). Antisense oligomeric compound was mixed with FuGENE 6 in 1 mL of serum-free RPMI to achieve the desired concentration of oligonucleotide with a FuGENE 6 to oligomeric compound ratio of 1 to 4 .mu.L of FuGENE 6 per 100 nM.

[0331] Another technique used to introduce antisense oligonucleotides into cultured cells includes electroporation (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001).

[0332] Cells are treated with antisense oligonucleotides by routine methods. Cells are typically harvested 16-24 hours after antisense oligonucleotide treatment, at which time RNA or protein levels of target nucleic acids are measured by methods known in the art and described herein (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001). In general, when treatments are performed in multiple replicates, the data are presented as the average of the replicate treatments.

[0333] The concentration of antisense oligonucleotide used varies from cell line to cell line. Methods to determine the optimal antisense oligonucleotide concentration for a particular cell line are well known in the art (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001). Antisense oligonucleotides are typically used at concentrations ranging from 1 nM to 300 nM when transfected with LIPOFECTAMINE2000.RTM. (Invitrogen, Carlsbad, Calif.), Lipofectin.RTM. (Invitrogen, Carlsbad, Calif.) or Cytofectin.TM. (Genlantis, San Diego, Calif.). Antisense oligonucleotides are used at higher concentrations ranging from 625 to 20,000 nM when transfected using electroporation.

RNA Isolation

[0334] RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. Methods of RNA isolation are well known in the art (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001). For example, RNA can be prepared using TRIZOL.RTM. (Invitrogen, Carlsbad, Calif.) according to the manufacturer's recommended protocols.

Analysis of Inhibition of Target Levels or Expression

[0335] Inhibition of levels or expression of an apo(a) nucleic acid can be assayed in a variety of ways known in the art (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001). For example, target nucleic acid levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or quantitative real-time PCR. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. Methods of RNA isolation are well known in the art. Northern blot analysis is also routine in the art. Quantitative real-time PCR can be conveniently accomplished using the commercially available ABI PRISM 7600, 7700, or 7900 Sequence Detection System, available from PE-Applied Biosystems (Foster City, Calif.) and used according to manufacturer's instructions.

Quantitative Real-Time PCR Analysis of Target RNA Levels

[0336] Quantitation of target RNA levels can be accomplished by quantitative real-time PCR using the ABI PRISM.RTM. 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer's instructions. Methods of quantitative real-time PCR are well known in the art.

[0337] Prior to real-time PCR, the isolated RNA is subjected to a reverse transcriptase (RT) reaction, which produces complementary DNA (cDNA) that is then used as the substrate for the real-time PCR amplification. The RT and real-time PCR reactions are performed sequentially in the same sample well. RT and real-time PCR reagents are obtained from Invitrogen (Carlsbad, Calif.). RT and real-time-PCR reactions are carried out by methods well known to those skilled in the art.

[0338] Gene (or RNA) target quantities obtained by real time PCR can be normalized using either the expression level of a gene whose expression is constant, such as cyclophilin A or GAPDH, or by quantifying total RNA using RIBOGREEN.RTM. (Invitrogen, Inc. Carlsbad, Calif.). Cyclophilin A or GAPDH expression can be quantified by real time PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RIBOGREEN.RTM. RNA quantification reagent (Invitrogen, Inc. Carlsbad, Calif.). Methods of RNA quantification by RIBOGREEN.RTM. are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374). A CYTOFLUOR.RTM. 4000 instrument (PE Applied Biosystems, Foster City, Calif.) is used to measure RIBOGREEN.RTM. fluorescence.

[0339] Probes and primers can be designed to hybridize to an apo(a) nucleic acid. Methods for designing real-time PCR probes and primers are well known in the art, and may include the use of software such as PRIMER EXPRESS.RTM. Software (Applied Biosystems, Foster City, Calif.).

Analysis of Protein Levels

[0340] Antisense inhibition of apo(a) nucleic acids can be assessed by measuring apo(a) protein levels. Protein levels of apo(a) can be evaluated or quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA), quantitative protein assays, protein activity assays (for example, caspase activity assays), immunohistochemistry, immunocytochemistry or fluorescence-activated cell sorting (FACS) (Sambrooke and Russell in Molecular Cloning. A Laboratory Manual. Third Edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001). Antibodies directed to a target can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional monoclonal or polyclonal antibody generation methods well known in the art. Antibodies useful for the detection of apo(a) are commercially available.

In Vivo Testing of Antisense Compounds

[0341] Antisense compounds, for example, antisense oligonucleotides, are tested in animals to assess their ability to inhibit expression of apo(a) and produce phenotypic changes. Testing can be performed in normal animals, or in experimental disease models. For administration to animals, antisense oligonucleotides are formulated in a pharmaceutically acceptable diluent, such as saline or phosphate-buffered saline. Administration includes parenteral routes of administration. Calculation of antisense oligonucleotide dosage and dosing frequency depends upon factors such as route of administration and animal body weight. Following a period of treatment with antisense oligonucleotides, RNA is isolated from tissue and changes in apo(a) nucleic acid expression are measured. Changes in apo(a) protein levels are also measured.

Certain Indications

[0342] In certain embodiments, provided herein are methods of treating an individual comprising administering one or more pharmaceutical compositions as described herein. In certain embodiments, the individual has an apo(a) related disease. In certain embodiments, the individual has an Lp(a) related disease. In certain embodiments, the individual has an inflammatory, cardiovascular and/or a metabolic disease, disorder or condition.

[0343] In certain embodiments, the cardiovascular diseases, disorders or conditions include, but are not limited to, aneurysm (e.g., abdominal aortic aneurysm), angina, arrhythmia, atherosclerosis, cerebrovascular disease, coronary artery disease, coronary heart disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, myocardial infarction, peripheral vascular disease (e.g., peripheral artery disease), stroke and the like.

[0344] In certain embodiments, the compounds targeted to apo(a) described herein modulate physiological markers or phenotypes of the cardiovascular disease, disorder or condition. For example, administration of the compounds to animals can decrease LDL and cholesterol levels in those animals compared to untreated animals. In certain embodiments, the modulation of the physiological markers or phenotypes can be associated with inhibition of apo(a) by the compounds.

[0345] In certain embodiments, the physiological markers of the cardiovascular disease, disorder or condition can be quantifiable. For example, LDL or cholesterol levels can be measured and quantified by, for example, standard lipid tests. For such markers, in certain embodiments, the marker can be decreased by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values.

[0346] Also, provided herein are methods for preventing, treating or ameliorating a symptom associated with the cardiovascular disease, disorder or condition in a subject in need thereof. In certain embodiments, provided is a method for reducing the rate of onset of a symptom associated with the cardiovascular disease, disorder or condition. In certain embodiments, provided is a method for reducing the severity of a symptom associated with the cardiovascular disease, disorder or condition. In such embodiments, the methods comprise administering a therapeutically effective amount of a compound targeted to an apo(a) nucleic acid to an individual in need thereof.

[0347] The cardiovascular disease, disorder or condition can be characterized by numerous physical symptoms. Any symptom known to one of skill in the art to be associated with the cardiovascular disease, disorder or condition can be prevented, treated, ameliorated or otherwise modulated with the compounds and methods described herein. In certain embodiments, the symptom can be any of, but not limited to, angina, chest pain, shortness of breath, palpitations, weakness, dizziness, nausea, sweating, tachycardia, bradycardia, arrhythmia, atrial fibrillation, swelling in the lower extremities, cyanosis, fatigue, fainting, numbness of the face, numbness of the limbs, claudication or cramping of muscles, bloating of the abdomen or fever.

[0348] In certain embodiments, the metabolic diseases, disorders or conditions include, but are not limited to, hyperglycemia, prediabetes, diabetes (type I and type II), obesity, insulin resistance, metabolic syndrome and diabetic dyslipidemia.

[0349] In certain embodiments, compounds targeted to apo(a) as described herein modulate physiological markers or phenotypes of the metabolic disease, disorder or condition. For example, administration of the compounds to animals can decrease glucose and insulin resistance levels in those animals compared to untreated animals. In certain embodiments, the modulation of the physiological markers or phenotypes can be associated with inhibition of apo(a) by the compounds.

[0350] In certain embodiments, physiological markers of the metabolic disease, disorder or condition can be quantifiable. For example, glucose levels or insulin resistance can be measured and quantified by standard tests known in the art. For such markers, in certain embodiments, the marker can be decreased by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values. In another example, insulin sensitivity can be measured and quantified by standard tests known in the art. For such markers, in certain embodiments, the marker can be increase by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values.

[0351] Also, provided herein are methods for preventing, treating or ameliorating a symptom associated with the metabolic disease, disorder or condition in a subject in need thereof. In certain embodiments, provided is a method for reducing the rate of onset of a symptom associated with the metabolic disease, disorder or condition. In certain embodiments, provided is a method for reducing the severity of a symptom associated with the metabolic disease, disorder or condition. In such embodiments, the methods comprise administering a therapeutically effective amount of a compound targeted to an apo(a) nucleic acid to an individual in need thereof.

[0352] The metabolic disease, disorder or condition can be characterized by numerous physical symptoms. Any symptom known to one of skill in the art to be associated with the metabolic disease, disorder or condition can be prevented, treated, ameliorated or otherwise modulated with the compounds and methods described herein. In certain embodiments, the symptom can be any of, but not limited to, excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), blurred vision, unexplained weight loss and lethargy.

[0353] In certain embodiments, the inflammatory diseases, disorders or conditions include, but are not limited to, coronary artery disease (CAD), Alzheimer's Disease and thromboembolic diseases, disorder or conditions. Certain thromboembolic diseases, disorders or conditions include, but are not limited to, stroke, thrombosis, myocardial infarction and peripheral vascular disease.

[0354] In certain embodiments, the compounds targeted to apo(a) described herein modulate physiological markers or phenotypes of the inflammatory disease, disorder or condition. For example, administration of the compounds to animals can decrease inflammatory cytokine or other inflammatory markers levels in those animals compared to untreated animals. In certain embodiments, the modulation of the physiological markers or phenotypes can be associated with inhibition of apo(a) by the compounds.

[0355] In certain embodiments, the physiological markers of the inflammatory disease, disorder or condition can be quantifiable. For example, cytokine levels can be measured and quantified by standard tests known in the art. For such markers, in certain embodiments, the marker can be decreased by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values.

[0356] Also, provided herein are methods for preventing, treating or ameliorating a symptom associated with the inflammatory disease, disorder or condition in a subject in need thereof. In certain embodiments, provided is a method for reducing the rate of onset of a symptom associated with the inflammatory disease, disorder or condition. In certain embodiments, provided is a method for reducing the severity of a symptom associated with the inflammatory disease, disorder or condition. In such embodiments, the methods comprise administering a therapeutically effective amount of a compound targeted to an apo(a) nucleic acid to an individual in need thereof.

[0357] In certain embodiments, provided are methods of treating an individual with an apo(a) related disease, disorder or condition comprising administering a therapeutically effective amount of one or more pharmaceutical compositions as described herein. In certain embodiments, the individual has elevated apo(a) levels. In certain embodiments, provided are methods of treating an individual with an Lp(a) related disease, disorder or condition comprising administering a therapeutically effective amount of one or more pharmaceutical compositions as described herein. In certain embodiments, the individual has elevated Lp(a) levels. In certain embodiments, the individual has an inflammatory, cardiovascular and/or metabolic disease, disorder or condition. In certain embodiments, administration of a therapeutically effective amount of an antisense compound targeted to an apo(a) nucleic acid is accompanied by monitoring of apo(a) or Lp(a) levels. In certain embodiments, administration of a therapeutically effective amount of an antisense compound targeted to an apo(a) nucleic acid is accompanied by monitoring of markers of inflammatory, cardiovascular and/or metabolic disease, or other disease process associated with the expression of apo(a), to determine an individual's response to the antisense compound. An individual's response to administration of the antisense compound targeting apo(a) can be used by a physician to determine the amount and duration of therapeutic intervention with the compound.

[0358] In certain embodiments, administration of an antisense compound targeted to an apo(a) nucleic acid results in reduction of apo(a) expression by at least about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values. In certain embodiments, apo(a) expression is reduced to .ltoreq.100 mg/dL, .ltoreq.90 mg/dL, .ltoreq.80 mg/dL, .ltoreq.70 mg/dL, .ltoreq.60 mg/dL, .ltoreq.50 mg/dL, .ltoreq.40 mg/dL, .ltoreq.30 mg/dL, .ltoreq.20 mg/dL or .ltoreq.10 mg/dL.

[0359] In certain embodiments, administration of an antisense compound targeted to an apo(a) nucleic acid results in reduction of Lp(a) expression by at least about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values.

[0360] In certain embodiments, pharmaceutical compositions comprising an antisense compound targeted to apo(a) are used for the preparation of a medicament for treating a patient suffering or susceptible to an inflammatory, cardiovascular and/or a metabolic disease, disorder or condition.

Dosing

[0361] In certain embodiments, pharmaceutical compositions are administered according to a dosing regimen (e.g., dose, dose frequency, and duration) wherein the dosing regimen can be selected to achieve a desired effect. The desired effect can be, for example, reduction of apo(a) or the prevention, reduction, amelioration or slowing the progression of a disease or condition associated with apo(a).

[0362] In certain embodiments, the variables of the dosing regimen are adjusted to result in a desired concentration of pharmaceutical composition in a subject. "Concentration of pharmaceutical composition" as used with regard to dose regimen can refer to the compound, oligonucleotide, or active ingredient of the pharmaceutical composition. For example, in certain embodiments, dose and dose frequency are adjusted to provide a tissue concentration or plasma concentration of a pharmaceutical composition at an amount sufficient to achieve a desired effect.

[0363] Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Dosing is also dependent on drug potency and metabolism. In certain embodiments, dosage is from 0.01 .mu.g to 100 mg per kg of body weight, or within a range of 0.001 mg-1000 mg dosing, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Following successful treatment, it can be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 .mu.g to 100 mg per kg of body weight or ranging from 0.001 mg to 1000 mg dosing, once or more daily, weekly, monthly, yearly to once every 2 to 20 years.

Certain Combination Therapies

[0364] In certain embodiments, a first agent comprising the compound described herein is co-administered with one or more secondary agents or therapy. In certain embodiments, such second agents are designed to treat the same disease, disorder, or condition as the first agent described herein. In certain embodiments, such second agents are designed to treat a different disease, disorder, or condition as the first agent described herein. In certain embodiments, a first agent is designed to treat an undesired side effect of a second agent. In certain embodiments, second agents are co-administered with the first agent to treat an undesired effect of the first agent. In certain embodiments, such second agents are designed to treat an undesired side effect of one or more pharmaceutical compositions as described herein. In certain embodiments, second agents are co-administered with the first agent to produce a combinational effect. In certain embodiments, second agents are co-administered with the first agent to produce a synergistic effect. In certain embodiments, the co-administration of the first and second agents permits use of lower dosages than would be required to achieve a therapeutic or prophylactic effect if the agents were administered as independent therapy.

[0365] In certain embodiments, one or more compositions described herein and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more compositions of the invention and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more compositions described herein and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more compositions described herein and one or more other pharmaceutical agents are prepared separately.

[0366] In certain embodiments, second agents include, but are not limited to, an apo(a) lowering agent, a Lp(a) lowering agent, an agent for treating Alzheimer's Disease, an agent to reduce thromboembolism formation, a cholesterol lowering agent, a non-HDL lipid lowering (e.g., LDL) agent, a HDL raising agent, fish oil, niacin, nicotinic acid, a fibrate, a statin, DCCR (salt of diazoxide), a glucose-lowering agent, an anti-inflammatory agent and/or an anti-diabetic agent. In certain embodiments, the first agent is administered in combination with the maximally tolerated dose of the second agent. In certain embodiments, the first agent is administered to a subject that fails to respond to a maximally tolerated dose of the second agent.

[0367] Examples of apo(a) lowering agents include an apo(a) antisense oligonucleotide different from the first agent, niacin, nicotinic acid, or an apoB antisense oligonucleotide (i.e. Mipomersen). An example of an apo(a) lowering therapy is Lp(a) apheresis.

[0368] Examples of glucose-lowering and/or anti-diabetic agents include, but are not limited to, a therapeutic lifestyle change, PPAR agonist, a dipeptidyl peptidase (IV) inhibitor, a GLP-1 analog, insulin or an insulin analog, an insulin secretagogue, a SGLT2 inhibitor, a human amylin analog, a biguanide, an alpha-glucosidase inhibitor, metformin, sulfonylurea, rosiglitazone, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor and the like. The sulfonylurea can be acetohexamide, chlorpropamide, tolbutamide, tolazamide, glimepiride, a glipizide, a glyburide, or a gliclazide. The meglitinide can be nateglinide or repaglinide. The thiazolidinedione can be pioglitazone or rosiglitazone. The alpha-glucosidase can be acarbose or miglitol.

[0369] Examples of cholesterol or lipid lowering therapy include, but are not limited to, a therapeutic lifestyle change, statins, bile acids sequestrants, niacin, nicotinic acid, CETP inhibitors and peroxisome proliferation activated receptor agonists such as fibrates. The statins can be atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin and the like. The bile acid sequestrants can be colesevelam, cholestyramine, colestipol and the like. The fibrates can be gemfibrozil, fenofibrate, clofibrate and the like. The CETP inhibitor can be a CETP antisense oligonucleotide or Torcetrapib.

Certain Treatment Populations

[0370] Certain subjects with high Lp(a) levels are at a significant risk of various diseases (Lippi et al., Clinica Chimica Acta, 2011, 412:797-801; Solfrizz et al.). In many subjects with high Lp(a) levels, current treatments cannot reduce their Lp(a) levels to safe levels. Apo(a) plays an important role in the formation of Lp(a), hence reducing apo(a) can reduce Lp(a) and prevent, treat or ameliorate a disease associated with Lp(a).

[0371] In certain embodiments, treatment with the compounds and methods disclosed herein is indicated for a human animal with elevated apo(a) levels and/or Lp(a) levels. In certain embodiments, the human has elevated apo(a) levels .gtoreq.30 mg/dL, .gtoreq.40 mg/dL, .gtoreq.50 mg/dL, .gtoreq.60 mg/dL, .gtoreq.70 mg/dL, .gtoreq.80 mg/dL, .gtoreq.90 mg/dL or .gtoreq.100 mg/dL.

Certain Compounds

[0372] Selected gapmer antisense oligonucleotides from PCT application WO2005/000201 (incorporated by reference in its entirety herein) were assessed (Example 1) and the most potent compound, ISIS 144367, was used as a benchmark comparison for the newly designed antisense oligonucleotides described herein.

[0373] About 90 of the newly designed antisense oligonucleotides were found to be more potent than the benchmark, ISIS 144367, as assessed by single dose in vitro studies (Examples 2-3, 5). Of the about 90 antisense oligonucleotides, about 83 were selected for in vitro multi-dose response studies and 64 antisense oligonucleotides were found to be more potent than the benchmark (Examples 4, 6).

[0374] About 32 antisense oligonucleotides were further selected for in vivo studies in human apo(a) transgenic mice (Example 7). Multiple antisense oligonucleotides were identified that were more potent than the benchmark in vivo.

[0375] About 24 antisense oligonucleotides were further selected for viscosity testing in vitro (Example 13). Antisense oligonucleotides that were viscous were not carried forward in further studies.

[0376] About 14 antisense oligonucleotides were further selected for in vivo studies in rodent tolerability and pharmacokinetics (Examples 8-10). The studies indicated that ISIS 494372 was the best tolerated antisense oligonucleotide.

[0377] ISIS 494283, 494284, 494286, 494301, 494302 and 494372 were tested in cynomolgus monkeys (Examples 11-12). The studies indicated that ISIS 494372 was well tolerated and potent in monkeys.

EXAMPLES

Non-Limiting Disclosure and Incorporation by Reference

[0378] While certain compounds, compositions, and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

Example 1: Dose-Dependent Antisense Inhibition of Human Apolipoprotein (a) (Apo(a)) in Human Primary Hepatocytes

[0379] Selected gapmer antisense oligonucleotides from a previous publication (WO2005/000201, the content of which is incorporated by reference in its entirety herein) were tested in a single dose assay in human primary hepatocytes. Cells were obtained from Tissue Transformation Technologies (BD Biosciences, Franklin Lakes, N.J.) and treated with 150 nM of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Human apo(a) primer probe set hAPO(a)3' (forward sequence ACAGCAATCAAACGAAGACACTG, designated herein as SEQ ID NO: 5; reverse sequence AGCTTATACACAAAAATACCAAAAATGC, designated herein as SEQ ID NO: 6; probe sequence TCCCAGCTACCAGCTATGCCAAACCTT, designated herein as SEQ ID NO: 7) was used to measure mRNA levels. Additionally, mRNA levels were also measured using human apo(a) primer probe set hAPO(a)12 kB (forward sequence CCACAGTGGCCCCGGT, designated herein as SEQ ID NO: 8; reverse sequence ACAGGGCTTTTCTCAGGTGGT, designated herein as SEQ ID NO: 9; probe sequence CCAAGCACAGAGGCTCCTTCTGAACAAG, designated herein as SEQ ID NO: 10). Apo(a) mRNA levels were normalized to GAPDH mRNA expression. Results are presented in Table 1 as percent inhibition of apo(a), relative to untreated control cells.

TABLE-US-00001 TABLE 1 Antisense inhibition of human apo(a) in human primary hepatocytes % inhibition % inhibition ISIS No (hAPO(a)3' PPset) (hAPO(a)12 kB PPset) 144367 68 77 144368 42 59 144369 43 69 144370 80 75 144371 42 57 144372 87 54 144373 63 49 144374 45 80 144375 33 11 144376 62 82 144377 42 72 144378 0 72 144379 73 46 144380 75 78 144381 63 64 144382 0 58 144383 63 79 144384 38 0 144385 40 94 144386 47 61 144387 38 60 144388 0 57 144389 52 39 144390 12 0 144391 73 57 144392 43 50 144393 83 82 144394 40 76 144395 80 84 144396 53 72 144397 23 64 144398 7 33 144399 43 44 144400 70 75 144401 87 72

[0380] Several antisense oligonucleotides were selected for further testing in a dose response assay.

[0381] The selected antisense oligonucleotides were tested in human primary hepatocytes with 25 nM, 50 nM, 150 nM, or 300 nM concentrations of antisense oligonucleotide, as specified in Table 2 below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Human apo(a) primer probe set hAPO(a)3' was used to measure mRNA levels. Apo(a) mRNA levels were normalized to GAPDH mRNA expression. Results are presented as percent inhibition of apo(a), relative to untreated control cells.

TABLE-US-00002 TABLE 2 Dose-dependent antisense inhibition of human apo(a) in human primary hepatocytes, as measured with hAPO(a)3' ISIS No 25 nM 50 nM 150 nM 300 nM 144367 52 78 76 74 144370 64 74 68 66 144385 0 15 43 5 144393 0 9 39 25 144395 17 9 8 32

[0382] ISIS 144367 demonstrated better efficacy and dose-dependency than the other antisense oligonucleotides. Hence, ISIS 144367 was considered the benchmark antisense oligonucleotide to compare the potency of newly designed antisense oligonucleotides disclosed herein.

Example 2: Antisense Inhibition of Human Apo(a) in Transgenic Mouse Primary Hepatocytes

[0383] Antisense oligonucleotides were newly designed targeting an apo(a) nucleic acid and were tested for their effects on apo(a) mRNA in vitro. The antisense oligonucleotides were tested for potency in a series of parallel experiments that had similar culture conditions. Primary hepatocytes from human apo(a) transgenic mice (Frazer, K. A. et al., Nat. Genet. 1995. 9: 424-431) were used in this study. Hepatocytes at a density of 35,000 cells per well were transfected using electroporation with 1,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Human primer probe set hAPO(a)12 kB was used to measure mRNA levels. Apo(a) mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. The results for each experiment are presented in separate tables shown below. ISIS 144367 from was used as a benchmark for the new antisense oligonucleotides and also included in the studies. Results are presented as percent inhibition of apo(a), relative to untreated control cells. A total of 1,511 gapmers were tested under these culture conditions. Only those antisense oligonucleotides that were selected for further study are presented in the table below with each table representing a separate experiment.

[0384] The newly designed chimeric antisense oligonucleotides were designed as 5-10-5 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on the 5' direction and the 3' direction comprising five nucleosides each. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has a 2'-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P.dbd.S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

[0385] The apo(a) target sequence contains multiple Kringle repeat sequences, therefore, an antisense oligonucleotide may target one or more regions of apo(a) depending whether on the oligonucleotide targets a Kringle sequence or not. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human sequence. An apo(a) antisense oligonucleotide may have more than one "Start site" or "Stop site" depending on whether or not it targets a Kringle repeat.

[0386] Most gapmers listed in the Tables are targeted with 100% complementarity to one or more regions of either the human apo(a) mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_005577.2) or the human apo(a) genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007422.12 truncated from nucleotides 3230000 to 3380000), or both. `n/a` indicates that the antisense oligonucleotide does not target that particular sequence with 100% complementarity.

TABLE-US-00003 TABLE 3 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 90 21210 21229 11 494157 238 257 CCTGTGACAGTGGTGGAGTA 95 21199 21218 12 580 599 26690 26709 922 941 32237 32256 1606 1625 43330 43349 1948 1967 48874 48893 2290 2309 54420 54439 3316 3335 72037 72056 494158 239 258 TCCTGTGACAGTGGTGGAGT 95 21200 21219 13 581 600 26691 26710 923 942 32238 32257 1607 1626 43331 43350 1949 1968 48875 48894 2291 2310 54421 54440 3317 3336 72038 72057 494159 241 260 CTTCCTGTGACAGTGGTGGA 97 21202 21221 14 583 602 26693 26712 925 944 32240 32259 1609 1628 43333 43352 1951 1970 48877 48896 2293 2312 54423 54442 3319 3338 72040 72059 4663 4682 94404 94423 5005 5024 115515 115534 494160 242 261 CCTTCCTGTGACAGTGGTGG 97 21203 21222 15 4664 4683 94405 94424 5006 5025 115516 115535 494161 243 262 TCCTTCCTGTGACAGTGGTG 96 21204 21223 16 4665 4684 94406 94425 5007 5026 115517 115536 494162 244 263 GTCCTTCCTGTGACAGTGGT 95 21205 21224 17 3664 3683 77585 77604 4666 4685 94407 94426 5008 5027 115518 115537 494163 245 264 GGTCCTTCCTGTGACAGTGG 96 21206 21225 18 4667 4686 94408 94427 494164 246 265 AGGTCCTTCCTGTGACAGTG 93 21207 21226 19 4668 4687 94409 94428 494165 247 266 CAGGTCCTTCCTGTGACAGT 91 21208 21227 20 4669 4688 94410 94429 494166 248 267 GCAGGTCCTTCCTGTGACAG 89 21209 21228 21 494167 250 269 TGGCAGGTCCTTCCTGTGAC 92 21211 21230 22 494168 251 270 TTGGCAGGTCCTTCCTGTGA 89 21212 21231 23 494169 252 271 CTTGGCAGGTCCTTCCTGTG 92 21213 21232 24 494170 253 272 GCTTGGCAGGTCCTTCCTGT 88 21214 21233 25

TABLE-US-00004 TABLE 4 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 91 21210 21229 11 84 494283 584 603 TCTTCCTGTGACAGTGGTGG 93 26694 26713 26 926 945 32241 32260 1610 1629 43334 43353 1952 1971 48878 48897 2294 2313 54424 54443 3320 3339 72041 72060 494284 585 604 TTCTTCCTGTGACAGTGGTG 95 26695 26714 27 927 946 32242 32261 1611 1630 43335 43354 1953 1972 48879 48898 2295 2314 54425 54444 3321 3340 72042 72061 494285 586 605 GTTCTTCCTGTGACAGTGGT 95 26696 26715 28 928 947 32243 32262 1612 1631 43336 43355 1954 1973 48880 48899 2296 2315 54426 54445 3322 3341 72043 72062 494286 587 606 GGTTCTTCCTGTGACAGTGG 95 26697 26716 29 929 948 32244 32263 1613 1632 43337 43356 1955 1974 48881 48900 2297 2316 54427 54446 494287 588 607 AGGTTCTTCCTGTGACAGTG 95 26698 26717 30 930 949 32245 32264 1614 1633 43338 43357 1956 1975 48882 48901 2298 2317 54428 54447 494288 589 608 CAGGTTCTTCCTGTGACAGT 91 26699 26718 31 931 950 32246 32265 1615 1634 43339 43358 1957 1976 48883 48902 2299 2318 54429 54448 2983 3002 66500 66519 494290 592 611 TGGCAGGTTCTTCCTGTGAC 90 26702 26721 32 934 953 32249 32268 1618 1637 43342 43361 1960 1979 48886 48905 2302 2321 54432 54451 2986 3005 66503 66522 494291 593 612 TTGGCAGGTTCTTCCTGTGA 89 26703 26722 33 935 954 32250 32269 1619 1638 43343 43362 1961 1980 48887 48906 2303 2322 54433 54452 2987 3006 66504 66523 494292 594 613 CTTGGCAGGTTCTTCCTGTG 94 26704 26723 35 936 955 32251 32270 1620 1639 43344 43363 1962 1981 48888 48907 2304 2323 54434 54453 2988 3007 66505 66524 494294 596 615 AGCTTGGCAGGTTCTTCCTG 90 26706 26725 36 938 957 32253 32272 1622 1641 43346 43365 1964 1983 48890 48909 2306 2325 54436 54455 2990 3009 66507 66526 494299 626 645 ACTATGCGAGTGTGGTGTCA 91 26736 26755 37 968 987 32283 32302 1310 1329 37830 37849 1652 1671 43376 43395 1994 2013 48920 48939 2336 2355 54466 54485 2678 2697 60021 60040 3020 3039 66537 66556 494300 627 646 GACTATGCGAGTGTGGTGTC 93 26737 26756 38 969 988 32284 32303 1311 1330 37831 37850 1653 1672 43377 43396 1995 2014 48921 48940 2337 2356 54467 54486 2679 2698 60022 60041 3021 3040 66538 66557 494301 628 647 CGACTATGCGAGTGTGGTGT 93 26738 26757 39 970 989 32285 32304 1312 1331 37832 37851 1654 1673 43378 43397 1996 2015 48922 48941 2338 2357 54468 54487 2680 2699 60023 60042 3022 3041 66539 66558 494302 629 648 CCGACTATGCGAGTGTGGTG 94 26739 26758 40 971 990 32286 32305 1313 1332 37833 37852 1655 1674 43379 43398 1997 2016 48923 48942 2339 2358 54469 54488 2681 2700 60024 60043 3023 3042 66540 66559 494303 630 649 TCCGACTATGCGAGTGTGGT 93 26740 26759 41 972 991 32287 32306 1314 1333 37834 37853 1656 1675 43380 43399 1998 2017 48924 48943 2340 2359 54470 54489 2682 2701 60025 60044 3024 3043 66541 66560 494304 631 650 GTCCGACTATGCGAGTGTGG 94 26741 26760 42 973 992 32288 32307 1315 1334 37835 37854 1657 1676 43381 43400 1999 2018 48925 48944 2341 2360 54471 54490 2683 2702 60026 60045 3025 3044 66542 66561 494305 632 651 GGTCCGACTATGCGAGTGTG 93 26742 26761 43 974 993 32289 32308 1316 1335 37836 37855 1658 1677 43382 43401 2000 2019 48926 48945 2342 2361 54472 54491 2684 2703 60027 60046 3026 3045 66543 66562 494306 633 652 GGGTCCGACTATGCGAGTGT 92 26743 26762 44 975 994 32290 32309 1317 1336 37837 37856 1659 1678 43383 43402 2001 2020 48927 48946 2343 2362 54473 54492 2685 2704 60028 60047 3027 3046 66544 66563 494307 1190 1209 CTGCTCAGTCGGTGCTTGTT 91 n/a n/a 45 2558 2577 494310 1193 1212 CCTCTGCTCAGTCGGTGCTT 90 n/a n/a 46 2561 2580 494311 1194 1213 GCCTCTGCTCAGTCGGTGCT 88 37714 37733 47 2562 2581 59905 59924 494334 1267 1286 CTTCCAGTGACAGTGGTGGA 90 37787 37806 48 2635 2654 59978 59997 494336 1269 1288 TTCTTCCAGTGACAGTGGTG 90 37789 37808 49 2637 2656 59980 59999 494337 1270 1289 GTTCTTCCAGTGACAGTGGT 95 37790 37809 50 2638 2657 59981 60000 494338 1271 1290 GGTTCTTCCAGTGACAGTGG 91 37791 37810 133 2639 2658 59982 60001 494521 6393 6412 GACCTTAAAAGCTTATACAC 82 140049 140068 51 494525 6397 6416 GTCAGACCTTAAAAGCTTAT 84 140053 140072 52 494530 6402 6421 TGTCAGTCAGACCTTAAAAG 82 140058 140077 53 494535 6407 6426 GAATTTGTCAGTCAGACCTT 85 140063 140082 54 494536 6408 6427 AGAATTTGTCAGTCAGACCT 83 140064 140083 55 494544 6417 6436 CCTTAATACAGAATTTGTCA 82 140073 140092 56

TABLE-US-00005 TABLE 5 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 84 21210 21229 11 494371 3900 3919 GCTCCGTTGGTGCTTGTTCA 93 n/a n/a 57 494372 3901 3920 TGCTCCGTTGGTGCTTGTTC 93 n/a n/a 58 494373 3902 3921 TTGCTCCGTTGGTGCTTGTT 83 n/a n/a 59 494374 3903 3922 TTTGCTCCGTTGGTGCTTGT 89 n/a n/a 60 494375 3904 3923 CTTTGCTCCGTTGGTGCTTG 85 n/a n/a 61 494386 3977 3996 TCCTGTAACAGTGGTGGAGA 86 81985 82004 62 494387 3978 3997 TTCCTGTAACAGTGGTGGAG 82 81986 82005 63 494388 3979 3998 CTTCCTGTAACAGTGGTGGA 86 81987 82006 64 494389 3980 3999 CCTTCCTGTAACAGTGGTGG 92 81988 82007 65 494390 3981 4000 TCCTTCCTGTAACAGTGGTG 92 81989 82008 66 494391 3982 4001 GTCCTTCCTGTAACAGTGGT 84 81990 82009 67 494392 3983 4002 TGTCCTTCCTGTAACAGTGG 81 81991 82010 68

TABLE-US-00006 TABLE 6 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 86 21210 21229 11 498369 3203 3222 TGGAGCCAGAATAACATTCG 91 70667 70686 69 498379 3213 3232 CCTCTAGGCTTGGAGCCAGA 85 70677 70696 70 498408 3323 3342 AGTTCTTCCTGTGACAGTGG 86 72044 72063 71 498433 3367 3386 GTCCGACTATGCTGGTGTGG 87 72088 72107 72 498434 3368 3387 GGTCCGACTATGCTGGTGTG 86 72089 72108 73 498435 3369 3388 GGGTCCGACTATGCTGGTGT 83 72090 72109 74

TABLE-US-00007 TABLE 7 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 90 21210 21229 11 498229 2871 2890 CCTCTAGGCTTGGAATCGGG 90 65117 65136 75 498238 2883 2902 GTTCAGAAGGAGCCTCTAGG 93 65129 65148 76 498239 2884 2903 TGTTCAGAAGGAGCCTCTAG 94 65130 65149 77 498240 2887 2906 GCTTGTTCAGAAGGAGCCTC 98 n/a n/a 78 4573 4592 498241 2888 2907 TGCTTGTTCAGAAGGAGCCT 94 n/a n/a 79 4574 4593 498242 2889 2908 GTGCTTGTTCAGAAGGAGCC 96 n/a n/a 80 4575 4594 498243 2890 2909 GGTGCTTGTTCAGAAGGAGC 97 n/a n/a 81 4576 4595 498244 2891 2910 TGGTGCTTGTTCAGAAGGAG 92 n/a n/a 82 4577 4596 498251 2898 2917 GCTCAGTTGGTGCTTGTTCA 90 n/a n/a 83 498252 2899 2918 TGCTCAGTTGGTGCTTGTTC 90 n/a n/a 84

TABLE-US-00008 TABLE 8 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 91 21210 21229 11 498517 3548 3567 GCTTGGATCTGGGACCACCG 89 76233 76252 85

TABLE-US-00009 TABLE 9 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 94 21210 21229 11 498833 4900 4919 GCCTCCATGCTTGGAACTGG 94 114205 114224 86 498859 4926 4945 GCTCAGTTGGTGCTGCTTCA 92 n/a n/a 87 498868 4978 4997 CCTCGATAACTCTGGCCATT 94 115488 115507 88 498875 5003 5022 TCCTGTGACAGTGGTGGAGA 94 115513 115532 89

TABLE-US-00010 TABLE 10 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 92 21210 21229 11 499020 6257 6276 GTAGGTTGATGCTTCACTCT 91 139913 139932 90 499041 6318 6337 CGTTTGATTGCTGTCTATTA 90 139974 139993 91

TABLE-US-00011 TABLE 11 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 91 21210 21229 11 498523 3554 3573 CTCTGTGCTTGGATCTGGGA 94 76239 76258 92 498524 3555 3574 CCTCTGTGCTTGGATCTGGG 96 76240 76259 93 498525 3556 3575 GCCTCTGTGCTTGGATCTGG 94 76241 76260 94 498529 3560 3579 AGAAGCCTCTGTGCTTGGAT 89 76245 76264 95 498535 3566 3585 TTCAGAAGAAGCCTCTGTGC 89 76251 76270 96 498550 3582 3601 GCTCCGTTGGTGCTTCTTCA 90 n/a n/a 97 498553 3585 3604 TTTGCTCCGTTGGTGCTTCT 87 n/a n/a 98 498555 3587 3606 GCTTTGCTCCGTTGGTGCTT 90 n/a n/a 99 3905 3924 498556 3588 3607 GGCTTTGCTCCGTTGGTGCT 89 77509 77528 100 3906 3925 81914 81933 498557 3589 3608 GGGCTTTGCTCCGTTGGTGC 89 77510 77529 101 3907 3926 81915 81934 498579 3662 3681 CCTTCCTGTGACAGTGGTAG 87 77583 77602 102 498580 3663 3682 TCCTTCCTGTGACAGTGGTA 92 77584 77603 103 498581 3665 3684 TGTCCTTCCTGTGACAGTGG 94 77586 77605 104 5009 5028 115519 115538

TABLE-US-00012 TABLE 12 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 100 21210 21229 11 494230 477 496 CCTCTAGGCTTGGAACCGGG 95 25380 25399 105 819 838 30927 30946 1161 1180 36471 36490 1503 1522 42020 42039 1845 1864 47564 47583 2187 2206 53110 53129 2529 2548 58662 58681 494243 494 513 TGCTTGTTCGGAAGGAGCCT 93 n/a n/a 106 836 855 1178 1197 1520 1539 1862 1881 2204 2223 2546 2565 494244 495 514 GTGCTTGTTCGGAAGGAGCC 95 n/a n/a 107 837 856 1179 1198 1521 1540 1863 1882 2205 2224 2547 2566

TABLE-US-00013 TABLE 13 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 96 21210 21229 11 494466 4208 4227 GCTTGGAACTGGGACCACCG 95 85138 85157 108 494470 4212 4231 CTGTGCTTGGAACTGGGACC 94 85142 85161 109 494472 4214 4233 CTCTGTGCTTGGAACTGGGA 92 85144 85163 110

Example 3: Dose-Dependent Antisense Inhibition of Apo(a) in Transgenic Mouse Primary Hepatocytes

[0387] Gapmers from the studies described above exhibiting significant in vitro inhibition of apo(a) mRNA were selected and tested at various doses in transgenic mouse primary hepatocytes in a series of parallel studies with similar culture conditions. Cells were plated at a density of 35,000 per well and transfected using electroporation with 0.0625 .mu.M, 0.125 .mu.M, 0.25 .mu.M, 0.500 .mu.M, or 1.000 .mu.M concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Apo(a) primer probe set hAPO(a)12 kB was used to measured mRNA levels. Apo(a) mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of apo(a), relative to untreated control cells.

[0388] The results of each of the studies are depicted in the Tables presented below with each table representing a separate experiment. The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in the Tables. Apo(a) mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. The potency of the newly designed oligos was compared with the benchmark oligonucleotide ISIS 144367.

TABLE-US-00014 TABLE 14 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 11 27 46 62 80 0.31 494157 11 47 53 76 87 0.23 494158 19 57 75 84 88 0.13 494159 41 65 77 84 92 0.07 494160 44 69 76 85 91 0.06 494161 40 64 74 85 91 0.08 494162 36 63 76 87 88 0.09 494163 20 59 75 85 92 0.13 494164 3 45 62 74 90 0.21 494165 25 39 57 71 75 0.19 494166 17 30 47 59 76 0.31 494167 30 43 55 72 80 0.18 494168 25 36 44 59 75 0.28 494169 19 39 51 61 81 0.25

TABLE-US-00015 TABLE 15 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 23 40 58 76 88 0.19 494170 38 34 60 76 84 0.13 494230 55 71 89 95 97 0.03 494243 47 73 87 92 97 0.05 494244 58 73 86 92 96 0.03 494283 54 70 84 93 94 0.05 494284 45 62 83 92 95 0.07 494285 56 70 84 92 95 0.04 494286 51 70 87 93 95 0.05 494287 32 60 67 87 91 0.11 494288 26 41 61 79 88 0.17 494290 30 43 64 81 87 0.15 494291 29 40 56 75 85 0.18

TABLE-US-00016 TABLE 16 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 10 38 62 68 84 0.23 494292 17 36 74 85 90 0.17 494294 10 34 53 80 91 0.22 494299 32 29 56 77 88 0.16 494300 34 46 76 86 90 0.12 494301 44 56 72 86 89 0.09 494302 42 59 78 88 89 0.08 494303 37 58 70 86 89 0.10 494304 46 71 78 89 90 0.05 494305 39 58 62 85 87 0.10 494306 31 52 65 79 88 0.13 494307 23 23 39 65 78 0.34 494310 14 29 62 70 88 0.25

TABLE-US-00017 TABLE 17 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 0 29 45 73 92 0.27 494311 28 53 65 85 95 0.13 494334 20 44 66 86 96 0.16 494336 15 38 54 84 97 0.20 494337 28 50 77 90 98 0.12 494338 21 40 68 91 98 0.15 494371 19 0 71 89 97 0.15 494372 33 44 77 91 97 0.12 494373 15 36 65 83 95 0.19 494374 3 17 51 83 90 0.24 494375 1 34 56 80 93 0.23 494386 13 26 46 73 91 0.25 494387 17 27 45 67 88 0.28

TABLE-US-00018 TABLE 18 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 35 42 62 70 91 0.15 494537 19 34 54 79 90 0.21 494544 10 38 73 86 94 0.17 498229 36 58 80 92 97 0.10 498238 41 57 75 91 97 0.09 498239 56 71 79 90 94 0.03 498240 91 94 98 99 100 <0.06 498241 75 84 91 96 98 <0.06 498242 11 27 42 47 63 0.49 498243 91 93 96 98 99 <0.06 498244 4 0 0 13 43 >1.00 498251 30 30 42 73 89 0.26 498252 37 33 58 80 92 0.20 498369 22 22 10 22 34 >1.00

TABLE-US-00019 TABLE 19 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 15 32 54 75 90 0.22 498379 29 48 71 80 95 0.13 498408 38 57 77 88 96 0.09 498433 29 36 70 88 96 0.15 498434 49 43 50 78 90 0.19 498435 27 39 57 78 93 0.18 498517 64 72 82 93 98 <0.06 498721 77 84 88 96 97 <0.06 498833 73 78 91 95 99 <0.06 498859 7 24 37 62 75 0.36 498868 7 14 39 63 81 0.36 498875 16 21 33 55 81 0.39 499020 7 24 23 55 78 0.36 499041 6 16 33 64 83 0.35

TABLE-US-00020 TABLE 20 ISIS 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 14 47 64 79 91 0.14 498523 36 50 80 87 95 0.11 498524 43 79 87 93 97 0.01 498525 32 49 75 86 96 0.12 498529 21 49 57 78 90 0.17 498535 20 34 55 76 86 0.21 498550 12 50 69 84 96 0.11 498553 8 43 55 77 91 0.21 498555 13 35 68 86 94 0.19 498556 27 37 71 85 91 0.15 498557 18 42 75 89 95 0.16 498579 16 38 67 89 95 0.16 498580 36 57 81 91 96 0.10 498581 34 64 75 93 97 0.05

TABLE-US-00021 TABLE 21 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 0 9 26 49 77 0.47 494388 0 0 21 33 55 0.89 494389 0 15 22 50 79 0.46 494390 5 20 37 68 81 0.33 494391 7 20 32 54 68 0.46 494392 18 24 40 57 76 0.35 494466 33 45 58 69 82 0.16 494470 45 58 68 79 87 0.08 494472 37 50 60 69 83 0.13 494521 0 0 0 15 54 0.17 494525 0 0 2 28 65 0.85 494530 0 6 27 51 80 0.46 494535 0 7 24 53 74 0.49 494536 0 2 15 42 67 0.63

TABLE-US-00022 TABLE 22 0.0625 0.125 0.250 0.500 1.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 0 4 16 26 77 0.65 498379 12 18 27 32 63 0.81 498408 0 11 46 50 77 0.41 498433 22 30 46 60 83 0.27 498434 39 29 25 47 78 0.40 498435 21 28 26 43 73 0.50 498517 44 48 63 70 84 0.11 498721 54 54 66 75 89 <0.06 498833 44 51 58 67 83 0.11 498859 0 29 14 35 66 0.69 498868 0 12 9 26 60 1.07 498875 0 30 31 53 78 0.40 499020 0 27 19 45 74 0.51 499041 0 12 10 37 65 0.77

As presented in the Tables above, ISIS 494157 (SEQ ID NO: 12), ISIS 494158 (SEQ ID NO:13), ISIS 494159 (SEQ ID NO:14), ISIS 494160 (SEQ ID NO: 15), ISIS 494161 (SEQ ID NO:16), ISIS 494162 (SEQ ID NO: 17), ISIS 494163 (SEQ ID NO: 18), ISIS 494164 (SEQ ID NO: 19), ISIS 494165 (SEQ ID NO: 20), ISIS 494167 (SEQ ID NO: 22), ISIS 494168 (SEQ ID NO: 23), ISIS 494169 (SEQ ID NO: 24), ISIS 494170 (SEQ ID NO: 25), ISIS 494230 (SEQ ID NO: 105), ISIS 494243 (SEQ ID NO: 106), ISIS 494244 (SEQ ID NO: 107), ISIS 494283 (SEQ ID NO: 26), ISIS 494284 (SEQ ID NO: 27), ISIS 494285 (SEQ ID NO: 28), ISIS 494286 (SEQ ID NO: 29), ISIS 494287 (SEQ ID NO: 30), ISIS 494288 (SEQ ID NO: 31), ISIS 494290 (SEQ ID NO: 32), ISIS 494291 (SEQ ID NO: 33), ISIS 494292 (SEQ ID NO: 35), ISIS 494294 (SEQ ID NO: 36), ISIS 494299 (SEQ ID NO: 37), ISIS 494300 (SEQ ID NO: 38), ISIS 494301 (SEQ ID NO: 39), ISIS 494302 (SEQ ID NO: 40), ISIS 494303 (SEQ ID NO: 41), ISIS 494304 (SEQ ID NO: 42), ISIS 494305 (SEQ ID NO:43), ISIS 494306 (SEQ ID NO: 44), ISIS 494311 (SEQ ID NO: 47), ISIS 494334 (SEQ ID NO: 48), ISIS 494336 (SEQ ID NO: 49), ISIS 494337 (SEQ ID NO: 50), ISIS 494338 (SEQ ID NO: 133), ISIS 494371 (SEQ ID NO: 57), ISIS 494372 (SEQ ID NO: 58), ISIS 494373 (SEQ ID NO: 59), ISIS 494374 (SEQ ID NO: 60), ISIS 494375 (SEQ ID NO: 61), ISIS 494386 (SEQ ID NO: 62), ISIS 494389 (SEQ ID NO: 65), ISIS 494390 (SEQ ID NO: 66), ISIS 494392 (SEQ ID NO: 68), ISIS 494466 (SEQ ID NO: 108), ISIS 494470 (SEQ ID NO: 109), ISIS 494472 (SEQ ID NO: 110), ISIS 494521 (SEQ ID NO: 51), ISIS 494530 (SEQ ID NO: 53), ISIS 498229 (SEQ ID NO: 75), ISIS 498238 (SEQ ID NO: 76), ISIS 498239 (SEQ ID NO: 77), ISIS 498240 (SEQ ID NO: 78), ISIS 498241 (SEQ ID NO: 79), ISIS 498243 (SEQ ID NO: 81), ISIS 498379 (SEQ ID NO: 70), ISIS 498408 (SEQ ID NO: 71), ISIS 498433 (SEQ ID NO: 72), ISIS 498434 (SEQ ID NO: 73), ISIS 498435 (SEQ ID NO: 74), ISIS 498517 (SEQ ID NO: 85), ISIS 498523 (SEQ ID NO: 92), ISIS 498524 (SEQ ID NO: 93), ISIS 498525 (SEQ ID NO: 94), ISIS 498550 (SEQ ID NO: 97), ISIS 498580 (SEQ ID NO: 103), ISIS 498581 (SEQ ID NO: 104), ISIS 498721 (ATGCCTCGATAACTCCGTCC; SEQ ID NO: 134), ISIS 498833 (SEQ ID NO: 86), ISIS 498875 (SEQ ID NO: 89), and ISIS 499020 (SEQ ID NO: 90) were more potent than ISIS 144367 (SEQ ID NO: 11).

Example 4: Dose-Dependent Antisense Inhibition of Apo(a) in Transgenic Mouse Primary Hepatocytes

[0389] Potent gapmers from the studies described above were further selected and tested at various doses in transgenic mouse primary hepatocytes in a series of studies with similar culture conditions. Cells were plated at a density of 35,000 per well and transfected using electroporation with 0.049 .mu.M, an 0.148 .mu.M, an 0.444 .mu.M, an 1.333 .mu.M, an or 4.000 .mu.M concentrations of antisense oligonucleotide, as specified in Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Apo(a) primer probe set hAPO(a)12 kB was used to measured mRNA levels. Apo(a) mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of apo(a), relative to untreated control cells.

[0390] The results of each of the studies are depicted in the Tables presented below with each table representing a separate experiment. The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in the Tables. Apo(a) mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. The potency of the newly designed oligos was compared with the benchmark oligonucleotide, ISIS 144367. As presented in the Tables below, ISIS 494157 (SEQ ID NO: 12), ISIS 494158 (SEQ ID NO:13), ISIS 494159 (SEQ ID NO:14), ISIS 494160 (SEQ ID NO: 15), ISIS 494161 (SEQ ID NO:16), ISIS 494162 (SEQ ID NO: 17), ISIS 494163 (SEQ ID NO: 18), ISIS 494164 (SEQ ID NO: 19), ISIS 494230 (SEQ ID NO: 105), ISIS 494243 (SEQ ID NO: 106), ISIS 494244 (SEQ ID NO: 107), ISIS 494283 (SEQ ID NO: 26), ISIS 494284 (SEQ ID NO: 27), ISIS 494285 (SEQ ID NO: 28), ISIS 494286 (SEQ ID NO: 29), ISIS 494287 (SEQ ID NO: 30), ISIS 494290 (SEQ ID NO: 32), ISIS 494292 (SEQ ID NO: 35), ISIS 494300 (SEQ ID NO: 38), ISIS 494301 (SEQ ID NO: 39), ISIS 494302 (SEQ ID NO: 40), ISIS 494303 (SEQ ID NO: 41), ISIS 494304 (SEQ ID NO: 42), ISIS 494305 (SEQ ID NO: 43), ISIS 494306 (SEQ ID NO: 44), ISIS 494310 (SEQ ID NO: 46), ISIS 494311 (SEQ ID NO: 47), ISIS 494337 (SEQ ID NO: 50), ISIS 494371 (SEQ ID NO: 57), ISIS 494372 (SEQ ID NO: 58), ISIS 494375 (SEQ ID NO: 61), ISIS 494388 (SEQ ID NO: 64), ISIS 494389 (SEQ ID NO: 65), ISIS 494390 (SEQ ID NO: 66), ISIS 494392 (SEQ ID NO: 68), ISIS 494466 (SEQ ID NO: 108), ISIS 494470 (SEQ ID NO: 109), ISIS 494472 (SEQ ID NO: 110), ISIS 498238 (SEQ ID NO: 76), ISIS 498239 (SEQ ID NO: 77), ISIS 498433 (SEQ ID NO: 72), ISIS 498434 (SEQ ID NO: 73), ISIS 498435 (SEQ ID NO: 74), ISIS 498523 (SEQ ID NO: 92), ISIS 498524 (SEQ ID NO: 93), ISIS 498525 (SEQ ID NO: 94), ISIS 498580 (SEQ ID NO: 103), and ISIS 498581 (SEQ ID NO: 104) were more potent than ISIS 144367 (SEQ ID NO: 11).

TABLE-US-00023 TABLE 23 0.049 0.148 0.444 1.333 4.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 0 26 67 89 92 0.32 494157 23 50 83 96 96 0.15 494158 26 62 85 96 96 0.11 494159 42 65 87 95 94 0.07 494160 51 70 88 94 94 <0.05 494161 36 67 87 95 96 0.08 494162 40 69 89 94 95 0.07 494163 41 57 87 95 94 0.08 494164 15 43 75 93 96 0.20 494230 39 77 94 99 99 0.05 494243 39 76 92 98 99 0.06 494244 58 79 91 97 99 0.02 494283 18 45 80 93 91 0.18 494284 9 53 80 95 94 0.18

TABLE-US-00024 TABLE 24 0.049 0.148 0.444 1.333 4.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 21 40 79 94 93 0.18 494285 53 68 90 97 97 <0.05 494286 46 69 89 96 97 0.05 494287 31 38 79 94 95 0.15 494290 22 53 74 93 94 0.16 494292 37 51 81 93 95 0.11 494294 22 40 72 91 94 0.19 494299 15 43 75 93 95 0.20 494300 25 38 79 95 95 0.17 494301 23 48 82 92 95 0.15 494302 26 59 86 93 94 0.12 494303 10 58 84 92 91 0.16 494304 25 62 83 93 93 0.12

TABLE-US-00025 TABLE 25 0.049 0.148 0.444 1.333 4.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 23 40 70 90 94 0.19 494305 20 48 82 93 95 0.16 494306 26 53 78 91 92 0.14 494310 36 50 79 88 92 0.12 494311 38 50 74 93 95 0.12 494334 20 42 73 90 94 0.19 494336 5 39 74 92 95 0.23 494337 23 51 87 96 96 0.14 494338 12 42 82 93 95 0.19 494371 28 49 82 94 94 0.14 494372 28 54 81 93 88 0.13 494373 21 28 67 86 92 0.25 494375 26 40 77 85 92 0.18

TABLE-US-00026 TABLE 26 0.049 0.148 0.444 1.333 4.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 5 33 65 78 81 0.32 494388 30 32 60 82 86 0.25 494389 30 45 69 84 84 0.17 494390 32 47 67 83 87 0.16 494392 23 38 54 79 82 0.31 494466 48 67 86 91 95 0.04 494470 74 87 92 96 98 <0.05 494472 69 84 92 96 97 <0.05 494544 5 18 49 74 79 0.48 498238 25 51 76 92 96 0.15 498239 25 62 83 93 97 0.12 498379 5 21 53 71 81 0.55 498408 1 38 63 79 80 0.32 498433 23 43 70 77 79 0.21

TABLE-US-00027 TABLE 27 0.049 0.148 0.444 1.333 4.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 0 40 76 90 93 0.26 498434 32 44 64 78 84 0.20 498435 24 42 64 77 79 0.23 498517 28 23 53 81 85 0.45 498523 50 64 81 90 93 <0.05 498524 53 70 84 93 96 <0.05 498525 38 55 80 92 96 0.09 498550 12 18 62 81 83 0.33 498557 13 33 67 79 83 0.33 498579 6 42 69 80 85 0.31 498580 6 46 76 82 83 0.23 498581 5 40 78 81 84 0.25 498721 40 31 58 78 83 0.35 498833 21 20 58 80 90 0.44

Example 5: Antisense Inhibition of Human Apo(a) in Transgenic Mouse Primary Hepatocytes

[0391] Additional antisense oligonucleotides were newly designed targeting an apo(a) nucleic acid and were tested for their effects on apo(a) mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. Primary hepatocytes from human apo(a) transgenic mice were used in this study. Hepatocytes at a density of 35,000 cells per well were transfected using electroporation with 1,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Human primer probe set hAPO(a)12 kB was used to measure mRNA levels. Apo(a) mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. The results for each experiment are presented in separate tables shown below. ISIS 144367 was also included in the studies for comparison. Results are presented as percent inhibition of apo(a), relative to untreated control cells. A total of 231 antisense oligonucleotides were tested under these culture conditions. Only those antisense oligonucleotides that were selected for further studies are presented below.

[0392] The newly designed chimeric antisense oligonucleotides were designed as 3-10-4 MOE gapmers. The gapmers are 17 nucleosides in length, wherein the central gap segment comprises of ten 2'-deoxynucleosides and is flanked by wing segments on the 5' direction and the 3' direction comprising three nucleosides and four nucleosides respectively. Each nucleoside in the 5' wing segment and each nucleoside in the 3' wing segment has a 2'-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P.dbd.S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

[0393] The apo(a) target sequence contains multiple Kringle repeat sequences, therefore, an antisense oligonucleotide may target one or more regions of apo(a) depending whether on the oligonucleotide targets a Kringle sequence or not. "Start site" indicates the 5'-most nucleoside to which the gapmer is targeted in the human sequence. "Stop site" indicates the 3'-most nucleoside to which the gapmer is targeted human sequence. An apo(a) antisense oligonucleotide may have more than one "Start site" or "Stop site" depending on whether or not it targets a Kringle repeat.

[0394] Most gapmers listed in the Tables are targeted with 100% complementarity to multiple regions of either the human apo(a) mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_005577.2) or the human apo(a) genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_007422.12 truncated from nucleotides 3230000 to 3380000), or both. `n/a` indicates that the antisense oligonucleotide does not target that particular sequence with 100% complementarity.

TABLE-US-00028 TABLE 28 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 64 21210 21229 11 510542 241 257 CCTGTGACAGTGGTGGA 79 21202 21218 111 583 599 CCTGTGACAGTGGTGGA 26693 26709 925 941 CCTGTGACAGTGGTGGA 32240 32256 1609 1625 CCTGTGACAGTGGTGGA 43333 43349 1951 1967 CCTGTGACAGTGGTGGA 48877 48893 2293 2309 CCTGTGACAGTGGTGGA 54423 54439 3319 3335 CCTGTGACAGTGGTGGA 72040 72056 4663 4679 CCTGTGACAGTGGTGGA 94404 94420 5005 5021 CCTGTGACAGTGGTGGA 115515 115531 510543 242 258 TCCTGTGACAGTGGTGG 75 21203 21219 112 584 600 TCCTGTGACAGTGGTGG 26694 26710 926 942 TCCTGTGACAGTGGTGG 32241 32257 1610 1626 TCCTGTGACAGTGGTGG 43334 43350 1952 1968 TCCTGTGACAGTGGTGG 48878 48894 2294 2310 TCCTGTGACAGTGGTGG 54424 54440 3320 3336 TCCTGTGACAGTGGTGG 72041 72057 4664 4680 TCCTGTGACAGTGGTGG 94405 94421 5006 5022 TCCTGTGACAGTGGTGG 115516 115532 510544 243 259 TTCCTGTGACAGTGGTG 73 21204 21220 113 585 601 TTCCTGTGACAGTGGTG 26695 26711 927 943 TTCCTGTGACAGTGGTG 32242 32258 1611 1627 TTCCTGTGACAGTGGTG 43335 43351 1953 1969 TTCCTGTGACAGTGGTG 48879 48895 2295 2311 TTCCTGTGACAGTGGTG 54425 54441 3321 3337 TTCCTGTGACAGTGGTG 72042 72058 4665 4681 TTCCTGTGACAGTGGTG 94406 94422 5007 5023 TTCCTGTGACAGTGGTG 115517 115533 510545 244 260 CTTCCTGTGACAGTGGT 65 21205 21221 114 586 602 CTTCCTGTGACAGTGGT 26696 26712 928 944 CTTCCTGTGACAGTGGT 32243 32259 1612 1628 CTTCCTGTGACAGTGGT 43336 43352 1954 1970 CTTCCTGTGACAGTGGT 48880 48896 2296 2312 CTTCCTGTGACAGTGGT 54426 54442 3322 3338 CTTCCTGTGACAGTGGT 72043 72059 3664 3680 CTTCCTGTGACAGTGGT 77585 77601 4666 4682 CTTCCTGTGACAGTGGT 94407 94423 5008 5024 CTTCCTGTGACAGTGGT 115518 115534 510546 245 261 CCTTCCTGTGACAGTGG 74 21206 21222 115 3665 3681 CCTTCCTGTGACAGTGG 77586 77602 4667 4683 CCTTCCTGTGACAGTGG 94408 94424 5009 5025 CCTTCCTGTGACAGTGG 115519 115535 510547 246 262 TCCTTCCTGTGACAGTG 77 21207 21223 116 3666 3682 TCCTTCCTGTGACAGTG 77587 77603 4668 4684 TCCTTCCTGTGACAGTG 94409 94425 5010 5026 TCCTTCCTGTGACAGTG 115520 115536 510548 247 263 GTCCTTCCTGTGACAGT 73 21208 21224 117 3667 3683 GTCCTTCCTGTGACAGT 77588 77604 4669 4685 GTCCTTCCTGTGACAGT 94410 94426 5011 5027 GTCCTTCCTGTGACAGT 115521 115537 510549 248 264 GGTCCTTCCTGTGACAG 67 21209 21225 118 4670 4686 GGTCCTTCCTGTGACAG 94411 94427 510595 632 648 CCGACTATGCGAGTGTG 76 26742 26758 119 974 990 CCGACTATGCGAGTGTG 32289 32305 1316 1332 CCGACTATGCGAGTGTG 37836 37852 1658 1674 CCGACTATGCGAGTGTG 43382 43398 2000 2016 CCGACTATGCGAGTGTG 48926 48942 2342 2358 CCGACTATGCGAGTGTG 54472 54488 2684 2700 CCGACTATGCGAGTGTG 60027 60043 3026 3042 CCGACTATGCGAGTGTG 66543 66559 510597 634 650 GTCCGACTATGCGAGTG 70 26744 26760 120 976 992 GTCCGACTATGCGAGTG 32291 32307 1318 1334 GTCCGACTATGCGAGTG 37838 37854 1660 1676 GTCCGACTATGCGAGTG 43384 43400 2002 2018 GTCCGACTATGCGAGTG 48928 48944 2344 2360 GTCCGACTATGCGAGTG 54474 54490 2686 2702 GTCCGACTATGCGAGTG 60029 60045 3028 3044 GTCCGACTATGCGAGTG 66545 66561 510598 635 651 GGTCCGACTATGCGAGT 70 26745 26761 121 977 993 GGTCCGACTATGCGAGT 32292 32308 1319 1335 GGTCCGACTATGCGAGT 37839 37855 1661 1677 GGTCCGACTATGCGAGT 43385 43401 2003 2019 GGTCCGACTATGCGAGT 48929 48945 2345 2361 GGTCCGACTATGCGAGT 54475 54491 2687 2703 GGTCCGACTATGCGAGT 60030 60046 3029 3045 GGTCCGACTATGCGAGT 66546 66562

TABLE-US-00029 TABLE 29 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 83 21210 21229 11 510783 6400 6416 GTCAGACCTTAAAAGCT 75 140056 140072 122 512944 3561 3577 AAGCCTCTGTGCTTGGA 81 76246 76262 123 512947 3560 3576 AGCCTCTGTGCTTGGAT 85 76245 76261 124 512958 3559 3575 GCCTCTGTGCTTGGATC 82 76244 76260 125 512959 3585 3601 GCTCCGTTGGTGCTTCT 77 n/a n/a 126

TABLE-US-00030 TABLE 30 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ ISIS Start Stop % in- Start Stop ID NO Site Site Sequence hibition Site Site NO 144367 249 268 GGCAGGTCCTTCCTGTGACA 76 21210 21229 11 510701 4217 4233 CTCTGTGCTTGGAACTG 78 85147 85163 127 510702 219 235 TGCCTCGATAACTCTGT 79 21180 21196 128 561 577 26671 26687 903 919 32218 32234 1245 1261 37765 37781 1587 1603 43311 43327 1929 1945 48855 48871 2271 2287 54401 54417 2613 2629 59956 59972 4299 4315 86472 86488 510704 563 579 TGTGCCTCGATAACTCT 80 26673 26689 129 905 921 32220 32236 1247 1263 37767 37783 1589 1605 43313 43329 1931 1947 48857 48873 2273 2289 54403 54419 2615 2631 59958 59974 4301 4317 86474 86490 4985 5001 115495 115511 510757 4929 4945 GCTCAGTTGGTGCTGCT 74 n/a n/a 130

Example 6: Dose-Dependent Antisense Inhibition of Apo(a) in Transgenic Mouse Primary Hepatocytes

[0395] Potent gapmers from the studies described above were further selected and tested at various doses in transgenic mouse primary hepatocytes in a series of studies with similar culture conditions. Cells were plated at a density of 35,000 per well and transfected using electroporation with 0.156 .mu.M, 0.313 .mu.M, 0.625 .mu.M, 1.250 .mu.M, 2.500 .mu.M, or 5.000 .mu.M concentrations of antisense oligonucleotide, as specified in the Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and apo(a) mRNA levels were measured by quantitative real-time PCR. Apo(a) primer probe set hAPO(a)12 kB was used to measured mRNA levels. Apo(a) mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN.RTM.. Results are presented as percent inhibition of apo(a), relative to untreated control cells.

[0396] The results of each of the studies are depicted in the Tables presented below with each study represented in a separate table. The half maximal inhibitory concentration (IC.sub.50) of each oligonucleotide is also presented in the Tables.

TABLE-US-00031 TABLE 31 0.156 0.312 0.625 1.250 2.500 5.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 28 55 70 83 90 92 0.31 510542 33 58 75 87 89 90 0.27 510543 33 45 68 78 89 89 0.34 510544 33 50 65 78 88 90 0.33 510545 33 58 76 87 91 90 0.26 510546 39 62 76 87 89 91 0.22 510547 36 66 82 84 86 91 0.22 510548 50 70 82 91 88 90 0.13 510549 32 59 73 85 86 90 0.27 510595 26 57 78 88 90 90 0.29 510597 30 53 76 85 89 89 0.30

TABLE-US-00032 TABLE 32 0.156 0.312 0.625 1.250 2.500 5.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 36 52 78 87 93 94 0.26 510598 48 58 81 88 93 92 0.18 510701 45 59 78 87 95 95 0.18 510702 49 63 75 90 94 95 0.15 510704 55 67 80 93 94 95 <0.16 510757 34 48 68 79 90 93 0.33 510783 21 32 51 58 78 84 0.69 512944 57 72 81 91 96 97 <0.16 512947 64 74 86 92 96 97 <0.16 512958 48 69 83 91 96 97 0.13 512959 39 59 76 84 93 93 0.22

TABLE-US-00033 TABLE 33 0.156 0.312 0.625 1.250 2.500 5.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 41 58 75 81 88 87 0.22 510542 38 54 69 74 85 83 0.27 510545 21 43 73 77 80 78 0.39 510546 37 58 73 81 83 81 0.24 510547 38 58 72 79 84 86 0.24 510548 40 63 77 79 81 84 0.21 510549 37 47 67 77 81 83 0.31 510595 34 66 73 81 80 75 0.23 510597 39 59 74 83 76 77 0.23

TABLE-US-00034 TABLE 34 0.156 0.312 0.625 1.250 2.500 5.000 IC.sub.50 ISIS No .mu.M .mu.M .mu.M .mu.M .mu.M .mu.M (.mu.M) 144367 33 60 72 83 81 81 0.26 510598 47 62 75 75 76 76 0.18 510701 41 67 80 87 92 91 0.19 510702 51 64 77 80 80 83 0.13 510704 54 61 77 84 89 80 0.12 512944 71 74 81 88 92 94 0.02 512947 65 77 86 90 93 95 0.03 512958 63 73 84 92 93 96 0.06 512959 39 62 80 82 86 82 0.22

[0397] Apo(a) mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide-treated cells. The potency of the newly designed oligonucleotides was compared with the benchmark oligonucleotide, ISIS 144367. As presented in the Tables above, ISIS 510542 (SEQ ID NO: 111), ISIS 510545 (SEQ ID NO: 114), ISIS 510546 (SEQ ID NO: 115), ISIS 510547 (SEQ ID NO: 116), ISIS 510548 (SEQ ID NO: 117), ISIS 510549 (SEQ ID NO: 118), ISIS 510595 (SEQ ID NO: 119), ISIS 510597 (SEQ ID NO: 120), ISIS 510598 (SEQ ID NO: 121), ISIS 510701 (SEQ ID NO: 127), ISIS 510702 (SEQ ID NO: 128), ISIS 510704 (SEQ ID NO: 129), ISIS 512944 (SEQ ID NO: 123), ISIS 512947 (SEQ ID NO: 124), ISIS 512958 (SEQ ID NO: 125), and ISIS 512959 (SEQ ID NO: 126) were more potent than ISIS 144367 (SEQ ID NO: 11).

Example 7: Effect of In Vivo Antisense Inhibition of Human Apo(a) in Human Apo(a) Transgenic Mice

[0398] Transgenic mice with the human apo(a) gene (Frazer, K. A. et al., Nat. Genet. 1995. 9: 424-431) were utilized in the studies described below. ISIS antisense oligonucleotides that demonstrated statistically significant inhibition of apo(a) mRNA in vitro as described above were evaluated further in this model.

Study 1

[0399] Female human apo(a) transgenic mice were maintained on a 12-hour light/dark cycle and fed ad libitum normal lab chow. The mice were divided into treatment groups consisting of 4 mice each. The groups received intraperitoneal injections of ISIS 494159, ISIS 494160, ISIS 494161, ISIS 494162, ISIS 494163, ISIS 494230, ISIS 494243, ISIS 494244, ISIS 494283, ISIS 494284, ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302, ISIS 494304, ISIS 494466, ISIS 494470, ISIS 494472, ISIS 498239, ISIS 498408, ISIS 498517, ISIS 494158, ISIS 494311, ISIS 494337, ISIS 494372, ISIS 498238, ISIS 498523, ISIS 498525, ISIS 510548, ISIS 512944, ISIS 512947, or ISIS 512958 at a dose of 25 mg/kg twice a week for 2 weeks. One group of mice received intraperitoneal injections of PBS twice a week for 2 weeks. The PBS group served as the control group. Two days following the final dose, the mice were euthanized, organs harvested and analyses done.

Inhibition of Human Apo(a) mRNA

[0400] Total RNA was extracted from the livers of some of the treatment groups, and human apo(a) mRNA was quantitated by RT-PCR. The results are presented in Table 35, expressed as percent inhibition of apo(a) mRNA compared to the PBS control.

TABLE-US-00035 TABLE 35 Percent inhibition of human apo(a) mRNA in transgenic mice ISIS No % inhibition 144367 98 494159 100 494160 95 494161 98 494162 100 494163 100 494230 96 494243 99 494244 99 494283 100 494284 100 494285 100 494286 98 494301 99 494302 96 494304 94 494466 97 494470 93 494472 98 498239 72 498408 100 498517 98

[0401] The data demonstrates significant inhibition of apo(a) mRNA by several ISIS oligonucleotides. ISIS 494159 (SEQ ID NO: 14), ISIS 494162 (SEQ ID NO: 17), ISIS 494163 (SEQ ID NO: 18), ISIS 494243 (SEQ ID NO: 106), ISIS 494244 (SEQ ID NO: 107), ISIS 494283 (SEQ ID NO: 26), ISIS 494284 (SEQ ID NO: 27), ISIS 494285 (SEQ ID NO: 28), ISIS 494301 (SEQ ID NO: 39), and ISIS 498408 (SEQ ID NO: 71) were more potent than the benchmark ISIS 144367 (SEQ ID NO: 11).

Inhibition of Human Apo(a) Protein

[0402] Plasma human apo(a) protein was measured from all treatment groups using an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The results are presented in Table 36, expressed as percent inhibition of apo(a) mRNA compared to the PBS control.

TABLE-US-00036 TABLE 36 Percent inhibition of human apo(a) protein in transgenic mice ISIS No % inhibition 144367 86 494159 86 494160 0 494161 82 494162 84 494163 82 494230 60 494243 84 494244 87 494283 98 494284 98 494285 89 494286 89 494301 93 494302 88 494304 83 494466 76 494470 73 494472 72 498239 54 498408 84 498517 56 494158 71 494311 83 494337 80 494372 78 498238 58 498523 47 498525 58 510548 74 512944 18 512947 65 512958 72

[0403] The data demonstrates significant inhibition of apo(a) mRNA by several ISIS oligonucleotides. ISIS 494159 (SEQ ID NO: 14), ISIS 494244 (SEQ ID NO: 82), ISIS 494283 (SEQ ID NO: 26), ISIS 494284 (SEQ ID NO: 27), ISIS 494285 (SEQ ID NO: 28), ISIS 494286 (SEQ ID NO: 29), ISIS 494301 (SEQ ID NO: 39), and ISIS 494302 (SEQ ID NO: 40) were as potent as or more potent than the benchmark ISIS 144367 (SEQ ID NO: 11).

Study 2

[0404] ISIS 494159, ISIS 494161, ISIS 494162, ISIS 494163, and ISIS 494243 were further evaluated in this transgenic model. ISIS 144367 was included for comparison.

Treatment

[0405] Female human apo(a) transgenic mice were divided into treatment groups consisting of 4 mice each. The groups received intraperitoneal injections of ISIS 144367, ISIS 494159, ISIS 494161, ISIS 494162, ISIS 494163, or ISIS 494243 at doses of 1.5 mg/kg, 5 mg/kg, 15 mg/kg, or 50 mg/kg twice a week for 2 weeks. One group of mice received intraperitoneal injections of PBS twice a week for 2 weeks. The PBS group served as the control group. Two days following the final dose, the mice were euthanized, organs harvested and analyses done.

Inhibition of Human Apo(a) mRNA

[0406] Total RNA was extracted from the livers of the treatment groups, and human apo(a) mRNA was quantitated by RT-PCR. The results are presented in Table 37, expressed as percent inhibition of apo(a) mRNA compared to the PBS control.

TABLE-US-00037 TABLE 37 Dose-dependent inhibition of human apo(a) mRNA in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 144367 100 71 31 30 42 10 0 3 5 494159 100 91 5 30 67 10 48 3 39 494161 100 82 6 30 49 10 61 3 30 494162 100 90 5 30 67 10 58 3 25 494163 100 83 5 30 66 10 58 3 21 494243 100 80 32 30 26 10 0 3 6

[0407] The data demonstrates significant inhibition of apo(a) mRNA by several ISIS oligonucleotides. ISIS 494159 (SEQ ID NO: 14), ISIS 494161 (SEQ ID NO: 16), 494162 (SEQ ID NO:17), and ISIS 94163 (SEQ ID NO: 18) were more efficacious than the benchmark ISIS 144367 (SEQ ID NO: 11).

Reduction of Human Apo(a) Protein Levels

[0408] Blood was collected from the treatment groups, and human apo(a) protein levels were quantitated by an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The results are presented in Table 38, expressed as percent reduction of apo(a) protein levels compared to the PBS control.

TABLE-US-00038 TABLE 38 Dose-dependent inhibition of human apo(a) protein in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 144367 100 73 71 30 0 10 6 3 69 494159 100 88 2 30 88 10 85 3 36 494161 100 90 2 30 85 10 73 3 44 494162 100 89 3 30 78 10 76 3 24 494163 100 90 3 30 86 10 60 3 37 494243 100 61 174 30 0 10 0 3 0

[0409] The data demonstrates significant reduction of apo(a) plasma protein levels by several ISIS oligonucleotides. ISIS 494159 (SEQ ID NO: 14), ISIS 494161 (SEQ ID NO: 16), ISIS 494162 (SEQ ID NO: 17), and ISIS 494163 (SEQ ID NO: 18) were more efficacious than the benchmark ISIS 144367 (SEQ ID NO: 11).

Study 3

[0410] ISIS 494244, ISIS 494283, and ISIS 494284 were further evaluated in this model. ISIS 144367 was included for comparison.

Treatment

[0411] Female human apo(a) transgenic mice were divided into treatment groups consisting of 4 mice each. The groups received intraperitoneal injections of ISIS 144367, ISIS 494244, ISIS 494283, or ISIS 494284 at doses of 0.75 mg/kg, 2.5 mg/kg, 7.5 mg/kg, or 25 mg/kg twice a week for 2 weeks. One group of mice received intraperitoneal injections of PBS twice a week for 2 weeks. The PBS group served as the control group. Two days following the final dose, the mice were euthanized, organs harvested and analyses done.

Inhibition of Human Apo(a) mRNA

[0412] Total RNA was extracted from the livers of the treatment groups, and human apo(a) mRNA was quantitated by RT-PCR. The results are presented in Table 39, expressed as percent inhibition of apo(a) mRNA compared to the PBS control.

TABLE-US-00039 TABLE 39 Dose-dependent inhibition of human apo(a) mRNA in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 144367 50 75 22 15 60 5 0 1.5 0 494244 50 73 18 15 41 5 34 1.5 0 494283 50 74 16 15 52 5 24 1.5 0 494284 50 73 16 15 58 5 17 1.5 2

[0413] The data demonstrates significant inhibition of apo(a) mRNA by several ISIS oligonucleotides. ISIS 494244 (SEQ ID NO: 107), ISIS 494283 (SEQ ID NO: 26), and ISIS 494284 (SEQ ID NO: 27) were more efficacious than the benchmark, ISIS 144367 (SEQ ID NO: 11).

Reduction of Human Apo(a) Protein Levels

[0414] Blood was collected from the treatment groups, and human apo(a) protein levels were quantitated by an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The results are presented in Table 40, expressed as percent reduction of apo(a) protein levels compared to the PBS control.

TABLE-US-00040 TABLE 40 Dose-dependent inhibition of human apo(a) plasma protein in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 144367 50 64 16 15 14 5 0 1.5 0 494244 50 67 2 15 60 5 58 1.5 0 494283 50 64 4 15 65 5 64 1.5 69 494284 50 66 4 15 63 5 51 1.5 54

[0415] The data demonstrates significant reduction of apo(a) plasma protein levels by several ISIS oligonucleotides. ISIS 494244 (SEQ ID NO: 107), ISIS 494283 (SEQ ID NO: 26), and ISIS 494284 (SEQ ID NO: 27) were more efficacious than the benchmark, ISIS 144367 (SEQ ID NO: 11).

Study 4

[0416] ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302, and ISIS 494311 were further evaluated in this model.

Treatment

[0417] Male human apo(a) transgenic mice were divided into treatment groups consisting of 4 mice each. Each such group received intraperitoneal injections of ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302, or ISIS 494311 at doses of 5 mg/kg, 15 mg/kg, or 50 mg/kg once a week for 2 weeks. One group of 3 mice received intraperitoneal injections of PBS once a week for 2 weeks. The PBS group served as the control group. Two days following the final dose, the mice were euthanized, organs harvested and analyses done.

Inhibition of Human Apo(a) mRNA

[0418] Total RNA was extracted from the livers of the treatment groups, and human apo(a) mRNA was quantitated by RT-PCR. The results are presented in Table 41, expressed as percent inhibition of apo(a) mRNA compared to the PBS control. The data demonstrates significant inhibition of apo(a) mRNA by ISIS 494285 (SEQ ID NO: 28), ISIS 494286 (SEQ ID NO: 29), ISIS 494301 (SEQ ID NO: 39), ISIS 494302 (SEQ ID NO: 40) and ISIS 494311 (SEQ ID NO: 47).

TABLE-US-00041 TABLE 41 Dose-dependent inhibition of human Apo(a) mRNA in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 494285 50 98 1 15 97 5 79 494286 50 97 1 15 91 5 80 494301 50 98 3 15 96 5 59 494302 50 98 2 15 88 5 72 494311 50 99 1 15 96 5 87

Reduction of Human Apo(a) Protein Levels

[0419] Blood was collected from the treatment groups, and human apo(a) protein levels were quantitated by an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The results are presented in Table 42, expressed as percent reduction of apo(a) protein levels compared to the PBS control. The data demonstrates significant reduction of apo(a) plasma protein levels by ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302 and ISIS 494311.

TABLE-US-00042 TABLE 42 Dose-dependent inhibition of human apo(a) protein in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 494285 50 88 2 15 88 5 72 494286 50 90 2 15 85 5 75 494301 50 89 5 15 86 5 38 494302 50 90 3 15 82 5 61 494311 50 90 3 15 82 5 69

Study 5

[0420] ISIS 494372, ISIS 498524, ISIS 498581, ISIS 498721, and ISIS 498833 were further evaluated in this model.

Treatment

[0421] Female human apo(a) transgenic mice were divided into treatment groups consisting of 4 mice each. The groups received intraperitoneal injections of ISIS 494372, ISIS 498524, ISIS 498581, ISIS 498721, or ISIS 498833 at doses of 5 mg/kg, 15 mg/kg, or 50 mg/kg once a week for 2 weeks. One group of 3 mice received intraperitoneal injections of PBS once a week for 2 weeks. The PBS group served as the control group. Two days following the final dose, the mice were euthanized, organs harvested and analyses done.

Inhibition of Human Apo(a) mRNA

[0422] Total RNA was extracted from the livers of the treatment groups, and human apo(a) mRNA was quantitated by RT-PCR. The results are presented in Table 43, expressed as percent inhibition of apo(a) mRNA compared to the PBS control. The data demonstrates significant inhibition of apo(a) mRNA by ISIS 494372 (SEQ ID NO: 28), ISIS 498524 (SEQ ID NO: 93), ISIS 498581 (SEQ ID NO: 104), and ISIS 498721 (ATGCCTCGATAACTCCGTCC; SEQ ID NO: 134).

TABLE-US-00043 TABLE 43 Dose-dependent inhibition of human Apo(a) mRNA in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 494372 50 88 18 15 49 5 0 498524 50 83 8 15 74 5 34 498581 50 98 7 15 58 5 48 498721 50 97 14 15 68 5 0 498833 50 61 155 15 0 5 17

Reduction of Human Apo(a) Protein Levels

[0423] Blood was collected from the treatment groups, and human apo(a) protein levels were quantitated by an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The results are presented in Table 44, expressed as percent reduction of apo(a) protein levels compared to the PBS control. The data demonstrates significant reduction of apo(a) plasma protein levels by ISIS 494372 (SEQ ID NO: 28), ISIS 498581 (SEQ ID NO: 104), and ISIS 498721 (ATGCCTCGATAACTCCGTCC; SEQ ID NO: 134).

TABLE-US-00044 TABLE 44 Dose-dependent inhibition of human apo(a) protein in transgenic mice ISIS No Dose (mg/kg/wk) % inhibition ED.sub.50 494372 50 68 32 15 25 5 12 498524 50 38 118 15 0 5 0 498581 50 79 9 15 52 5 49 498721 50 81 10 15 63 5 29 498833 50 15 738 15 0 5 67

Example 8: Tolerability of Antisense Oligonucleotides Targeting Human Apo(a) in Rodent Models

[0424] Gapmer antisense oligonucleotides targeting human apo(a) were selected from the studies described above for tolerability studies in CD1 mice and in Sprague Dawley rats. Rodents do not express endogenous apo(a), hence these studies tested the tolerability of each human antisense oligonucleotide in an animal rather than any phenotypic changes that may be caused by inhibiting apo(a) in the animal.

Tolerability in CD1 Mice: Study 1

[0425] CD1.RTM. mice (Charles River, Mass.) are a multipurpose mice model, frequently utilized for safety and efficacy testing. The mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

[0426] Groups of male CD1 mice were injected subcutaneously twice a week for 6 weeks with 50 mg/kg of ISIS 494159, ISIS 494161, ISIS 494162, ISIS 494244, ISIS 494283, ISIS 494284, ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302, ISIS 494311, ISIS 494337, ISIS 494372, and ISIS 510548. One group of six-week old male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0427] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 45. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00045 TABLE 45 Plasma chemistry markers of CD1 mice ALT AST Albumin BUN Creatinine Bilirubin (IU/L (IU/L) (g/dL) (mg/dL) (mg/dL) (mg/dL) PBS 38 71 2.9 25.2 0.16 0.15 ISIS 494159 615 525 2.7 23.9 0.11 0.20 ISIS 494161 961 670 2.6 23.7 0.15 0.14 ISIS 494162 1373 1213 2.7 23.7 0.14 0.18 ISIS 494283 237 242 2.5 26.2 0.14 0.13 ISIS 494284 192 307 2.3 27.1 0.14 0.10 ISIS 494285 582 436 2.3 25.4 0.16 0.11 ISIS 494286 191 227 2.5 21.1 0.12 0.15 ISIS 494301 119 130 2.7 26.4 0.15 0.12 ISIS 494302 74 96 2.8 24.8 0.14 0.15 ISIS 494311 817 799 2.7 28.7 0.12 0.17 ISIS 494337 722 397 2.5 20.0 0.13 0.11 ISIS 494372 73 164 2.6 28.5 0.16 0.11 ISIS 510548 2819 2245 3.1 26.0 0.15 0.15

Organ Weights

[0428] Liver, spleen and kidney weights were measured at the end of the study, and are presented in Table 46. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00046 TABLE 46 Organ weights of CD1 mice (g) Kidney Liver Spleen PBS 0.68 2.0 0.13 ISIS 494159 0.68 3.0 0.21 ISIS 494161 0.62 3.5 0.20 ISIS 494162 0.60 3.3 0.20 ISIS 494283 0.65 2.8 0.24 ISIS 494284 0.69 2.7 0.29 ISIS 494285 0.59 3.2 0.21 ISIS 494286 0.64 2.8 0.25 ISIS 494301 0.72 3.0 0.43 ISIS 494302 0.63 2.3 0.23 ISIS 494311 0.61 3.2 0.19 ISIS 494337 0.56 2.3 0.17 ISIS 494372 0.60 2.5 0.27 ISIS 510548 0.55 3.7 0.20

Tolerability in Sprague Dawley Rats

[0429] Sprague-Dawley rats are a multipurpose model used for safety and efficacy evaluations. The rats were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

[0430] Groups of male Sprague Dawley rats were injected subcutaneously twice a week for 8 weeks with 30 mg/kg of ISIS 494159, ISIS 494161, ISIS 494162, ISIS 494244, ISIS 494283, ISIS 494284, ISIS 494285, ISIS 494286, ISIS 494301, ISIS 494302, ISIS 494311, ISIS 494337, ISIS 494372, and ISIS 510548. One group of six male Sprague Dawley rats was injected subcutaneously twice a week for 8 weeks with PBS. Rats were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis.

Plasma Chemistry Markers

[0431] To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, albumin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 47. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies.

TABLE-US-00047 TABLE 47 Plasma chemistry markers of Sprague Dawley rats Creat- ALT AST Bilirubin Albumin BUN inine (IU/L) (IU/L) (mg/dL) (mg/dL) (mg/dL) (mg/dL) PBS 30 82 0.09 3.2 19 0.28 ISIS 494159 182 208 0.14 3.4 22 0.35 ISIS 494161 36 86 0.13 3.4 23 0.35 ISIS 494162 102 158 0.17 2.6 28 0.32 ISIS 494283 53 156 0.13 2.9 24 0.32 ISIS 494284 34 113 0.08 2.0 28 0.32 ISIS 494285 110 294 0.10 1.4 110 0.52 ISIS 494286 40 83 0.07 1.6 48 0.44 ISIS 494301 38 132 0.08 3.0 18 0.33 ISIS 494302 47 105 0.09 3.2 19 0.34 ISIS 494311 93 185 0.51 2.7 23 0.30 ISIS 494372 54 119 0.12 3.0 19 0.33 ISIS 510548 116 181 0.11 1.7 65 0.66

Kidney Function

[0432] To evaluate the effect of ISIS oligonucleotides on kidney function, urine levels of total protein and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Results are presented in Table 48, expressed in mg/dL.

TABLE-US-00048 TABLE 48 Kidney function markers (mg/dL) in Sprague-Dawley rats Creatinine Total protein PBS 103 118 ISIS 494159 70 279 ISIS 494161 105 315 ISIS 494162 58 925 ISIS 494283 114 1091 ISIS 494284 97 2519 ISIS 494285 38 2170 ISIS 494286 51 625 ISIS 494301 62 280 ISIS 494302 101 428 ISIS 494311 48 1160 ISIS 494372 46 154 ISIS 510548 55 2119

Organ Weights

[0433] Liver, spleen and kidney weights were measured at the end of the study, and are presented in Table 49. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies.

TABLE-US-00049 TABLE 49 Organ weights of Sprague Dawley rats (g) Kidney liver Spleen PBS 3.5 13.1 0.9 ISIS 494159 3.1 11.7 1.6 ISIS 494161 2.8 12.5 2 ISIS 494162 3.1 14.2 1.6 ISIS 494283 3.3 12.9 2.3 ISIS 494284 4.1 15.8 2.7 ISIS 494285 3.8 13.4 0.8 ISIS 494286 4.2 16.7 2.5 ISIS 494301 3.2 12.1 2.3 ISIS 494302 3.4 13.3 2.4 ISIS 494311 3.5 17.4 3.2 ISIS 494372 3.6 12.9 3.2 ISIS 510548 6.4 21.2 1.5

[0434] The finding from the rodent tolerability studies showed that in general, taking into consideration all the tolerability markers screened, ISIS 494372 was the best tolerated antisense compound in both the CD1 mouse model and the Sprague Dawley rat model.

Example 9: Pharmacokinetics of Antisense Oligonucleotide in CD1 Mice

[0435] CD1 mice were treated with ISIS oligonucleotides and the oligonucleotide concentrations in the liver and kidney were evaluated.

Treatment

[0436] Groups of four CD1 mice each were injected subcutaneously twice per week for 6 weeks with 50 mg/kg of ISIS 494283, ISIS 494284, ISIS 494286, ISIS 494301, ISIS 494302, or ISIS 494372. The mice were sacrificed 2 days following the final dose. Livers were harvested for analysis.

Measurement of Oligonucleotide Concentration

[0437] The concentration of the total oligonucleotide concentration was measured. The method used is a modification of previously published methods (Leeds et al., 1996; Geary et al., 1999) which consist of a phenol-chloroform (liquid-liquid) extraction followed by a solid phase extraction. An internal standard (ISIS 355868, a 27-mer 2'-O-methoxyethyl modified phosphorothioate oligonucleotide, GCGTTTGCTCTTCTTCTTGCGTTTTTT, designated herein as SEQ ID NO: 131) was added prior to extraction. Tissue sample concentrations were calculated using calibration curves, with a lower limit of quantitation (LLOQ) of approximately 1.14 .mu.g/g. Half-lives were then calculated using WinNonlin software (PHARSIGHT).

[0438] The results are presented in Table 50, expressed as .mu.g/g liver or kidney tissue. The data indicates that ISIS 494372 was at an acceptable concentration in the liver and kidneys.

TABLE-US-00050 TABLE 50 Oligonucleotide concentration (.mu.g/g tissue) of ISIS oligonucleotides in CD1 mice ISIS No Liver Kidney 494283 581 549 494284 511 678 494286 368 445 494301 812 347 494302 617 263 494372 875 516

Example 10: Pharmacokinetics of Antisense Oligonucleotide in Sprague Dawley Rats

[0439] Male Sprague Dawley rats were treated with ISIS oligonucleotides and the oligonucleotide concentrations in the liver and kidney were evaluated.

Treatment

[0440] Groups of four rats each were injected subcutaneously twice per week for 3 weeks with 10 mg/kg of ISIS 494283, ISIS 494284, ISIS 494286, ISIS 494301, ISIS 494302, or ISIS 494372. The rats were sacrificed 2 days following the final dose. Livers were harvested for analysis.

Measurement of Oligonucleotide Concentration

[0441] The concentration of the total oligonucleotide concentration was measured. The method used is a modification of previously published methods (Leeds et al., 1996; Geary et al., 1999) which consist of a phenol-chloroform (liquid-liquid) extraction followed by a solid phase extraction. An internal standard (ISIS 355868, a 27-mer 2'-O-methoxyethyl modified phosphorothioate oligonucleotide, GCGTTTGCTCTTCTTCTTGCGTTTTTT, designated herein as SEQ ID NO: 131) was added prior to extraction. Tissue sample concentrations were calculated using calibration curves, with a lower limit of quantitation (LLOQ) of approximately 1.14 .mu.g/g. Half-lives were then calculated using WinNonlin software (PHARSIGHT).

[0442] The results are presented in Table 51, expressed as .mu.g/g liver or kidney tissue. The data indicates that ISIS 494372 was at an acceptable concentration in the liver and kidneys.

TABLE-US-00051 TABLE 51 Oligonucleotide concentration (.mu.g/g tissue) of ISIS oligonucleotides in Sprague Dawley rats ISIS No Liver Kidney 494283 220 434 494284 178 573 494286 234 448 494301 279 540 494302 205 387 494372 288 663

Example 11: Effect of ISIS Antisense Oligonucleotides Targeting Human Apo(a) in Cynomolgus Monkeys

[0443] Cynomolgus monkeys were treated with ISIS antisense oligonucleotides selected from studies described above. At the time this study was undertaken, the cynomolgus monkey genomic sequence was not available in the National Center for Biotechnology Information (NCBI) database; therefore, cross-reactivity with the cynomolgus monkey gene sequence could not be confirmed. Instead, the sequences of the ISIS antisense oligonucleotides used in the cynomolgus monkeys was compared to a rhesus monkey sequence for homology. It is expected that ISIS oligonucleotides with homology to the rhesus monkey sequence are fully cross-reactive with the cynomolgus monkey sequence as well.

[0444] The human antisense oligonucleotides tested are also cross-reactive with the rhesus mRNA sequence (XM_001098061.1; designated herein as SEQ ID NO: 132). The greater the complementarity between the human oligonucleotide and the rhesus monkey sequence, the more likely the human oligonucleotide can cross-react with the rhesus monkey sequence. The start and stop sites of each oligonucleotide to SEQ ID NO: 132 is presented in Table 52. Each antisense oligonucleotide targets more than one region in SEQ ID NO:132 and has multiple start sites. "Start site" indicates the 5'-most nucleotide to which the gapmer is targeted in the rhesus monkey sequence. `Mismatches` indicates the number of nucleotides mismatched between the human oligonucleotide sequence and the rhesus sequence.

[0445] Antisense oligonucleotide tolerability, as well as their pharmacokinetic profile in the liver and kidney, was evaluated.

TABLE-US-00052 TABLE 52 Antisense oligonucleotides complementary to SEQ ID NO: 132 ISIS No Start Site Mismatches 494283 278 2 620 2 923 2 1265 2 1607 1 1949 1 2267 1 2609 1 2951 1 3293 1 494284 279 1 621 1 924 1 1266 1 1608 1 1950 1 2268 1 2610 1 2952 1 3294 1 494286 281 1 623 1 926 1 1268 1 1610 2 1952 2 2270 2 2612 2 2954 2 3296 2 494301 322 2 664 2 967 2 1309 1 1651 2 494302 323 2 968 2 1310 1 1652 2 494372 1186 2 1870 1 2188 1

Treatment

[0446] Prior to the study, the monkeys were kept in quarantine for at least a 30-day period, during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed between 2 and 4 kg. Seven groups of four randomly assigned male cynomolgus monkeys each were injected subcutaneously with ISIS oligonucleotide or PBS using a stainless steel dosing needle and syringe of appropriate size into the one of four sites on the back of the monkeys. The injections were given in clock-wise rotation; one site per dosing. The monkeys were dosed four times a week for the first week (days 1, 3, 5, and 7) as loading doses, and subsequently once a week for weeks 2-12, with 40 mg/kg of ISIS 494283, ISIS 494284, ISIS 494286, ISIS 494301, ISIS 494302, or ISIS 494372. A control group of 8 cynomolgus monkeys was injected with PBS subcutaneously thrice four times a week for the first week (days 1, 3, 5, and 7), and subsequently once a week for weeks 2-12.

[0447] During the study period, the monkeys were observed at least once daily for signs of illness or distress. Any animal experiencing more than momentary or slight pain or distress due to the treatment, injury or illness was treated by the veterinary staff with approved analgesics or agents to relieve the pain after consultation with the Study Director. Any animal in poor health or in a possible moribund condition was identified for further monitoring and possible euthanasia. For instance, one animal in the treatment group of ISIS 494302 was found moribund on day 56 and was euthanized Scheduled euthanasia of the animals was conducted on days 86 and 87 by exsanguination under deep anesthesia. The protocols described in the Example were approved by the Institutional Animal Care and Use Committee (IACUC).

Target Reduction

RNA Analysis

[0448] On day 86, RNA was extracted from liver tissue for real-time PCR analysis of apo(a) using human primer probe set ABI Hs00916691_m1 (Applied Biosystems, Carlsbad Calif.). Results are presented as percent inhibition of apo(a) mRNA, relative to PBS control. As shown in Table 53, treatment with ISIS antisense oligonucleotides resulted in significant reduction of apo(a) mRNA in comparison to the PBS control.

[0449] The mRNA levels of plasminogen, another kringle-containing protein, were also measured. Treatment with ISIS 494372 did not alter the mRNA levels of plasminogen.

TABLE-US-00053 TABLE 53 Percent Inhibition of apo(a) mRNA in the cynomolgus monkey liver relative to the PBS control ISIS No % inhibition 494283 91 494284 99 494286 96 494301 88 494302 89 494372 93

Protein Analysis

[0450] On different days, one mL of blood was collected from the cephalic, saphenous, or femoral vein of all study monkeys. The blood samples were put into tubes containing K2-EDTA for plasma separation. The tubes were centrifuged at 3,000 rpm for 10 min at room temperature to obtain plasma. Apo(a) protein levels were analyzed by an Apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). Results are presented as percentage change of levels from the baseline. As shown in Table 54, treatment with several ISIS antisense oligonucleotides resulted in significant reduction of apo(a) protein levels in comparison to the PBS control. Specifically, treatment with ISIS 494372 reduced cynomolgous plasma protein levels of apo(a).

[0451] The protein levels of apoB were also measured in the study groups. Antisense inhibition of apo(a) had no effect on apoB levels.

TABLE-US-00054 TABLE 54 Apo(a) plasma protein levels (% inhibition over baseline values) in the cynomolgus monkey Day 16 Day 30 Day 44 Day 56 Day 72 Day 86 PBS 0 0 10 0 0 0 ISIS 494283 78 79 81 66 66 70 ISIS 494284 92 95 95 93 93 94 ISIS 494286 92 95 96 94 94 94 ISIS 494301 41 45 52 20 17 29 ISIS 494302 17 0 2 0 0 20 ISIS 494372 67 80 83 79 78 81

Tolerability Studies

Body and Organ Weight Measurements

[0452] To evaluate the effect of ISIS oligonucleotides on the overall health of the animals, body and organ weights were measured at day 86. Body weights were measured and are presented in Table 55. Organ weights were measured and the data is presented in Table 56. The results indicate that treatment with ISIS 494372 was well tolerated in terms of the body and organ weights of the monkeys.

TABLE-US-00055 TABLE 55 Body weights (g) in the cynomolgus monkey Day 14 Day 35 Day 49 Day 56 Day 70 Day 84 PBS 2637 2691 2748 2733 2739 2779 ISIS 494283 2591 2670 2698 2656 2704 2701 ISIS 494284 2559 2661 2676 2675 2662 2646 ISIS 494286 2693 2770 2838 2800 2796 2816 ISIS 494301 2587 2604 2627 2591 2596 2604 ISIS 494302 2759 2760 2839 2825 3113 3122 ISIS 494372 2719 2877 2985 2997 3037 3036

TABLE-US-00056 TABLE 56 Organ weights (% body weight) in the cynomolgus monkey Spleen Kidneys Liver Heart Lungs PBS 0.14 0.38 2.2 0.33 0.51 ISIS 494283 0.24 0.95 2.8 0.33 0.49 ISIS 494284 0.19 0.60 2.6 0.36 0.55 ISIS 494286 0.22 0.63 2.7 0.38 0.55 ISIS 494301 0.38 0.81 3.0 0.36 0.61 ISIS 494302 0.17 0.95 2.5 0.39 0.57 ISIS 494372 0.18 1.16 2.6 0.36 0.56

Liver Function

[0453] To evaluate the effect of ISIS oligonucleotides on hepatic function, monkeys were fasted overnight prior to blood collection. Approximately 1.5 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. Levels of various liver function markers were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). Plasma levels of ALT and AST were measured and the results are presented in Table 57, expressed in IU/L. Bilirubin, a liver function marker, was similarly measured and is presented in Table 57, expressed in mg/dL. The results indicate that treatment with ISIS 494372 was well tolerated in terms of the liver function in monkeys.

TABLE-US-00057 TABLE 57 Liver function markers in cynomolgus monkey plasma ALT (IU/L) AST (IU/L) Bilirubin (mg/dL) PBS 33 43 0.20 ISIS 494283 75 73 0.12 ISIS 494284 115 79 0.17 ISIS 494286 67 73 0.13 ISIS 494301 129 90 0.15 ISIS 494302 141 75 0.15 ISIS 494372 46 75 0.17

C-Reactive Protein Level Analysis

[0454] To evaluate any inflammatory effect of ISIS oligonucleotides in cynomolgus monkeys, blood samples were taken for analysis. The monkeys were fasted overnight prior to blood collection. Approximately 1.5 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. C-reactive protein (CRP), which is synthesized in the liver and which serves as a marker of inflammation, was measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). The results indicate that treatment with ISIS 494372 did not cause any inflammation in monkeys.

TABLE-US-00058 TABLE 58 C-reactive protein levels (mg/L) in cynomolgus monkey plasma CRP PBS 1.4 ISIS 494283 14.7 ISIS 494284 7.7 ISIS 494286 4.4 ISIS 494301 3.5 ISIS 494302 2.4 ISIS 494372 10.2

Complement C3 Analysis

[0455] To evaluate any effect of ISIS oligonucleotides on the complement pathway in cynomolgus monkeys, blood samples were taken for analysis on day 84 (pre-dose) and day 85 (24 hours post-dose). Approximately 0.5 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. C3 was measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). The results indicate that treatment with ISIS 494372 did not cause any effect on the complement pathway in monkeys.

TABLE-US-00059 TABLE 59 Complement C3 levels (mg/dL) in cynomolgus monkey plasma Pre-dose Post-dose PBS 140 139 ISIS 494283 127 101 ISIS 494284 105 75 ISIS 494286 84 38 ISIS 494301 118 76 ISIS 494302 98 58 ISIS 494372 123 109

Hematology

[0456] To evaluate any effect of ISIS oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 0.5 mL of blood was collected on day 87 from each of the available study animals in tubes containing K.sub.2-EDTA. Samples were analyzed for red blood cell (RBC) count, white blood cells (WBC) count, as well as for platelet count, using an ADVIA120 hematology analyzer (Bayer, USA). The data is presented in Table 60.

[0457] The data indicate that treatment with ISIS 494372 was well tolerated in terms of the hematologic parameters of the monkeys.

TABLE-US-00060 TABLE 60 Blood cell counts in cynomolgus monkeys WBC RBC Platelet (.times.10.sup.3/.mu.L) (.times.10.sup.6/.mu.L) (.times.10.sup.3/.mu.L) PBS 15 6.3 329 ISIS 494283 16 5.3 456 ISIS 494284 13 6.3 330 ISIS 494286 14 5.5 304 ISIS 494301 15 6.0 392 ISIS 494302 12 6.3 305 ISIS 494372 11 6.1 447

Example 12: Characterization of the Pharmacological Activity of ISIS 494372 in Cynomolgus Monkeys

[0458] The pharmacological activity of ISIS 494372 was characterized by measuring liver apo(a) mRNA and plasma apo(a) levels in monkeys administered the compound over 13 weeks and allowed to recover for another 13 weeks.

Treatment

[0459] Five groups of 14 randomly assigned male and female cynomolgus monkeys each were injected subcutaneously with ISIS oligonucleotide or PBS using a stainless steel dosing needle and syringe of appropriate size into the one of four sites on the back (scapular region) of the monkeys. The monkeys were dosed four times a week for the first week (days 1, 3, 5, and 7) as loading doses, and subsequently once a week for weeks 2-13 as maintenance doses, as shown in the table below. The loading dose during the first week is expressed as mg/kg/dose, while the maintenance doses on weeks 2-13 are expressed as mg/kg/week.

TABLE-US-00061 TABLE 61 Dosing groups in cynomolgus monkeys Number of animals for necropsy Group Test Article Dose Interim Terminal Recovery 1 PBS -- 4 6 4 2 ISIS 4 -- 6 -- 3 494372 8 -- 6 -- 4 12 4 6 4 5 40 4 6 4

[0460] Liver samples from animals were taken at the interim, terminal and recovery phases of the study for the analyses of apo(a) mRNA. In addition, plasma samples were collected on different days to measure apo(a) protein levels. This non-clinical study was conducted in accordance with the United States Food and Drug Administration (FDA) Good Laboratory Practice (GLP) Regulations, 21 CFR Part 58.

RNA Analysis

[0461] Liver samples were collected from monkeys on days 30, 93, and 182, and frozen. Briefly, a piece (0.2 g) of frozen liver was homogenized in 2 mL of RLT solution (Qiagen). The resulting lysate was applied to Qiagen RNeasy mini columns. After purification and quantification, the tissues were subjected to RT-PCR analysis. The Perkin-Elmer ABI Prism 7700 Sequence Detection System, which uses real-time fluorescent RT-PCR detection, was used to quantify apo(a) mRNA. The assay is based on a target-specific probe labeled with fluorescent reporter and quencher dyes at opposite ends. The probe was hydrolyzed through the 5'-exonuclease activity of Taq DNA polymerase, leading to an increasing fluorescence emission of the reporter dye that can be detected during the reaction. A probe set (ABI Rhesus LPA probe set ID Rh02789275_m1, Applied Biosystems, Carlsbad Calif.) targeting position 1512 of the rhesus monkey apo(a) mRNA transcript GENBANK Accession No XM_001098061.2 (SEQ ID NO: XXX) sequence was used to measure cynomolgus monkey liver apo(a) mRNA expression levels. Apo(a) expression was normalized using RIBOGREEN.RTM.. Results are presented as percent inhibition of apo(a) mRNA, relative to PBS control.

[0462] As shown in Table 62, treatment with ISIS 494372 resulted in a dose-dependent reduction of apo(a) mRNA in comparison to the PBS control. At day 30, hepatic apo(a) mRNA expression was reduced in a dose-dependent manner by 74% and 99% in the 12 mg/kg/week and 40 mg/kg/week dosing cohorts, respectively. These reductions are statistically significant by one-way ANOVA (Dunnett's multiple comparison test, P<0.05).

[0463] Apo(a) mRNA levels were also measured during the recovery phase. Liver expression levels at day 88 after the last dose were still reduced 49% and 69% in the 12 mg/kg/week and 40 mg/kg/week dosing cohorts, respectively.

TABLE-US-00062 TABLE 62 Percent inhibition levels of liver apo(a) mRNA in the dosing phase in cynomolgus monkeys treated with ISIS 494372 Day Dose (mg/kg/wk) % inhibition 30 12 73 40 99 93 4 44 8 43 12 53 40 93

Protein Analysis

[0464] Approximately 20 .mu.l of plasma was analyzed using a commercially available apo(a) ELISA kit (Mercodia 10-1106-01, Uppsala, Sweden). The assay protocol was performed as described by the manufacturer. The results are presented in Tables 63 and 64 as percentage change from Day 1 pre-dose apo(a) plasma protein concentrations. Statistically significant differences from Day 1 baseline plasma apo(a) using the Dunnett's multicomparison test are marked with an asterisk.

[0465] Maximal reduction in plasma apo(a) protein was observed in all dosing cohorts by Day 93. In the recovery phase, apo(a) plasma protein levels in the 40 mg/kg/week dosing cohort were at 22% and 93% of the baseline after 4 and 13 weeks (Days 121 and 182) of recovery, respectively. The rate of recovery in the 12 mg/kg/week cohort was similar to that seen in the 40 mg/kg/week cohort.

TABLE-US-00063 TABLE 63 Apo(a) plasma protein levels as a percent of Day 1 levels in the dosing phase in cynomolgus monkeys treated with ISIS 494372 Day Dose (mg/kg/wk) % 30 4 93 8 70 12 49 40 15* 93 4 73 8 56 12 32* 40 11*

TABLE-US-00064 TABLE 64 Apo(a) plasma protein levels as a percent of Day 1 levels in the recovery phase in cynomolgus monkeys treated with ISIS 494372 Day Dose (mg/kg/wk) % 121 12 38* 40 22* 182 12 84 40 93

Example 13: Measurement of Viscosity of ISIS Antisense Oligonucleotides Targeting Human Apo(a)

[0466] The viscosity of select antisense oligonucleotides from the studies described above was measured with the aim of screening out antisense oligonucleotides which have a viscosity more than 40 cP. Oligonucleotides having a viscosity greater than 40 cP would have less than optimal viscosity.

[0467] ISIS oligonucleotides (32-35 mg) were weighed into a glass vial, 120 .mu.L of water was added and the antisense oligonucleotide was dissolved into solution by heating the vial at 50.degree. C. Part (75 .mu.L) of the pre-heated sample was pipetted to a micro-viscometer (Cambridge). The temperature of the micro-viscometer was set to 25.degree. C. and the viscosity of the sample was measured. Another part (20 .mu.L) of the pre-heated sample was pipetted into 10 mL of water for UV reading at 260 nM at 85.degree. C. (Cary UV instrument). The results are presented in Table 65 and indicate that most of the antisense oligonucleotides solutions are optimal in their viscosity under the criterion stated above. Those that were not optimal are marked as `viscous`. Specifically, ISIS 494372 was optimal in its viscosity under the criterion stated above.

TABLE-US-00065 TABLE 65 Viscosity and concentration of ISIS antisense oligonucleotides targeting human Apo(a) Viscosity Concentration ISIS No Motif (cP) (mg/mL) 494158 5-10-5 MOE 9.0 350 494159 5-10-5 MOE 11.7 325 494161 5-10-5 MOE 12.0 350 494162 5-10-5 MOE 25.8 350 494163 5-10-5 MOE Viscous 275 494243 5-10-5 MOE 28.4 325 494244 5-10-5 MOE 19.2 300 494283 3-10-4 MOE 13.4 300 494284 5-10-5 MOE 13.4 350 494285 5-10-5 MOE 23.1 350 494286 5-10-5 MOE 16.5 275 494301 5-10-5 MOE 17.1 325 494302 5-10-5 MOE 24.3 350 494304 5-10-5 MOE 49.3 275 494311 5-10-5 MOE 10.8 325 494337 5-10-5 MOE 29.5 325 494372 5-10-5 MOE 12.5 350 494466 5-10-5 MOE Viscous 275 494470 5-10-5 MOE 16.7 350 494472 5-10-5 MOE 23.6 350 498408 5-10-5 MOE 31.5 300 510548 5-10-5 MOE 9.0 350 512947 3-10-4 MOE 6.8 350 512958 5-10-5 MOE 26.0 350

Sequence CWU 1

1

13416489DNAHomo sapiens 1aggtaccttt ggggctggct ttctcaagga agcccagctc cctgtgattg agaatgaagt 60gtgcaatcgc tatgactggg attgggacac actttctggg cactgctggc cagtcccaaa 120atggaacata aggaagtggt tcttctactt cttttatttc tgaaatcagc agcacctgag 180caaagccatg tggtccagga ttgctaccat ggtgatggac agagttatcg aggcacgtac 240tccaccactg tcacaggaag gacctgccaa gcttggtcat ctatgacacc acatcaacat 300aataggacca cagaaaacta cccaaatgct ggcttgatca tgaactactg caggaatcca 360gatgctgtgg cagctcctta ttgttatacg agggatcccg gtgtcaggtg ggagtactgc 420aacctgacgc aatgctcaga cgcagaaggg actgccgtcg cgcctccgac tgttaccccg 480gttccaagcc tagaggctcc ttccgaacaa gcaccgactg agcaaaggcc tggggtgcag 540gagtgctacc atggtaatgg acagagttat cgaggcacat actccaccac tgtcacagga 600agaacctgcc aagcttggtc atctatgaca ccacactcgc atagtcggac cccagaatac 660tacccaaatg ctggcttgat catgaactac tgcaggaatc cagatgctgt ggcagctcct 720tattgttata cgagggatcc cggtgtcagg tgggagtact gcaacctgac gcaatgctca 780gacgcagaag ggactgccgt cgcgcctccg actgttaccc cggttccaag cctagaggct 840ccttccgaac aagcaccgac tgagcaaagg cctggggtgc aggagtgcta ccatggtaat 900ggacagagtt atcgaggcac atactccacc actgtcacag gaagaacctg ccaagcttgg 960tcatctatga caccacactc gcatagtcgg accccagaat actacccaaa tgctggcttg 1020atcatgaact actgcaggaa tccagatgct gtggcagctc cttattgtta tacgagggat 1080cccggtgtca ggtgggagta ctgcaacctg acgcaatgct cagacgcaga agggactgcc 1140gtcgcgcctc cgactgttac cccggttcca agcctagagg ctccttccga acaagcaccg 1200actgagcaga ggcctggggt gcaggagtgc taccacggta atggacagag ttatcgaggc 1260acatactcca ccactgtcac tggaagaacc tgccaagctt ggtcatctat gacaccacac 1320tcgcatagtc ggaccccaga atactaccca aatgctggct tgatcatgaa ctactgcagg 1380aatccagatg ctgtggcagc tccttattgt tatacgaggg atcccggtgt caggtgggag 1440tactgcaacc tgacgcaatg ctcagacgca gaagggactg ccgtcgcgcc tccgactgtt 1500accccggttc caagcctaga ggctccttcc gaacaagcac cgactgagca aaggcctggg 1560gtgcaggagt gctaccatgg taatggacag agttatcgag gcacatactc caccactgtc 1620acaggaagaa cctgccaagc ttggtcatct atgacaccac actcgcatag tcggacccca 1680gaatactacc caaatgctgg cttgatcatg aactactgca ggaatccaga tgctgtggca 1740gctccttatt gttatacgag ggatcccggt gtcaggtggg agtactgcaa cctgacgcaa 1800tgctcagacg cagaagggac tgccgtcgcg cctccgactg ttaccccggt tccaagccta 1860gaggctcctt ccgaacaagc accgactgag caaaggcctg gggtgcagga gtgctaccat 1920ggtaatggac agagttatcg aggcacatac tccaccactg tcacaggaag aacctgccaa 1980gcttggtcat ctatgacacc acactcgcat agtcggaccc cagaatacta cccaaatgct 2040ggcttgatca tgaactactg caggaatcca gatgctgtgg cagctcctta ttgttatacg 2100agggatcccg gtgtcaggtg ggagtactgc aacctgacgc aatgctcaga cgcagaaggg 2160actgccgtcg cgcctccgac tgttaccccg gttccaagcc tagaggctcc ttccgaacaa 2220gcaccgactg agcaaaggcc tggggtgcag gagtgctacc atggtaatgg acagagttat 2280cgaggcacat actccaccac tgtcacagga agaacctgcc aagcttggtc atctatgaca 2340ccacactcgc atagtcggac cccagaatac tacccaaatg ctggcttgat catgaactac 2400tgcaggaatc cagatgctgt ggcagctcct tattgttata cgagggatcc cggtgtcagg 2460tgggagtact gcaacctgac gcaatgctca gacgcagaag ggactgccgt cgcgcctccg 2520actgttaccc cggttccaag cctagaggct ccttccgaac aagcaccgac tgagcagagg 2580cctggggtgc aggagtgcta ccacggtaat ggacagagtt atcgaggcac atactccacc 2640actgtcactg gaagaacctg ccaagcttgg tcatctatga caccacactc gcatagtcgg 2700accccagaat actacccaaa tgctggcttg atcatgaact actgcaggaa tccagatcct 2760gtggcagccc cttattgtta tacgagggat cccagtgtca ggtgggagta ctgcaacctg 2820acacaatgct cagacgcaga agggactgcc gtcgcgcctc caactattac cccgattcca 2880agcctagagg ctccttctga acaagcacca actgagcaaa ggcctggggt gcaggagtgc 2940taccacggaa atggacagag ttatcaaggc acatacttca ttactgtcac aggaagaacc 3000tgccaagctt ggtcatctat gacaccacac tcgcatagtc ggaccccagc atactaccca 3060aatgctggct tgatcaagaa ctactgccga aatccagatc ctgtggcagc cccttggtgt 3120tatacaacag atcccagtgt caggtgggag tactgcaacc tgacacgatg ctcagatgca 3180gaatggactg ccttcgtccc tccgaatgtt attctggctc caagcctaga ggcttttttt 3240gaacaagcac tgactgagga aacccccggg gtacaggact gctactacca ttatggacag 3300agttaccgag gcacatactc caccactgtc acaggaagaa cttgccaagc ttggtcatct 3360atgacaccac accagcatag tcggacccca gaaaactacc caaatgctgg cctgaccagg 3420aactactgca ggaatccaga tgctgagatt cgcccttggt gttacaccat ggatcccagt 3480gtcaggtggg agtactgcaa cctgacacaa tgcctggtga cagaatcaag tgtccttgca 3540actctcacgg tggtcccaga tccaagcaca gaggcttctt ctgaagaagc accaacggag 3600caaagccccg gggtccagga ttgctaccat ggtgatggac agagttatcg aggctcattc 3660tctaccactg tcacaggaag gacatgtcag tcttggtcct ctatgacacc acactggcat 3720cagaggacaa cagaatatta tccaaatggt ggcctgacca ggaactactg caggaatcca 3780gatgctgaga ttagtccttg gtgttatacc atggatccca atgtcagatg ggagtactgc 3840aacctgacac aatgtccagt gacagaatca agtgtccttg cgacgtccac ggctgtttct 3900gaacaagcac caacggagca aagccccaca gtccaggact gctaccatgg tgatggacag 3960agttatcgag gctcattctc caccactgtt acaggaagga catgtcagtc ttggtcctct 4020atgacaccac actggcatca gagaaccaca gaatactacc caaatggtgg cctgaccagg 4080aactactgca ggaatccaga tgctgagatt cgcccttggt gttataccat ggatcccagt 4140gtcagatggg agtactgcaa cctgacgcaa tgtccagtga tggaatcaac tctcctcaca 4200actcccacgg tggtcccagt tccaagcaca gagcttcctt ctgaagaagc accaactgaa 4260aacagcactg gggtccagga ctgctaccga ggtgatggac agagttatcg aggcacactc 4320tccaccacta tcacaggaag aacatgtcag tcttggtcgt ctatgacacc acattggcat 4380cggaggatcc cattatacta tccaaatgct ggcctgacca ggaactactg caggaatcca 4440gatgctgaga ttcgcccttg gtgttacacc atggatccca gtgtcaggtg ggagtactgc 4500aacctgacac gatgtccagt gacagaatcg agtgtcctca caactcccac agtggccccg 4560gttccaagca cagaggctcc ttctgaacaa gcaccacctg agaaaagccc tgtggtccag 4620gattgctacc atggtgatgg acggagttat cgaggcatat cctccaccac tgtcacagga 4680aggacctgtc aatcttggtc atctatgata ccacactggc atcagaggac cccagaaaac 4740tacccaaatg ctggcctgac cgagaactac tgcaggaatc cagattctgg gaaacaaccc 4800tggtgttaca caaccgatcc gtgtgtgagg tgggagtact gcaatctgac acaatgctca 4860gaaacagaat caggtgtcct agagactccc actgttgttc cagttccaag catggaggct 4920cattctgaag cagcaccaac tgagcaaacc cctgtggtcc ggcagtgcta ccatggtaat 4980ggccagagtt atcgaggcac attctccacc actgtcacag gaaggacatg tcaatcttgg 5040tcatccatga caccacaccg gcatcagagg accccagaaa actacccaaa tgatggcctg 5100acaatgaact actgcaggaa tccagatgcc gatacaggcc cttggtgttt taccatggac 5160cccagcatca ggtgggagta ctgcaacctg acgcgatgct cagacacaga agggactgtg 5220gtcgctcctc cgactgtcat ccaggttcca agcctagggc ctccttctga acaagactgt 5280atgtttggga atgggaaagg ataccggggc aagaaggcaa ccactgttac tgggacgcca 5340tgccaggaat gggctgccca ggagccccat agacacagca cgttcattcc agggacaaat 5400aaatgggcag gtctggaaaa aaattactgc cgtaaccctg atggtgacat caatggtccc 5460tggtgctaca caatgaatcc aagaaaactt tttgactact gtgatatccc tctctgtgca 5520tcctcttcat ttgattgtgg gaagcctcaa gtggagccga agaaatgtcc tggaagcatt 5580gtaggggggt gtgtggccca cccacattcc tggccctggc aagtcagtct cagaacaagg 5640tttggaaagc acttctgtgg aggcacctta atatccccag agtgggtgct gactgctgct 5700cactgcttga agaagtcctc aaggccttca tcctacaagg tcatcctggg tgcacaccaa 5760gaagtgaacc tcgaatctca tgttcaggaa atagaagtgt ctaggctgtt cttggagccc 5820acacaagcag atattgcctt gctaaagcta agcaggcctg ccgtcatcac tgacaaagta 5880atgccagctt gtctgccatc cccagactac atggtcaccg ccaggactga atgttacatc 5940actggctggg gagaaaccca aggtaccttt gggactggcc ttctcaagga agcccagctc 6000cttgttattg agaatgaagt gtgcaatcac tataagtata tttgtgctga gcatttggcc 6060agaggcactg acagttgcca gggtgacagt ggagggcctc tggtttgctt cgagaaggac 6120aaatacattt tacaaggagt cacttcttgg ggtcttggct gtgcacgccc caataagcct 6180ggtgtctatg ctcgtgtttc aaggtttgtt acttggattg agggaatgat gagaaataat 6240taattggacg ggagacagag tgaagcatca acctacttag aagctgaaac gtgggtaagg 6300atttagcatg ctggaaataa tagacagcaa tcaaacgaag acactgttcc cagctaccag 6360ctatgccaaa ccttggcatt tttggtattt ttgtgtataa gcttttaagg tctgactgac 6420aaattctgta ttaaggtgtc atagctatga catttgttaa aaataaactc tgcacttatt 6480ttgatttga 64892150001DNAHomo sapiens 2atctttcagc ctctatatta ttttattgtg atttttaatt tccttgaatt ggattttgcc 60attgtgctaa atcttgatga tcttcatttg tatccgtagt ctgaattata tttctgtcat 120ttgagttagc tcagtcttgt taagaaccct tgttggaaaa ctggtgcagt tgtttggagg 180acatatgacc ttctggccat ttgatttatt ggagttctta cgttggttct ttctcatgtc 240tctgtgtggg tgtttcttta actgcagtgt agattgagta cagccaatag acttcttctt 300tggaggtttt cacagggcca aggccttgta cagggtcttt atttgtagct gacttcttgt 360ctttggtttc atagtggggc atgttagcaa aatagttttg ctgttgaagt tttggggtgt 420gatccatttt ttattttaat gattgtgtat ttcctttata cctaaaacaa gcagaaaacc 480agtaaaggtc tttgagtctc tgaattcata actccagcat tcatattgct tcctcaggta 540agtggggttt tcacccagcc cttaagggtg ttagattatt ttttatgtga aattagccag 600attgtatttc taaacatgat gtaaaacaat aatgacaaaa gttataataa actagccttc 660ttaccaaatc cacatgtcta atgtgtgtgg gagggtgtta ggcaggggac ctgcagctaa 720gggagaggca gacaggcccc atggccccaa atctaggata gtatttggta ttggttgatg 780ggtgagagaa agagagggaa catctgtgca ggatgtggta tcagcacctg gactacatct 840tagggattcc ttcttcattt ttcagtatgc cctgacaata attatatcta tcagacttac 900ccccttgacc actggaacac taagactgtt ttgggatctc tgcctgactt tctcagaggt 960gctggtgagg acattatgag tctggaacct agaaaagcgt tctgactctg ctgactttct 1020cagaggtgct ggtgaggaca ttatgagtct ggagccctag aaaagcgttc tgactctgcc 1080actagccaga cagacctgga ctaggcacgt taactctttg tatgacttga ctccaacccc 1140tcatttgtaa aaccagcatt ttcaagtggt gttttccaca tcagcctttt gcataagctg 1200tcatttgaag aaaggttttt gtttgtttgt tttttgttta acaaaaaggt taaaaaccac 1260tggtctagat aattgcaaag tttgctttcc tttttctgtg ctttttctac tatttttaaa 1320atgtcatcct ccttggtttc ttgatccccc tttctgcact cctgagtctg ggaacactga 1380ggccaactaa aaggaaactt ggcaaaagag gaacaccttt gggtgtgcca ggctgctccc 1440agtgttttgc acttataaaa atttaaatgc tgcaaacctc taagacttag atattattgt 1500tcctatttta caagtgagga acctgaggct cagagaaggt gcaggatggc acagggagac 1560ctgaattgga accctggttc ccacttactg gctgtcggga cttagaaaag tcatgaactc 1620tcattgattg ttttcttata tgaaatgggg gctgcagggt tgtcggggga gaaacaataa 1680gaatgtgcat caagtgtcga gcacgtgcta cgcactccat catggcagct cctactaata 1740tacagaatag agttgtatct aacatgactc tttcttgcaa gtgacagaaa atccaactta 1800agatggatta agcaaaaaag gggaattctt gttgagctga aaagtcttta ggctcacatg 1860atggccccag ggcccaggcc ctgtccagcc atgcagtagg catcatcctt gggcacaaag 1920gtgagattct tgtggtggca gatgctgtgg cagctcttgc tttgccagga aagactgagg 1980aaggccactg tccccattaa gtgaacaata gttggccagg tctgagaggt tgaacttggg 2040tcacaggcct gtccctgaac ccatcactga ttggctccaa cctgcatcag ctattacatg 2100ctagaggtgg aggcaggacc ccactcatac ccagaagggc aaagggtgga tccctcaaca 2160ggattatggg atgtagggtg atagactgct gggcagccag aaagcaaaca gatcctctcc 2220aatacctcaa ctgatgaaag caccaagcta aaatcataag gatctgggtg tgaattctgg 2280ctctaccatc ttccatgtga cattgggcag ttatttaatc tcttttagcc ttggctttct 2340tacctgtact aacatataag gtgattgtga tgagcatcat catcgtcaac atcatcatca 2400ccatccacat tgccaccacc actcccatta tcatcttcat caacatcatc accaccgcca 2460ccatcaccat tatcattacc accaccgcta tcactattat catcaccctc aacatcatca 2520ccatcatcac tatcatcacc accaccatca tcgttactac cactaccacc accatcatca 2580ccacagccac caccaccatc accatcatta ctactcagca ccaccatcat cattccacca 2640ccatcaccat cattccacca tcaccattat cattaccacc accactgtca ctattatcat 2700caccctcaac atcatcacca ccaccatcat cattactacc accaccacca ccatcaccat 2760catcatcatt ctaccaccat caccattatc atcaccatca ccatcaccac cgctatcatc 2820atgataatca ttatcattac caccaccatt agcattatca ttaccaccac catcactatc 2880actatcacca tcaccacgac cactaccacc atcaccaaca ccatcattac tacccaccac 2940caccatcatc atcattccac caccatcaca attattacca ccaccaccat caccaccacc 3000accaccatca ctatcatcat cagtagacat catataacca gtttgtagct ggcccagagc 3060ctacttgctg tttcttctgc cccacaacca tccacacatt tctaaccacc atcccccact 3120aggcttctgc ctcgcctggt ctcacctgca ggtccactga gaaaatgatt ctcagaacac 3180taactagacc atgaggtgcc acaaaacata actcaggcct gttcatcaat tttctacatg 3240tcaataatga catcaggtca attggcgttc tcagcctctg agagggaggt caaagttttc 3300ctgctctccc cttcatgttt ccaggtgttc cctgacttgg atcaaatgca gagtttggag 3360gtgttgaggc caaggggatt ttccaggtca gtcgtcatcc acaatcaatg gactgatcct 3420gccgctggac ttaccctgct gccctctccc caaggcccca tcagggaggg cttcaatcct 3480cttgtcacct gtggcctacc tgccctcaga gatgacatct ctatgtcggc cactggatgg 3540cagcacctac tcgcagacca catcaacttt cctggcaact tgcggtaggt tttcaccatt 3600atcaggatgt ttgccttgct caaatagcag attctagaga acggtgctcc ctcacacaac 3660tatgtagtcc aggtgatgca ccctctgccc gatgcttggt agtcagaaac ttccatcatg 3720cagctctgcc cagattgagc tgagctggcc tctggagtga ggtgctggga caaacatctt 3780ccatgctgct catgtcaact ccagatgcag tcaggtttct gaaccaaagt caatgatcta 3840agtgcagtca aaggctctgg gggaagaaag agagagtgcc tcatctcttg cctgtgccat 3900gctcgcaaag caaggatttt tgcaaaattc taatgaaagc tgggcttgca aaattagaaa 3960actggattat ttgtgagaac actgaaacat ccctgggtgt gtccatctgg aaaaacagca 4020tttcctctgg caattttgca accgttctat ttgaatttgg caaagaaaat aaagcagttt 4080ttcacaaaag aataaacaca accaggagaa tcttcactct cccaaattgt caaagaagta 4140taaattagaa aatgaatcag gacaatttca acctgttaga ttagctaata tttaaaaatt 4200gaacactcat acaagtgtgg tgaagtgatt gttttctagt gacattttac actgtcataa 4260ccttctagaa aataaattgg cagtgttatt gggagacaga aatatgtcta tataatttat 4320gggaacttag gctcagaaaa tattaaggaa taagaatgaa ctttatgaac aaagatgtgg 4380agggttggaa gcaagagggg ggccaacgcg cacggggagg aagcatttgg gcagtgactc 4440cgcagaccca ggctcaggtt gaactagaca acctccttac acctcagttt ccttaactgt 4500agagcaggag tgatggaact gcctgtttca taggactgtt gtgaggatga agtgagatac 4560accacattat aagcttgtgc ctggaaagga taatgcttag taaatgatga ctattctttt 4620ttattgcaat aaaatgtaca cagcgtaaga gttactattt taaccatttt tgcagggtac 4680caccaagtgg catttagtac attcacagtg gtgtgcaacc atcatcatat ttccagaata 4740ttttcctcat ccccaaagga aacctcatgc tcattaatca gtagctctcc tttaaaatat 4800tagttatgaa gatcatagca ctatacaaaa ctcattatgt aatgttgagt gaaaaaatca 4860gggtgtgaaa ttttgtgata tgatgtaatt agtgaaagaa gcatacaaaa agtctgaaaa 4920tataaaaaca atagcaattg catttctcag actctacatt taaacattat tctttatggt 4980tttaaaagca aagaaaaagg taaagaaaca acaaccaacc gcaaagcacc atgacaaagc 5040tcagattgtt aaatccaggt ttttggaaca tagactctta tatgacgttt acactctcca 5100gggttcagag agtctggcag cattgggagc tgccttgtgt tctacagcct cacggacaga 5160caggaggtcc atcaccactg ctctgttctt ctggagtttc cttgtgaaca tgttgtggac 5220gtagttacca tttctttcat ctttttaaac acaggtacct ttggggctgg ctttctcaag 5280gaagcccagc tccctgtgat tgagaatgaa gtgtgcaatc gctatgagtt tctgaatgga 5340agagtcaaat ccactgagct ctgtgctggg catttggctg gaggcattga cagttgcaag 5400gtaagaaaag atcaagagac caaagttagt cttgtgctct cctgtctcag tctcagtccc 5460ttagacttga gtcccaaagt agcgaattca agtaggattt aatcaatgga agaccccagt 5520ctaagtgttg ctcagaaact ccctagatct gtcccaaatg tatattcaga tcatccaagg 5580ggacttcttg gggcttgagt tccagatcag cagcaaggga gccataagtg ccataactac 5640ctcagaccac tcaccctcct ggggtgtccc ggtggccagg gactaaagtg gtgatttttc 5700tggtagggaa ggaggtagag ggtacaggac agagactaac tgcacacaat atctgagact 5760ggagctcaga tattgctgat gatcagagtt ggcgtgtctc cccaattgat ttacaactgg 5820ggcttggata ctgttttaaa cgggaggagc ctcctaacca tcttgacaca accactgacg 5880tgactacact agagatagac tctttccact taattctacc actcttgctt tacttcatga 5940gaacgaaaat gtaagattgc accatgaatt catttgcgga aagattgata ctatgctttt 6000attttatttt attttatttt attttatttt attttatttt attgagactc tcaccccggt 6060tgaagtgcac tgacgtgatt ttggctcact gcaacttcca cctcctgggt tcaagtgaat 6120actccagcct ccctagtagc tgggattaca ggtgcccacc accacgcctg gctaattttt 6180gtatttttag tagagatggg gtttcaccac attggcctgg ctggtctcaa actcctgacc 6240ttgtgatcca cctgtcttgg cctcccaaag tgctgggatt acagagttga gccaccgcac 6300tcgaccctat gttttatttt taaaaatatt tatttattta tttaagccac aactactaga 6360ataggaagga ttgatatttt attaatttta tttggtattt attatttttt tttctttcct 6420gagacattct tgctctgtca cccaggctgg agtgcagtgg cacattcttg gctcactgca 6480acctccatct cctgtgttca agcaattcta gtgcctcagc ctacttagta gctgggatga 6540ctggcatgtg cctccacacc cagctaattt ttgtattttt tgtagagaca gggttttggc 6600atgttgccca ggcttgtctc aaactcctgg cctcaggtga tccatctgcc gtggcctccc 6660aaaatgctgg gattataggc atgagccacc accccctcct ggaaggattg atatcttata 6720acataattta taattacaga aaacatgtga gttcactagg aataaataaa ttttgaagat 6780aataaaagat tttcacttat gttgtcattt cggcacagtt tggtatagga tgtggagatg 6840ttaacattta tacctagctt gctcgtaaac taagacctga aagggttgtg tctatcagct 6900gcacccctgg gtagcgacac aacctcggga aggcctcagc cccctcctcg tacagcactg 6960cctgttggaa agcttgaggg aggctatgga tgtgcagcac ttggcagagg gtctggtcat 7020ggaagttacc agcaaatatg agctactttt atgattttat tttatccaaa agaaagagaa 7080tgaaagaaga ggggaggaaa caagactaat caggaaagat gaaggtctag gggtgaggga 7140aggagtaagg agacataaag gcaatgtgga gcagctgagg ggggaaatgg ctttcaccac 7200ttcccagcat ctattgacat tgcactctca aatattttat aagactctat attcaaggta 7260atgtttgaac cctgctgagc cagtggcatg ggtctctgag agaatcatta acttaatttg 7320actatctggt ttgtgggtgc gtttactctc atgtaagtca acaatgtcct gggattggga 7380cacactttct gggcactgct ggccagtccc aaaatggaac ataaggaagt ggttcttcta 7440cttcttttat ttctgaaatc aggtaagaca tagttttttt aaattataag aattattttt 7500tctcccacaa tgtagtaaaa atacatatgc catggcttta tgtgcaattc atttaatttt 7560tgattcatga aattcccagt tcaaaatctt gtatatgatt gaaaaattct taaaaaaata 7620agtttaattt ccccgtgaag actgtcacgg tgctggaatg aatgggcaga aaaaataatg 7680gttgattttt ctaatctaaa agagtgtgcc tacatgatgg ccagtctggc tgaaaaataa 7740atagccattg tagctaacta tgcaaaggat ggctaagctc ttcgcttggt tctcagtttc 7800attaatttat atcatctctg ttcaggtgcc atgctcccct cactagcaag ttgaaacaat 7860gaaataactc tttgaatatg tttggttcct tgacctgttc atggagtggg actcagcatt 7920tctctctttg ttatggcctg agtaaggctt tccatcggta tacatttgct tcttatccct 7980ggagaaatta tacacatcca tttgccagat gatatacgca tataatgatt caacaaatac 8040tcagggtatt tgttgagtgg gttaggtccc cacattttta tacatacata cacacataca 8100caccgtgtgt gattgtgaat gtaagtgtgt gtcctttaca aatactagct tatttagctc 8160atggtatagg tagggtagca tagtcatccc cattttataa acaaagaaat ctagacttag 8220gaaaatcatg ttatttgtct cgtgaccaaa ttcccaaatc aaggaaataa agaaacctgg 8280atttaagcca gatttccaag aaaaaatcta gggctcttct cactttttca tctttgttcc 8340aacatttgaa aaaataaatc taaacacatt ccaatgtaac tgaagagcag gttaattgtt 8400tgccacttgc agaatccaat taagaagaga gaagtctggt ataaagaaag tgatttgctt 8460ccaaagctag cttaggggaa

gaaatgcagc agtcctgccg tactacttca ctttaggagc 8520agaaagtggc acttttaaaa ggcaacagag gaggcgagca aggattcagg ggtccatgct 8580agcttgggca ccttatccac caggtagttg agcagttgcc tgctggtgcc tttgtgagca 8640gggtgttgtc ccttgaggca aatctctgga gggtgagagt tttgtagtgg gcatgctttg 8700gtttataaat cacctgtgaa ctcaggagtt ccatcttgaa gcacatacat agttagatga 8760acttgccctg cagggagagt ctgatgaaag ggaggtagat gcttgcaatt taatctataa 8820attaccagat aaaattttac aagttgactt taaagtcaaa cacatttgaa tttagtggaa 8880gccattcaag aaaatatcaa agaaaataca gagcaggaga agattaagca aagagttttt 8940tggggaaatt ggtgtctatg tctgtgtgtg tagggagtgc aggggatatg aatattctat 9000ttcagcccat ggaaactagg atgtagatca ctgtgaactt attcagcagg ctacacccaa 9060aggctagaac aaacttctct gccacaggat taacatatgt tttaatcgac ctggggggca 9120cattctctga taagctcttt tggaaagcca ggctttctgt ggacgtgtta tctttccaat 9180gtgtgctgga atgcccgggg agaggaaaaa gtttctttta cagccatgct cagtgagaag 9240cggagaaaca tcttctattc acaaattgct aagtctttta cacatgcaaa tatgcataca 9300cattcacaca ccacagtgag gaagaaattc tcacaccatt aataaaatac atttacttca 9360gtagcaatat acatctacat tttgcctata atataaaagt atttttccta ttaaaagatt 9420tgtttaatgt ttcttcacca acaaataaac cctattaaat ccccattgcc atatgagccc 9480tggaggtgaa tcagagaaac aaaaggattg tggaaaaatc atcaggttaa aaaaagaaaa 9540attgattctg ttttgggata tttcctagca acatgagctg gggaggggat ctcagcagtg 9600atgctctatg aagcataata aaatgacaca gttacaggta acttagttaa agggggaaat 9660aaatggaagt ttcctctttt tgaatatcaa ttgtagcctg ctctgctaca tttcaaaaac 9720actcttcaaa atgtttaact gaactcactg taggaagcac cttattaatt tattgtgtgt 9780tttgaagtca cactgtgagc tatagaattt acccaagcac aactcttcct ggaaaagaga 9840gttcaaatga gaaacagtgc ggggtgaaga catggatatg ggcctaaaat atctatttct 9900caatgatatt ttgatatatc tatcaagtgc tttttagtgg attaggttca gaatgcatca 9960gccaatgcct gttcaataat ccagttttcc agcatagagc atattaaatt gaggaaggac 10020aaagtcacag aggtggggag caggtggact gtggccaagg actttgcatg aaacagtgag 10080cgtgcatcct cctccttgcc ctgccctcat ggtctgtgta ctctcaggag gtcaggacag 10140gcctttctga gaatgagaat ctgttcatct gcctttctac tggatacttg tcatcggcat 10200acaaacacat gttctctgca gtgtgtcatc tttcagaacc tcccctgacc ctgtattccc 10260tagaagtctc gctgctttca gagccaggct tctctcctgc tgccaccccc actgctcttc 10320tagtcactct ttaacccact ccatctgcat gtggccccca ccacacccct caaagtggtc 10380aaggttgtcc tgttgcttaa ttccatggaa gcttggctat cttcatttta ttagcctctt 10440ttggcctctc accctgtgaa aatcactaca ttttgtgcca gagatggagc tggcatctcc 10500aggcttggaa gagggctgct gaagctcagc caggtgtcct aaggagcctc aggacagggg 10560atgctcagta gccttgcaat gggaacacag ctgagcccca cttggccacc ctttgccaca 10620accaggcaga aagcagcttt tgaacagatt tgttgcctca gatttgatct caaagaaaaa 10680tcgtgggcag tattggtccc aggttctgct tttttacaat ttcctctgaa atctggatgc 10740ctatcaacac cttggaaaaa ctgaattctc cccaactaat agtggtgtgt cactgtagta 10800agcctagtac aaaaatggcc ttctttgtgg aggagcttca tatcctccat tttttttttg 10860cttaattttt gcccaagatg agaacataat ttagttcact ttttatttat tcccaacatc 10920atccatgcac caacattttt gtaactaaag gagggaccat tcagaagatg cttatcaact 10980gtcaaagtga cagtgttaca accaatgcac atattgtaag aaatcaaaca atggcctcca 11040aggttcattt ctacacaggg attagcagat caacatcaat cttggcaaca cagttgccac 11100tgatggtgtc ttattttttt tatcatgaca tggcaatcaa gagcaaacat gatttattct 11160tatttaagat tttatggtta gactaggcag atagctagat atgagcagga ggtggaagcc 11220cctgagagaa tggaggtctg gagaatctga aaccccagag attacccaag tcctgcatgc 11280tagacatgag tggaggaggg ggaataccta ggtagaaaag aatgcccctt aagatgccca 11340gcagtcgctc actgtgcagt taacttttca gaatgctgct agatacatgc tgatagggag 11400ggaagagggc aaaggagaaa ttcctaagag atacacggtt gcagttagta tacatctgag 11460tgctatacaa ccttctttgg gtggtggcaa gaagcaatgc agccattacg tagaattcat 11520atcaaacacc tgtatcacag gtgttaaaga aacaagaaac attgtacttc ttgtattctt 11580aataatgatt tgcaatattg tctttagtat cactgcaaac ctctataaat atgattttta 11640aaaagtattt ctttaggttg gaattacttc tacgcattga cttatcttcc tgggtttcat 11700tagccgtacc cgttgtactt tcttccttac cactgtttat ctcaaactct tgagattaaa 11760gtatgggctc aggagggagc gaggagcttc aggactctca cggacctcca gcacagtgta 11820gctgccttat ggaaaagtgg ccacactgtt ttctgcactg gtccctgccc ctactattcc 11880tcactgggca gagcacagcc accctggccc tgcctgaaca ttttagtcag tgttggctct 11940gtgcttctct ggggaggaaa tccaagagac aacccacagc ccctctgcca tttcagctgc 12000agcagtacca ccgttaatgc ccttgggctt gagaaagaag ggacctggcc acttccctga 12060cacctccagc acacagcagg gaaagaattc cagtttctct ttcttgtgag ctttcacctg 12120ctactcttca ccaggcaagg ctcctggctt gggcccacag tgcaggcacc tcgaactcag 12180ttgaacattt ccactggctg cactctgtgt ttttgtgggg tgaagctccc agaggtgact 12240gaaagtcctt ctgccactaa cactgcagtc atactgccct tgctgtactt ggactaggga 12300aggaaaaaag atcctgagtg ctttactcac accccagtgt gccccagcca ccctatggaa 12360aagaggccag tgtgtcatcc ctgcaagcac cctgaggccc ctgcccctgc tgcccccaag 12420ctgtagagcc agaatataaa gctggcagaa aaatgtaaaa aggctagact ggcttagcct 12480cccagcctac atctttctcc tgtgctggat ccttcctgct cttgaacatc ggactccaag 12540ttcttcagct gtgggacttg gactgtcttc cttgctcctc agattgcagg tggcctatta 12600tgggaccttg taatcttgtg agttaatacc acttaataag ctcccctttg tgtgagtata 12660tctatatcta tagatagata taggtatact cactatatat acacatatat acatatactc 12720tctctctctc tctctcatat atatatatat ataatctcct attagttctg tccctctaga 12780gaaccccgac taatacagat tttcatacca gaagtggttc ttgaggaaca gaatattaag 12840gatggaattc tttcattggt tttgggactt ctggtgttgg ctgattaata tgattagacc 12900aaaaaatgct aaggactcta cttctaatag tatggagaac actgatagta cttggcctga 12960attgtttaga gagttatgca aaataaatgc atttgacact actgattcat cacttatgag 13020aggcaaggag tttagtgact ctatacataa tacctttgac tatatgtgga gaaccaagga 13080acataatgaa gttggttgat tgctcctaag ttctctggag aaagagatga aagaaaatga 13140tgatctcagg ggatctgtct cccaccttca gaagcagata ctgagccaca aatctgctaa 13200gattgccctg aatgagagtt ttaactcctg tagagaaaga gttgaaattg tgaaaaaaca 13260gagacaagct gttatcatgc gagtagctga tctgcaacaa gaggtgcatg cacagccttg 13320ccaggtgttt actgttaaag tgagggcatt gactggaaaa aaatgggacc ctggaacttg 13380gagtggggat gtgtgggaga accctgatga agctgaggac actgagtttg tgaactctga 13440tgaaactttt ttgccagaag aaacagtttc cccatcccca gtagtggtaa catcccctcc 13500ctgacccgtg ctgccattag cctttccacc tttgtctgag gatgtaaacc ctgcactgct 13560tgaggcaaca gtgatggcct tccctgaggc agctgccagg caagataatg ttgattctcc 13620tcaagaggca cccctaatgc ccctgaatgc ttctagacct ataactaggc taaattcctt 13680gcgggcccca gaggtgaggt tcagagtgtg acccatgagg aggtgcatta tactctaaaa 13740gaactgctta agctttctaa tttatattgg cagaaatctg gagaacaggc atgggaatgg 13800atattaaggg taagggataa tggtggaagg gacatagagt tggatcaagc tgaatttatt 13860ggtttggccc tactaagtag ggattctgca tttaatgttg cagctcgggg acttagaaaa 13920ggttctgata gggccgggag cagtggctca cgcctgtaat cccagcacct tgggaggcgg 13980gggcgggcag atcacgagat caggagattg agacaattct ggctaaaatg gtgaaacccc 14040atctctgcta aaaatacaaa aattagctgg gcatggtgat gcgtaactgt aatctcatct 14100acttgggagg ctgaggcaag agaactgctt gaacctgtga ggcagagatt gcagtgagcc 14160aagatcgccc cactgcattc cagcctggta acagagcaag actccatttc caaaaaaaaa 14220aaaaaaaaag ttataatagt ttatttgctt ggttagctga aatatggatt aaaagatggt 14280ccaatgttag tgagctggaa atgccttggt ttaatgtaga ggaagtgatc caaaggctta 14340gggagattag gatggtggag tggattagtc actttagacc tactcatccc agctgggagg 14400gtccagaaga tacacccttg gccgaagctt tgtgaaatag atttgtgaga gcagcacctg 14460tatttttgaa gagcccgtaa ttgctcttct ctgtatgtca gatctaacag taggaaccac 14520agtcactcaa ctacaaaatt taaatacaat gggaataatt ggatcctgag gtggcagggg 14580ccaagtgttg gcactgaacc atcaaaggca aggtgggcat aactaccata atagacagca 14640gaggcaaagc agccatcaga atagtctgac tcatgtagag ctctggcatt ggctaattaa 14700tcatggtgtt cctagaagtg aaattgatgg gaaacctact gtattcctac ttgatttata 14760taaacaaaaa actgccaggt agaatggact aaagactaat ctgaattata aaaacagaga 14820atcatgggcc ctcaatcaat ttccagactc gaacctgtta cagttccaga acccactgaa 14880tgaaggggag gctggatccc cttgaggaag gacaccacta ggctactgac aacttatgct 14940gttactcttt ctcccatcct tccctaagga gacctctggc cttttaccag ggtaactgtg 15000tgtactggag aaagggaagt aatgagacat ttcagaaagt actggacact ggctctgagc 15060tgacgttgat tccagggtac ccaaaacgtt attgtggttc cccagttaaa gtaggggctt 15120atggaggtta ggtaattaat ggagttttag ctcatttctg acttacagtg gttccagtgg 15180gtccctggac ttatcctctg gtcattttcc cagtgccaaa atgcataatt tgtatagaca 15240tacttattag ctggcagaaa tgccacattg gctccctgac tggtaggatg agggctatta 15300tggtgggaaa ggccaaacag aagccattag agctgtctct acctagaaaa ataaaaaaat 15360caaaaacaat atcccatccc tggagggact gaagtgatta gtgtcaccat caaggacttg 15420aaagacgcag gggtggtgat tcccaccaca tccctgttca actctcccat ttgacctgtg 15480cagaggacag atggatcttg gaaaatgatg gtggattatt ttaagcttaa ccaagtggtg 15540actccaattg cagctgctct accagttgtg gttttgttgc ttgagcaaat taacacatct 15600cctggtgcct ggtatgcagc cattggcttg gcaagtggct ttttctccat tcctgtccat 15660aagacccacc agaagcaatt tgccttcagc tgacaaggcc agcattatac ctttaccacc 15720ctacctcagg ggtgtatcaa ctctccagct ttgtgtcata atcttatttg gagagacctt 15780gctcgctttt cacttccacg agatataaca ctggtccatt acattcatga cattatgatg 15840attggataca gtgagcaaga agtagcaaac acactgaact tattggtgag acatttgtat 15900gccagaggat gggaaataaa tccagctaaa atttagggac tttctacctc ggtaaaattt 15960ctagggttcc agtggcatga gacctatgga gatattcctt ctaaggtgaa gcataacttg 16020ctgcgtttgg cccctcttac aaccaagaaa gaggcacaat gcctggtggg cctatttgga 16080ttttggaggc aacacattcc tcgtttgggt gtgttactct ggcccattta tcgagtgacc 16140tgaaaggctg ccagatttaa gtgcagtcta gaacaaaaga aggctctgaa acaggtccag 16200gctgctgtga aagctgctct gccatttggg ccacatgacc ccgcagatcc aatggtgctt 16260gaggtgtcag tggcagatag ggatgctgtt tggagccttt ggcaggcccc cataggtgaa 16320tcacagtgga gacctctagg attttggagc aaggccctgc cacttctgca gataactact 16380ctccttttga gagacagcta ttggtctgtt attgggcttt ggtggtaact gaacgtttga 16440ctgtgggtca taaagtcacc atgctacctg aacctgccta tcatgaactg gttgctttct 16500gacccatcta gccatgaagt gggtcagcac agcggcattt catcatcaaa ttgaagtggt 16560gtgtatgtga tcgggcttga gcaggtcctg aaggcacaag taagttacat aaggaagtgg 16620ctcaaatgcc catgttctcc actcatgcca ccctgccttc cctcccccag cctgcaccaa 16680tggcctcatg gggagttccc tatgatcagt tgacagagga agggaagact aaggactggt 16740tcatagatgg ttctgcacga tatgcaggca ccacccgaaa gtggacagct gcagcactat 16800atccactttc taaatgcatg tgtacacttg tgctaagaaa atatctttat tttatttcct 16860ttatttttcc tttatcatgt gaccttagat ttatggactt cacatcagca tttaagcatt 16920taagtgttgt tcatatcagc atttaaatat tgttaacctt atgtaataac ttttggtttg 16980gggattggtg cgtttctggt tgtatgagga tagttgtatt atattaggca taattatgac 17040cttattattg tctttatttg aagattatgt atgatttcag gatgtgtgta tgggttcaag 17100ttgacaagga gttggacttg tgatggttaa tactgtcaac ttgattggat tgaaagatgc 17160aaagtattaa tctcggttat gtctgtgagg gtgtggcaaa aggagattaa catttgagtc 17220agtgggctgg gaaggcagac ccacccttaa tctgggtaca caccatctaa tcaagttcca 17280gtgtggccag attgtaaagc agggagaaaa atgtgaaaag actagactga attagcttcc 17340cagcctacat ctttctcctg tgccaaatgc ttcctgctct tgaacatcgg actccaagtt 17400cttcagcgtt gggagttgga ctggctttct tgctcctcag cttgcagagg gcctgttgtg 17460gaaccttgtg atccgctgag ttaatactac ttaataagat cccctttata tacatataat 17520atattatatt atatataata tatataatat atattatata taatatatat aatatattat 17580atattatata taatatatat tatatattat atataatata tattatatat aatatatatt 17640atatattata tattatatat aatatatatt atatataata tatataaaat atatatatat 17700cctattagtt ctgtccctct agagaaccct gactaataca atttatgtca ttaatctcat 17760ttattgattt gtatacattg aaccaacctt atatcccagg aataaaacct acttgattgt 17820ggtggattag ctttttgatg tactcttgga ttcaattgct ggtattttat tgagaatttt 17880tgcatctgtg ttcatcaagg atattggctt gaagttttct ttttttgttg ttccatatca 17940gaatgatgac gacctcatag aatgagttag tctgtcctct tttatctttt ggaattgttt 18000caggaggctt gatatcagct cttctttata tgactggtat actttggcta ggaatctctc 18060tggtccaggg gtttttctgg tgtaggtttt taattactga ttcaacttca gaactcatta 18120ctcattattg agttctaaaa ctcactttca tgtactcttc aaaagactgt cttcttctgt 18180tgttgagcgg ggtgttctct caaggtcgtt taggtgaagg tggttgctgg tgttcttctg 18240tatccttact gcttgtcttt ctcttttttt attgactact gaggattaat ggtgatgtgt 18300ccaactttaa ctctagatta gtctatttct cttttagatt gtaactctgt tttatatatt 18360ttgaagctct gttgttaggc atgtgtattt ggattgttag gtcttcttga tgatgacctt 18420tatcattatg taatgtttct tcttatctct ggaagtattc gttgttctga agtctatttg 18480tgctgatatg aatacagcct tcacagctct attttcacta gtatttgtat atctttttct 18540cagcttttaa attgagatgt tcagaccatt tgcattaaag tagttgttaa taggattaaa 18600tttaaatcta ccattaagtt ggttatttct ctttgtccca tttaaacttt gttccttttt 18660tcatattttt ctgccttcat ttatattgag tttatctcca cgacttactt attaaattaa 18720tttttaatgg ttttagtatt ttccacaatg tttataatat atactttgat tttttcacat 18780tccaccttca aatgacagaa ttatactgga tatatagaaa tcttacatca ttgcacttct 18840ccttcctccc tctcaaaatg ttgtgctatt gctctttgta atagaggctt acttctatta 18900tgttatagct ctcataatac attgacacta tttttaccct gaataatcag ttgtttttta 18960aagtgattat gactacaaat attttgaata atttctttat tttaccattt ctggtgctcc 19020ttatctttta cagtagatcc caatttccat ctggagtcac attctttctg tgaaaaacaa 19080cctttagcat ttcttatagc acgggactgc tgttgctgtt gtctttcagc ttttctttgt 19140ctgaagaagt ctttattttg ccttcagttt ttaaaagtga ttttgctgag tatagatact 19200gggttgagag tttcattcct tgtatcattt taacaatgat gttccattat attccgtttt 19260gaatagtttc tgactagaaa tctgatcttt gtttctttgt attcaatagt tcctttttct 19320ctgactgcct ttaagatatt ctcatctttg tttttcaaca gtttgactat aatttgttta 19380ttattaactt tttgtattta ttctgcttga ggtttcctga gctccttgga tttgcagatt 19440gttgattttt attgtttttg taaaattcat agccattatc tattctactg ttttgttttt 19500tttttcactt ctctctctct gtattcttct ttttggactg taagtattca aatgttagat 19560cattcatatt gcttcataaa ccttatatgc ttcttctgct tttttttttt tgtcaggaac 19620tctttttttg tatctgtgtt ggtttggata agttctagta gactatgttc aagtttatgg 19680attattttgt tagttgtgtc taattgactc ctcagtgcat tcagagaatt cttcatctct 19740gatattataa atctcttcct agcattttca tgttactctt ttctatagtt tccatctctt 19800tgctgaaatt ctccccctat ccatggatat tgtccacctt taccacaaga ttctttaaca 19860tattaacata ggtatcatac aaacccaaac tgatagtttc cagatggtgt cttttctgag 19920tctgtctgtc ttgattgctt tattatttaa cagtgactta tcttccctct tcagcttttg 19980gtgtgtcttg taattgttta atcaaacact gggtatcata aatggaggaa cagtagagat 20040tgcagtaaat attatttatg ctttgaaatg ggcacccatc ttctgttgaa aatatgtttt 20100gtggtcaatt gagtcaacct agtaactggt tgaactgaat ttggcatttg tgcttgttgc 20160ttttatctta aatgcaccac aggtttaaat tcctccagtg atgggttgct gctatctttt 20220gcttagagtg gggcctgggg tgtggaagaa ttttctcagt gttcctatct attattagat 20280tttagcagtc actgcatgcc tgcactacag aggggatatc ttcatacaca taatctaacc 20340ccattgaaac tgctgtttct tcttaatgaa tgctcaatct ttggtggaaa taaacaaatg 20400ctgtatctcc tggagccact tcagtcttag tcaggttctg cagggctttg aagggaatgc 20460attctcagta ttcttgtgcc ttatttggat ggaacttgaa cctgtggtgg gtttggagag 20520aaagagtagc agacgtctgc tatgttgcaa tgcaggatgc tgggcacaag aaaatttcca 20580gtctctcctc caaggaaata agatttgatc atctacctat ccctgagaag tgaagggctt 20640tgcctgcggt gctagatgca aaaccatttt tctcccccca ttgcccagaa acttaaggct 20700ttggcttttc tgagcagtgg tctagggaat tgtgcaaggt tttcatattt gaccctgaca 20760gcccatcacc acctacagct tgcagtgcca aatgtatctc cctctgatct ctcctgtcct 20820gtggtcctca tgaacattaa gaagagattt ctaaaaaaga gcttgcacat gagcatagtt 20880tctggtgaga agaattctga tatgttaact tcctctaaac ttttaaataa aatatttcta 20940agaattaaat aaagttctag aatgatatga atctattcct ttggtttttt gcacgtctgt 21000ctgcctgcta atcaagagaa gagaatggtc gtaattctca gagacttttt cctgtttgtg 21060tcataaatga cttcacattt ttttctgttc taagaactat tcagcttgat ttcttctgtt 21120ttaattttag cagcacctga gcaaagccat gtggtccagg attgctacca tggtgatgga 21180cagagttatc gaggcacgta ctccaccact gtcacaggaa ggacctgcca agcttggtca 21240tctatgacac cacatcaaca taataggacc acagaaaact acccaaatgc gtatgtcatt 21300aatcttacag taagcaaaac aaggtccaag taaaatttgt cttagaaaag gtgtgcgtca 21360agctaacttc ttatgattaa atttttctca cacatagaat gcatggcaaa atgtctgaga 21420aacattactt tgagcaaaga gtatgataga agagaaatgt taagctggct ctctttcctg 21480agagtttgat aaaatcagga gaatatctgg cggtggtgag gccacaataa tggaaaatca 21540gaatgtttag acagagtcag cttcaacaac actcactaaa ggtcaatgtg atctttaccc 21600cttgaaattc tataattcta atctccaatt cctgaagtga aggttgtgtt ggccttttct 21660gtcttggctc acaagtaaat gatatgtgca tatctatgga aaggcgaatc tatctttttc 21720tatatctatg tctattccaa cgggtagaaa caccctgggt cctgagcacc agtggtctga 21780aggaatacgg gttgccagga agagagaagc aaaggcagga aggcagatga aagtaagaaa 21840tgagacagat gctaaacaat aaaaagtgcg ggaagataga cagaagctgg ggtctgacca 21900caccatggcc agtctttcac acataagtga ctaccaaaga caagaaaaaa tgatttccgc 21960ttgttggaca atagatggta gaggaccaag ggaattgcga gagagagaac aatgagatca 22020actcaacaga tgcactggtt ttcttcctgg agacccttcc tgcactgaag ggcaggagat 22080ggagcccaaa aaaaactgta gccatcttgc tgaacagagg agggacattg gagtttggga 22140ttattcaggt ggctaggatt ttctaggcct gctaacaatg agaacagatt tgtggaggaa 22200aggagttcta gaaatatgca tagaaatctc ctcgagtcat tggctaaaca tgaagctgca 22260tgtacacaga aaatagatcc acaagaaagt agggcaaaga acatctacgg aagagcagca 22320actacaatgg aacagtgagc tcaataaaca tgacagagct caaatagcac taagggatat 22380tggagtttgg accacacaga ggagagagac ttcactgaac atcttgggca ttcagtagag 22440acccaggaaa agccatactt taggagtaga attagtatat tcttagaata aaggcagctc 22500cacacaaaca atagcaaaac tgaaaaggaa gtctccaagc atcagaatga tgtccaagtc 22560aatgaactgc ctctgagagg aaaactcaac catctttaga ggtaaacatc aaagtcaagt 22620ggctcagcta tgcagtatcc acagtgtgag gcctaaatat aaaacttgac tacacataga 22680aaccttttag tgtgacccac aagcaggagg aaaatcagcc aatacaaaca gacccagaag 22740agacagaaat gattagaatg gcataaaaat ttgacatatc actatataat aattgagttc 22800taggatttaa gaaaacatga atatagaatg caacagacac cttatccaga gacagtaaga 22860gtataaagag ccaaatcgaa gaactactaa gagatatgtc ttaaatgaaa aaattactag 22920atggcctccc catctagtta gacatttcag aagaaaatac caaatgaaaa ataattgcat 22980agaacctaca gaaccagata cacacataca aaacacacgc atgcatacac acacactcaa 23040acatgtataa gcttacaaac acacacacac atccacaaat gctgaaaaat gaaatcaacc 23100gagccacaca gacataaagg aaaacataaa aagatttcct acatgtggga agcaagtcac 23160agaaaggggg aaggagattg gaacagaaat atatactgaa agcaaggatg gctgaaaatt 23220ttccaaatat aaagaagatt aaaaaatcac ggactcaaga agctcaatgg atcagaaaaa 23280taatttctaa aatgacaatt ataggatgcc actgggtaca tagcagttca actgtcagag 23340ggcaaagaca taatacacag aaaaatctcg taaggaacgg gaaaaacaaa aagctgtgtc 23400ttgctagagg aacagtgata caagtgacta atgtgttccc atcagaaaca ctgcaacctg 23460gacacaaaag aataacatta aagtaataaa cgtaagaaag aagagctcaa ctgagaaggc 23520tacatccagc aataaaatgc

cttgaagttc atccatgttg gaggaatgca cattgtgcac 23580tcccctaaac aaagaaaccg gaaactgtaa gactttggaa tcagcaggct tatgtaacaa 23640aagaggtgac cctaaggaat taaggagaag aagaatagaa caagaaggga actttctgca 23700gcctatataa tgaagaacct agcaattggc aaatgtagat gaaaatgcta catgttttct 23760tgatcaaacg tttatatctt tttaaatgag agttgacgag ttgaagcaaa atgataccaa 23820tatatttaac tttaccatat gtagaagtaa aaatttgaac atgtagcata aatcatgtag 23880ggattaattg gaagtgtacc actgtaagtt tcttacctca tgcacgatag tatgtaatac 23940taataaaagg ttaatgtgtg ggttcaaagg gatattgcaa atcctagagc aatcacaaag 24000tttttaactc tgaggtttgt tgtataataa caatatttta tgtattcaaa agagggaagc 24060caaggaagaa aaaaaagtct ttaaagagct ctggctctta gtacatccag ttgctcattg 24120aatgagcttc ctggaatgga gggtctggga ctgagactag gccacatgtg tagagccact 24180agagacacaa tgttggatcc ccatggccca taatacattt cccattttct caggcagcca 24240caggtcatga atgtgaggat actgagaggt tggagcaacg ttcttgggag gcataaggaa 24300gagcgaatgc ttcaagatcc ccgcagccca aactcctcag ctgctttgcc tcctaattca 24360ttgttttttg ctcctccata gctgtccgac ctcttcagat ctcttagtct tcctgccatc 24420ttcctttatg ccatgggacc cactgttctt tcaactcatc ccccagttct ggagtggctg 24480tggacagcag aggatagact gagagcagga gagaaggtcc tgcccaggaa cccattctag 24540agatactgca ttctgcctgg gagcaagttt tccagggcag ctttgagaag tcttgcagaa 24600acaaacctac ttgaccgaca tgatatggga atgacagaca gtaatactat ttgcacaatg 24660cttttccatg ggaaaggtag agccttttca ctaggttttg agtacatgga gtgtgagagt 24720tgacctggaa aggttatcct ccttgatgcc atgttttctc tgaagaacta catgttcgtt 24780gcaactccca cattagaata tgaagtccta ccgagagaga tacggagact agacagatac 24840agatgcattt gcatgtgaat acacaatccc acaatacaga cgtcaaaacc cataccagtt 24900attccagaga gatggattgg gcagaaggca gaaggagaat actctgatcg tttttcggcc 24960acgtgtgtgt gttatctcag tgtttctaag aagcgtttgc tactttagat tttttattta 25020aaaaaaatag taataatcta ttaagtatga gagatgtgca gagaggatta gtgatcgaga 25080gccatttttg ctggtggcaa tcatatggta cttttaatgg gaatattaga aaggcaccgg 25140taatgacctt gttgcagcac aaaggagaga gtgtggggtg cccctgcatg ttgtcccacc 25200tcttgtgacg tgtatcgttt tggaatttcc agtggcttga tcatgaacta ctgcaggaat 25260ccagatgctg tggcagctcc ttattgttat acgagggatc ccggtgtcag gtgggagtac 25320tgcaacctga cgcaatgctc agacgcagaa gggactgccg tcgcgcctcc gactgttacc 25380ccggttccaa gcctagaggc tccttccgaa caaggtaagg agtctgtggc cagacatcta 25440cacgcttcga tgctgggatg aaaagccatg gaaattccca ctgatgcagc cgccttcaat 25500ggtaaacgga tgctcgagtg ttgcctgagt tctaccatgt aggaggaagc ctccgtgcac 25560tctctggggg agccagcgga gtgatttctg gtgcaacgtg gttgggcttt gtctttagga 25620tgggcacaaa ccctccaggg ggatcgactt caaaattcac cttgttgtaa aacgggctac 25680ctcagtgtcc cagccaaaat ttttattgta acatgctgtc aggtgtgtca ctctttccaa 25740gccagtaagc ttttccgggg atttcttcaa gtagccagca ttcagagcaa tcttcagcat 25800tgcagattct gagaaatgtg gctctggagc ctgtcaccct cgagaaacct aagagggctg 25860cattgattcc atgtggccct gggtctatgg agcagtacat gagctcccag tgctctaagg 25920ctcttcagcc ctaggctttg aagggagtga tttctcagta ttcttaaacc tctttctgat 25980gacacttgta cctgtgaggg gtctagagag aaagagtagt agactcctac tttactacaa 26040ttcaggatgc agggcatgag aggattccct ctctcctcca agggaagaag cttttggcgt 26100gcacacatcc ctgagaagca aagtgtcttt gtcttcagtc agatacatag gaccgttttc 26160tgccccatgg cccggaagcc aaaggccttg gctttcatga tcaacggtct agggaaacat 26220gcaaaatttc catgtctgtc ccaaactctg cccccgacag ccaattacca cctgcagccc 26280gcattgccaa atgcggtgcc gtttgcatga agattcagta gagtttccta gaaaggtgct 26340acctcgtgag ctcactttcc aatgaggaat ctgatctgtt gtgtttctct aaggtgtcag 26400gtgaaatatt tccaagaact tactacagtt ctagaatggg aggaatctgt tgctttggtg 26460tttgtttgtt ggtcggtttt ctcacatcca tctgcctatg gataaggaaa agagaacggt 26520cgtaattctc atagactcct ttctggttgt gtcacaaatg gcttcacatg tttctctatg 26580ctcagagata ctcagcttga tttcccgtgt tttcatttca gcaccgactg agcaaaggcc 26640tggggtgcag gagtgctacc atggtaatgg acagagttat cgaggcacat actccaccac 26700tgtcacagga agaacctgcc aagcttggtc atctatgaca ccacactcgc atagtcggac 26760cccagaatac tacccaaatg cgtatgtctt tgttctttac cataagagaa gaaagggcca 26820agtgaagttt ctgttacaag agatgtgtct caagctgagt tctccgaact caacttgtga 26880cagatgcaga tggcgtagca aaatgtctca ggatgattgc cttggagcta agggtctgag 26940agaagggaaa tgttaagctc cctctccttc ctcctagttc tattgagcag aagggaaatc 27000tggaggtgag gagatcacat tatgaagaaa gtcagaatga caaaggacca gacacttaga 27060ttacccttcc acaacaccaa ctaaacgtca atggagactt tccagttgga attccgttat 27120tctggcttcc acttcctgaa gggaaggttg cgtttgcctt ttctctctgg gttcaagagg 27180aaagaatagg tgcttattta tggacaggtg aattgatctg tttctatatc tacgtatatt 27240ccgattgtca gaaaaacact cgttcctaag taccagtggc ctgaagggat acaggttccc 27300agcaagagaa gatccaagga aggaaggcag atgagagtca gcacagagag ggatgctgaa 27360aagtaaaagg gatgggtgga tggagagaag cccgggtctg accacccaat ggccaatatt 27420ttggccacaa gcgactacca gagacatgga aaaatggttt ctacatgtgg gacaacagat 27480ggtagaggac ctagagaatt gagagagggg caatgatggg ctccactccg cagatgcctt 27540ggctttcttc ctggataccc ttcctgcact gaatagcaag gagatggagc ccaagcagac 27600tgtagccatc ttgctgaatg gaggagaggg attggagttt gggatgactg tggtagctga 27660aatttttcta ggtctgctag aaataagaac tggtttgtgt ggaggaaaag agctctacaa 27720atacgcatag aagtctcctc cagtcgttgg cctgacatga cgctgcctgt gcacaggaaa 27780tggttccacg agaaagtgtg gcaaagaaca tttactgaga aacagcaagt acaagagcac 27840aggaagctca ataaagaaga gagagatcac atagcactct gggatactgg agttcttccc 27900agctagacca gagagtcctc acggagcaca ttgccaattc agtggagacc ccagaacagc 27960cgtaatttaa aggtacactt agtatattac tagaataaag tcagctgcag acaacccctt 28020gcacagctgg aaagcaagtg tccaagcatc aaatcggttt ccaatcaatg aagtgcctgt 28080gagaggaaat ctcaactctc tttagaagta aacaacaaag tcgattgcct cagctatgcg 28140gtatccgcag agtgagtcct aaatttaaaa tctgactaca tgtagaaaag cgtttcgtgt 28200gacccatgac caggaaataa atcgggtaat acaaacaggc tcaggaatga gagaaatgat 28260tagaattgcg tgaaaatttg acatatcagt atgataactg atttcaaata tttaaaaaaa 28320caacatgcaa gaaagcagat atcatatcaa gagaaattaa cagtacagaa tagccaaatt 28380aaattaaaga ggtagtataa aaaaagtatg tcttaattga aaaaaattac tgtatggccg 28440gctgatcaat ttagacgttt cagaggaaaa cattacccaa cacacaattc tagagaacct 28500acagaatgag ctacacacac acacacacac acacacacac acactgaaaa cacacccata 28560ctcacacaca cgcagaaact cacaagttct aacacacaca gacacgcgca cccctgaaga 28620aacagtgaaa tataaaatta agcgagcctc acagacatgt aggaaaatat gaaaagattt 28680cctgcatgtg ggaagcaagt cacagtaaag agcaagggag tttataatag aaacaaatac 28740cagaatcaag gatggctgat aacttttcaa ttacgaagaa cattaaaaaa aatcacagaa 28800tcgtgaaact caagggatca tatagggaat ttcggaaaaa aaacccaacc tgtatgatgt 28860acttttgtac atcacagttc gaaggtaaca aggcaaagat gtaataagaa gaaacctgtc 28920acgagaaact ggaggaaaaa gagctgtgtc ttcctacaag tacactgata caaattgcca 28980atgtgttcac ctcagaaaca ctggaagcca gataccaggg aatattgtta aaatgataat 29040caggaacaaa aagagatcaa ccgggaatgc tgaatccagc aataaaatgc cttgaaggtc 29100atccatgtcg gataaatgca tattgtgcac tgccccaaag aaagaaaccg gaaactgtaa 29160gaattggaaa tcagcaggct tatgtaacaa gagaggtgac ccgaaggaat taggtagaag 29220aagaattgaa caagaaagga actttctgca gcccacgtaa tgaagaatcc agcaattggc 29280aaatgtagat agatgtaaat gcaaaatatt ttcttgatca aatttctata tctttgtaaa 29340tgagagttga ctacttgaaa caaaatgata gcaagatatt taacttcagc atatgtagag 29400gtaagaattt gaaatggtag cataaatcac gaagggatta attcgaagtg taccgttgta 29460agtttcttta cctcatgcac gatggtgtgt catattaata aaagggtact gtgcgggttc 29520gaagggatat tgcaaatcct agagcaatca caaaggtttg aactctgagg tttttggtat 29580aataagaata gtccatgcat tcaaaagagg gaagccaagg aagaactaga agtctttcaa 29640gagctcaggc tcttatacat ccagttgctc attgaaccag cttcctggaa tggagggtct 29700ggggttgaga ctaggccaca agtctagagt ctctagagag acagtgttgg aaccccatgg 29760cccataatac atttcccatt ttctcaggca gccagaggtc atgaatgtga ggatactggg 29820aggttggagc aacgttcttg ggaggcataa ggaagagcga atgcttcaag atccccgcag 29880cccaaactac tcgcctgctt tgccccctaa tgcatttttc tctgctgctc cgtagctgtc 29940cgacctcttc agatctctta gtccaccctg ccgtcttcct ttatgccatg ggtcccactg 30000ttctttcaac tcatccccct ttccctcagt cccggagtag ctgcggccag cagagggtag 30060actgagagca ggagagaagg acctgcctag gaaccccttc tagagatact gcatcctgcc 30120tgggagcaag ttttccaggg cagctttgag aagtcttgga gaaacaaacc tactaaacct 30180gacagacagt aatactattt gcacaatgct tttctgtggg aaaggtagag ccttttcact 30240acgtattgag tacatagagt gtgagggttg acctggaacg gctatcctcc tggatgacgt 30300gtgttttctg aagaactaca tgttcgttgc aactcccaca ttagaatatg aagtcctacc 30360gagagagata cggagactag acagatacag atgcatttgc atgtgaatac acaatcccac 30420aatacagacg tcaaaaccca taccagttat tccagagaga tggattgggc agaaggcaga 30480aggagaatac tctgatcgtt tttcggccac gtgtgtgtgt tatctcagtg tttctaagaa 30540gcgtttgcta ctttagattt tttatttaaa aaaatagtaa taatctatta agtatgagag 30600atgtgcagag aggattagtg atcgagagcc atttttgctg gtggcaatca tatggtactt 30660ttaatgggaa tattagaaag gcaccggtaa tgaccttgtt gcagcacaaa ggagagagtg 30720tggggtgccc ctgcatgttg tcccacctct tgtgacgtgt atcgttttgg aatttccagt 30780ggcttgatca tgaactactg caggaatcca gatgctgtgg cagctcctta ttgttatacg 30840agggatcccg gtgtcaggtg ggagtactgc aacctgacgc aatgctcaga cgcagaaggg 30900actgccgtcg cgcctccgac tgttaccccg gttccaagcc tagaggctcc ttccgaacaa 30960ggtaaggagt ctgtggccag acatctacac gcttcgatgc tgggatgaaa agccatggaa 31020attcccactg atgcagccgc cttcaatggt aaacggatgc tcgagtgttg cctgagttct 31080accatgtagg aggaagcctc cgtgcactct ctgggggagc cagcggagtg atttctggtg 31140caacgtggtt gggctttgtc tttaggatgg gcacaaaccc tccaggggga tcgacttcaa 31200aattcacctt gttgtaaaac gggctacctc agtgtcccag ccaaaatttt tattgtaaca 31260tgctgtcagg tgtgtcactc tttccaagcc agtaagcttt tccggggatt tcttcaagta 31320gccagcattc agagcaatct tcagcattgc agattctgag aaatgtggct ctggagcctg 31380tcaccctcga gaaacctaag agggctgcat tgattccatg tggccctggg tctatggagc 31440agtacatgag ctcccagtgc tctaaggctc ttcagcccta ggctttgaag ggagtgattt 31500ctcagtattc ttaaacctct ttctgatgac acttgtacct gtgaggggtc tagagagaaa 31560gagtagtaga ctcctacttt actacaattc aggatgcagg gcatgagagg attccctctc 31620tcctccaagg gaagaagctt ttggcgtgca cacatccctg agaagcaaag tgtctttgtc 31680ttcagtcaga tacataggac cgttttctgc cccatggccc ggaagccaaa ggccttggct 31740ttcatgatca acggtctagg gaaacatgca aaatttccat gtctgtccca aactctgccc 31800ccgacagcca attaccacct gcagcccgca ttgccaaatg cggtgccgtt tgcatgaaga 31860ttcagtagag tttcctagaa aggtgctacc tcgtgagctc actttccaat gaggaatctg 31920atctgttgtg tttctctaag gtgtcaggtg aaatatttcc aagaacttac tacagttcta 31980gaatgggagg aatctgttgc tttggtgttt gtttgttggt cggttttctc acatccatct 32040gcctatggat aaggaaaaga gaacggtcgt aattctcata gactcctttc tggttgtgtc 32100acaaatggct tcacatgttt ctctatgctc agagatactc agcttgattt cccgtgtttt 32160catttcagca ccgactgagc aaaggcctgg ggtgcaggag tgctaccatg gtaatggaca 32220gagttatcga ggcacatact ccaccactgt cacaggaaga acctgccaag cttggtcatc 32280tatgacacca cactcgcata gtcggacccc agaatactac ccaaatgcgt atgtctttgt 32340tctttaccat aagagaagaa agggccaagt gaagtttctg ttacaagaga tgtgtctcaa 32400gctgagttct ccgaactcaa cttgtgacag atgcagatgg cgtagcaaaa tgtctcagga 32460tgattgcctt ggagctaagg gtctgagaga agggaaatgt taagctccct ctccttcctc 32520ctagttctat tgagcagaag ggaaatctgg aggtgaggag atcacattat gaagaaagtc 32580agaatgacaa aggaccagac acttagatta cccttccaca acaccaacta aacgtcaatg 32640gagactttcc agttggaatt ccgttattct ggcttccact tcctgaaggg aaggttgcgt 32700ttgccttttc tctctgggtt caagaggaaa gaataggtgc ttatttatgg acaggtgaat 32760tgatctgttt ctatatctac gtatattccg attgtcagaa aaacactcgt tcctaagtac 32820cagtggcctg aagggataca ggttcccagc aagagaagat ccaaggaagg aaggcagatg 32880agagtcagca cagagaggga tgctgaaaag taaaagggat gggtggatgg agagaagccc 32940gggtctgacc acccaatggc caatattttg gccacaagcg actaccagag acatggaaaa 33000atggtttcta catgtgggac aacagatggt agaggaccta gagaattgag agaggggcaa 33060tgatgggctc cactccgcag atgccttggc tttcttcctg gatacccttc ctgcactgaa 33120tagcaaggag atggagccca agcagactgt agccatcttg ctgaatggag gagagggatt 33180ggagtttggg atgactgtgg tagctgaaat ttttctaggt ctgctagaaa taagaactgg 33240tttgtggagg aaaagagctc tacaaatacg catagaagtc tcctccagtc gttggcctga 33300catgacgctg cctgtgcaca ggaaatggtt ccacgagaaa gtgtggcaaa gaacatttac 33360tgagaaacag caagtacaag agcacaggaa gctcaataaa gaagagagag atcacatagc 33420actctgggat actggagttc ttcccagcta gaccagagag tcctcacgga gcacattgcc 33480aattcagtgg agaccccaga acagccgtaa tttaaaggta cacttagtat attactagaa 33540taaagtcagc tgcagacaac cccttgcaca gctggaaagc aagtgtccaa gcatcaaatc 33600ggtttccaat caatgaagtg cctgtgagag gaaatctcaa ctctctttag aagtaaacaa 33660caaagtcgat tgcctcagct atgcggtatc cgcagagtga gtcctaaatt taaaatctga 33720ctacatgtag aaaagcgttt cgtgtgaccc atgaccagga aataaatcgg gtaatacaaa 33780caggctcagg aatgagagaa atgattagaa ttgcgtgaaa atttgacata tcagtatgat 33840aactgatttc aaatatttaa aaaaacaaca tgcaagaaag cagatatcat atcaagagaa 33900attaacagta cagaatagcc aaattaaatt aaagagctag tataaaaaaa gtatgtctta 33960attgaaaaaa attactgtat ggccggctga tcaatttaga cgtttcagag gaaaacatta 34020cccaacacac aattctagag aacctacaga atgagctaca cacacacaca cacacacaca 34080cacaaactga aaacacaccc atactcacac acacgcagaa actcacaagt tctaacacac 34140acagacacgc gcacccctga agaaacagtg aaatataaaa ttaagcgagc ctcacagaca 34200tgtaggaaaa tatgaaaaga tttcctgcat gtgggaagca agtcacagta aagagcaagg 34260gagtttggaa tagaaacaaa taccggaatc aaggatggct gataactttt caattacgaa 34320gaacattaaa aaaaatcaca gaatcgtgaa actcaaggga tcacataggg aatttcggaa 34380aaaaaaccca acctgtatga tgtacttttg tacatcacag ttcgaaggta acaaggcaaa 34440gatataataa gaagaaacct gtcacgagaa actggaggaa aaagagctgt gtcttcctac 34500aagtacactg atacaaattg ccaatgtgtt cacctcagaa acactggaag ccagatacca 34560gggaatattg ttaaaatgat aatcaggaac aaaaagagat caaccgggaa tgctgaatcc 34620agcaataaaa tgccttgaag atcatccatg tcggataaat gcatattgtg cactgcccca 34680aagaaagaaa ccggaaactg taagaattgg aaatcagcag gcttatgtaa caagagaggt 34740gacccgaagg aattaggtag aagaagaatt gaacaagaaa ggaactttct gcagcccacg 34800taatgaagaa tccagcaatt ggcaaatgta gatagatgta aatgcaaaat attttcttga 34860tcaaatttct atatctttgt aaatgagagt tgactacttg aaacaaaatg atagcaagat 34920atttaacttc agcatatgta gaggtaagaa tttgaaatgg tagcataaat cacgaaggga 34980ttaattcgaa gtgtaccgtt gtaagtttct ttacctcatg cacgatggtg tgtcatatta 35040ataaaagggt actgtgcggg ttcgaaggga tattgcaaat cctagagcaa tcacaaaggt 35100ttgaactctg aggtttttgg tataataaga atagtccatg cattcaaaag agggaagcca 35160aggaagaact agaagtcttt caagagctca ggctcttata catccagttg ctcattgaac 35220cagcttcctg gaatggaggg tctggggttg agactaggcc acaagtctag agtctctaga 35280gagacagtgt tggaacccca tggcccataa tacatttccc attttctcag gcagccagag 35340gtcatgaatg tgaggatact gggaggttgg agcaacgttc ttgggaggca taaggaagag 35400cgaatgcttc aagatccccg cagcccaaac tactcgcctg ctttgccccc taatgcattt 35460ttctctgctg ctccgtagct gtccgacctc ttcagatctc ttagtccacc ctgccgtctt 35520cctttatgcc atgggtccca ctgttctttc aactcatccc cctttccctc agtcccggag 35580tagctgcggc cagcagaggg tagactgaga gcaggagaga aggacctgcc taggaacccc 35640ttctagagat actgcatcct gcctgggagc aagttttcca gggcagcttt gagaagtctt 35700ggagaaacaa acctactaaa cctgacagac agtaatacta tttgcacaat gcttttctgt 35760gggaaaggta gagccttttc actacgtatt gagtacatag agtgtgaggg ttgacctgga 35820acggctatcc tcctggatga cgtgtgtttt ctgaagaact acatgttcgt tgcaactccc 35880acattagaat atgaagtcct accgagagag atacggagac tagacagata cagatgcatt 35940tgcatgtgaa tacacaatcc cacaatacag acgtcaaaac ccataccagt tattccagag 36000agatggattg ggtaggaggc agaaggagaa tactctgatc gtttttcggc cacgtgtgtg 36060tgttatctca gtgtttctaa gaagcgtttg ctactttaga ttttttattt aaaaaaaata 36120gtaataatct attaagtatg agagatgtgc agagaggatt agtgatcgag agccattttt 36180gctggtggca atcatatggt acttttaatg ggaatattag aaaggcaccg gtaatgacct 36240tgttgcagca caaaggagag agtgtggggt gcccctgcat gttgtcccac ctcttgtgac 36300gtgtatcgtt ttggaatttc cagtggcttg atcatgaact actgcaggaa tccagatgct 36360gtggcagctc cttattgtta tacgagggat cccggtgtca ggtgggagta ctgcaacctg 36420acgcaatgct cagacgcaga agggactgcc gtcgcgcctc cgactgttac cccggttcca 36480agcctagagg ctccttccga acaaggtaag gagtctgtgg ccagacatct acacgcttcg 36540atgctgggat gaaaagccat ggaaattccc actgatgcag ccgccttcaa tggtaaacgg 36600atgctcgagt gttgccggag ttctgccatg ttgggggaag cctccgtgta ctctctgggg 36660gagccagcgg agtgatttct ggtgcaactt gggtgggctt tgtctttaga atgggcacaa 36720accttccagg gtgatgggct tcacaactca cctccttcta aaatgggcta tctcagtgtc 36780ttagccaaaa tttttattgt aacgtgctgt caggtgtgtg attctttctg tcgcagtaag 36840cttttctggg gatttcttca agtagccagc agtcagtgca atcttcagca ttgcagattt 36900caaaaaatgt ggctctggag cctgtcatcc tcgagaaacc taacagggct gcattaattc 36960catatggtcc tgggtctatg gagcagtata tgagctccca atgctctaag gctcttcagt 37020cctaggcttt gaagggagtg atttctcagt gttcttaaac ctctttctga tggcacttgt 37080acctgtgagg ggtctagaga gaaaggttag tagacttctc ctttactgca attcaggatg 37140cagggcatga gaagattccc tccctcctcc aagggaagaa ggttttggcg tgcacacatc 37200cttgagaagc aaagtgtctt tgccttcagt cagatatata ggatcgtttt ctgccccatg 37260gcctggaagc cagaggcctt ggctttcatg atcaacgatc tagggaaaca tgcaaaattt 37320ccatgtcttt cccctcctct gccctcgaca gccaattacc acctgcatcc tgcattgcca 37380aatgcagtgc cctttgtatg aacattcagt agagtttcat agaaaggtgc tacttcgtga 37440gcgcactttg cagtgagaag gagtctgttc tgttctgttt ttctaaggat ttcaggtgaa 37500atatttccta gaacttacta cagttctaga ttggtaggaa tctgtaggtt tgctgtatgt 37560tttttggttg gttttctccc atccatctgc ctacaggtaa gggaaagata acgttcgtaa 37620ttctcataga ctcctttctg gttgtgtcat aaatggcttc acatatttcg ttattctcag 37680agatactcag tttatttctt gtgttttcat ttcagcaccg actgagcaga ggcctggggt 37740gcaggagtgc taccacggta atggacagag ttatcgaggc acatactcca ccactgtcac 37800tggaagaacc tgccaagctt ggtcatctat gacaccacac tcgcatagtc ggaccccaga 37860atactaccca aatgcgtatg tctttgttct ttaccataag agaagaaagg gccaagtgaa 37920gtttctgtta caagagatgt gtctcaagct gagttctccg aactcaactt gtgacagatg 37980cagatggcgt agcaaaatgt ctcaggatga ttgccttgga gctaagggtc tgagagaagg 38040gaaatgttaa gctccctctc cttcctccta gttctattga gcagaaggga aatctggagg 38100tgaggagatc acattatgaa gaaagtcaga atgacaaagg accagacact tagattaccc 38160ttccacaaca ccaactaaac gtcaatggag actttccagt tggaattccg ttattctggc 38220ttccacttcc tgaagggaag gttgcgtttg ccttttctct ctgggttcaa gaggaaagaa 38280taggtgctta tttatggaca ggtgaattga tctgtttcta tatctacgta tattccgatt 38340gtcagaaaaa cactcgttcc taagtaccag tggcctgaag ggatacaggt tcccagcaag 38400agaagatcca aggaaggaag gcagatgaga gccagcacag agagggatgc tgaaaagtaa 38460aagggatggg tggatggaga gaagcccggg tctgaccacc caatggccaa tattttggcc 38520acaagcgact accagagaca tggaaaaatg gtttctacat gtgggacaac agatggtaga 38580ggacctagag aattgagaga

ggggcaatga tgggctccac tccgcagatg ccttggcttt 38640cttcctggat acccttcctg cactgaatag caaggagatg gagcccaagc agactgtagc 38700catcttgctg aatggaggag agggattgga gtttgggatg actgtggtag ctgaaatttt 38760tctaggtctg ctagaaataa gaactggttt gtggaggaaa agagctctac aaatacgcat 38820agaagtctcc tccagtcgtt ggcctgacat gacgctgcct gtgcacagga aatggttcca 38880cgagaaagtg tggcaaagaa catttactga gaaacagcaa gtacaagagc acaggaagct 38940caataaagaa gagagagatc acatagcact ctgggatact ggagttcttc ccagctagac 39000cagagagtcc tcacggagca cattgccaat tcagtggaga ccccagaaca gccgtaattt 39060aaaggtacac ttagtatatt actagaataa agtcagctgc agacaacccc ttgcacagct 39120ggaaagcaag tgtccaagca tcaaatcggt ttccaatcaa tgaagtgcct gtgggaggaa 39180atctcaactc tctttagaag taaacaacaa agtcgattgc ctcagctatg cggtatccgc 39240agagtgagtc ctaaatttaa aatctgacta catgtagaaa agcgtttcgt gtgacccatg 39300accaggaaat aaatcgggta atacaaacag gctcaggaat gagagaaatg attagaattg 39360cgtgaaaatt tgacatatca gtatgataac tgatttcaaa tatttaaaaa aacaacatgc 39420aagaaagcag atatcatatc aagagaaatt aacagtacag aatagccaaa ttaaattaaa 39480gagctagtat aaaaaaagta tgtcttaatt gaaaaaaatt actgtatggc cggctgatca 39540aattagacgt ttcagaggaa aacattaccc aacacacaat tctagagaac ctacagaatg 39600agctacacac acacacacac acacacacac acacactgaa aacacaccca tactcacaca 39660cacgcagaaa ctcacaagtt ctaacacaca cagacacgcg cacccctgaa gaaacagtga 39720aatataaaat taagcgagcc tcacagacat gtaggaaaat atgaaaagat ttcctgcatg 39780tgggaagcaa gtcacagtaa agagcaaggg agtttggaat agaaacaaat accggaatca 39840aggatggctg ataacttttc aattacgaag aacattaaaa aaaatcacag aatcgtgaaa 39900ctcaagggat catataggga atttcggaaa aaaaacccaa cctgtatgat gtacttttgt 39960acatcacagt tcgaaggtaa caaggcaaag atataataag aagaaacctg tcacgagaaa 40020ctggaggaaa aagagctgtg tcttcctaca agtacactga tacaaattgc caatgtgttc 40080acctcagaaa cactggaagc cagataccag ggaatattgt taaaatgata atcaggaaca 40140aaaagagatc aaccgggaat gctgaatcca gcaataaaat gccttgaaga tcatccatgt 40200cggataaatg catattgtgc actgccccaa agaaagaaac cggaaactgt cagaattgga 40260aatcagcagg cttatgtaac aagagaggtg acccgaagga attaggtaga agaagaattg 40320aacaagaaag gaactttctg cagcccacgt aatgaagaat ccagcaattg gcaaatgtag 40380atagatgtaa atgcaaaata ttttcttgat caaatttcta tatctttgta aatgagagtt 40440gactacttga aacaaaatga tagcaagata tttaacttca gcatatgtag aggtaagaat 40500ttgaaatggt agcataaatc acgaagggat taattcgaag tgtaccgttg taagtttctt 40560tacctcatgc acgatggtgt gtcatattaa taaaagggta ctgtgcgggt tcgaagggat 40620attgcaaatc ctagagcaat cacaaaggtt tgaactctga ggtttttggt ataataagaa 40680tagtccatgc attcaaaaga gggaagccaa ggaagaacta gaagtctttc aagagctcag 40740gctcttatac atccagttgc tcattgaacc agcttcctgg aatggagggt ctggggttga 40800gactaggcca caagtctaga gtctctagag agacagtgtt ggaaccccat ggcccataat 40860acatttccca ttttctcagg cagccagagg tcatgaatgt gaggatactg ggaggttgga 40920gcaacgttct tgggaggcat aaggaagagc gaatgcttca agatccccgc agcccaaact 40980actcgcctgc tttgccccct aatgcatttt tctctgctgc tccgtagctg tccgacctct 41040tcagatctct tagtccaccc tgccgtcttc ctttatgcca tgggtcccat tgttctttca 41100actcatcccc ctttccctca gtcccggagt agctgcggcc agcagagggt agactgagag 41160caggagagaa ggacctgcct aggaacccct tctagagata ctgcatcctg cctgggagca 41220agttttccag ggcagctttg agaagtcttg gagaaacaaa cctactaaac ctgacagaca 41280gtaatactat ttgcacaatg cttttctgtg ggaaaggtag agccttttca ctacgtattg 41340agtacataga gtgtgagggt tgacctggaa cggctatcct cctggatgac gtgcgttttc 41400tgaagaacta catgttcgtt gcaactccca cattagaata tgaagtccta ccgagagaga 41460tacggagact agacagatac agatgcattt gcatgtgaat acacaatccc acaatacaga 41520cgtcaaaacc cataccagtt attccagaga gatggattgg gcagaaggca gaaggagaat 41580actctgatcg tttttcggcc acgtgtgtgt gttatctcag tgtttctaag aagcgtttgc 41640tactttagat tttttattta aaaaaaatag taataatcta ttaagtatga gagatgtgca 41700gagaggatta gtgatcgaga gccatttttg ctggtggcaa tcatatggta cttttaatgg 41760gaatattaga aaggcaccgg taatgacctt gttgcagcac aaaggagaga gtgtggggtg 41820cccctgcatg ttgtcccacc tcttgtgacg tgtatcgttt tggaatttcc agtggcttga 41880tcatgaacta ctgcaggaat ccagatgctg tggcagctcc ttattgttat acgagggatc 41940ccggtgtcag gtgggagtac tgcaacctga cgcaatgctc agacgcagaa gggactgccg 42000tcgcgcctcc gactgttacc ccggttccaa gcctagaggc tccttccgaa caaggtaagg 42060agtctgtggc cagacatcta cacgcttcga tgctgggatg aaaagccatg gaaattccca 42120ctgatgcagc cgccttcaat ggtaaacgga tgctcgagtg ttgcctgagt tctaccatgt 42180aggaggaagc ctccgtgcac tctctggggg agccagcgga gtgatttctg gtgcaacgtg 42240gttgggcttt gtctttagga tgggcacaaa ccctccaggg ggatcgactt caaaattcac 42300cttgttgtaa aacgggctac ctcagtgtcc cagccaaaat ttttattgta acatgctgtc 42360aggtgtgtca ctctttccaa gccagtaagc ttttccgggg atttcttcaa gtagccagca 42420ttcagagcaa tcttcagcat tgcagattct gagaaatgtg gctctggagc ctgtcaccct 42480cgagaaacct aagagggctg cattgattcc atgtggccct gggtctatgg agcagtacat 42540gagctcccag tgctctaagg ctcttcagcc ctaggctttg aagggagtga tttctcagta 42600ttcttaaacc tctttctgat gacacttgta cctgtgaggg gtctagagag aaagagtagt 42660agactcctac tttactacaa ttcaggatgc agggcatgag aggattccct ctctcctcca 42720agggaagaag cttttggcgt gcacacatcc ctgagaagca aagtgtcttt gtcttcagtc 42780agatacatag gaccgttttc tgccccatgg cccggaagcc aaaggccttg gctttcatga 42840tcaacggtct agggaaacat gcaaaatttc catgtctgtc ccaaactctg cccccgacag 42900ccaattacca cctgcagccc gcattgccaa atgcggtgcc gtttgcatga agattcagta 42960gagtttccta gaaaggtgct acctcgtgag ctcactttcc aatgaggaat ctgatctgtt 43020gtgtttctct aaggtgtcag gtgaaatatt tccaagaact tactacagtt ctagaatggg 43080aggaatctgt tgctttggtg tttgtttgtt ggtcggtttt ctcacatcca tctgcctatg 43140gataaggaaa agagaacggt cgtaattctc atagactcct ttctggttgt gtcacaaatg 43200gcttcacatg tttctctatg ctcagagata ctcagcttga tttcccgtgt tttcatttca 43260gcaccgactg agcaaaggcc tggggtgcag gagtgctacc atggtaatgg acagagttat 43320cgaggcacat actccaccac tgtcacagga agaacctgcc aagcttggtc atctatgaca 43380ccacactcgc atagtcggac cccagaatac tacccaaatg cgtatgtctt tgttctttac 43440cataagagaa gaaagggcca agtgaagttt ctgttacaag agatgtgtct caagctgagt 43500tctccgaact caacttgtga cagatgcaga tggcgtagca aaatgtctca ggatgattgc 43560cttggagcta agggtctgag agaagggaaa tgttaagctc cctctccttc ctcctagttc 43620tattgagcag aagggaaatc tggaggtgag gagatcacat tatgaagaaa gtcagaatga 43680caaaggacca gacacttaga ttacccttcc acaacaccaa ctaaacgtca atggagactt 43740tccagttgga attccgttat tctggcttcc acttcctgaa gggaaggttg cgtttgcctt 43800ttctctctgg gttcaagagg aaagaatagg tgcttattta tggacaggtg aattgatctg 43860tttctatatc tacgtatatt ccgattgtca gaaaaacact cgttcctaag taccagtggc 43920ctgaagggat acaggttccc agcaagagaa gatccaagga aggaaggcag atgagagtca 43980gcacagagag ggatgctgaa aagtaaaagg gatgggtgga tggagagaag cccgggtctg 44040accacccaat ggccaatatt ttggccacaa gcgactacca gagacatgga aaaatggttt 44100ctacatgtgg gacaacagat ggtagaggac ctagagaatt gagagagggg caatgatggg 44160ctccactccg cagatgcctt ggctttcttc ctggataccc ttcctgcact gaatagcaag 44220gagatggagc ccaagcagac tgtagccatc ttgctgaatg gaggagaggg attggagttt 44280gggatgactg tggtagctga aatttttcta ggtctgctag aaataagaac tggtttgtgg 44340aggaaaagag ctctacaaat acgcatagaa gtctcctcca gtcgttggcc tgacatgacg 44400ctgcctgtgc acaggaaatg gttccacgag aaagtgtggc aaagaacatt tactgagaaa 44460cagcaagtac aagagcacag gaagctcaat aaagaagaga gagatcacat agcactctgg 44520gatactggag ttcttcccag ctagaccaga gagtcctcac ggagcacatt gccaattcag 44580tggagacccc agaacagccg taatttaaag gtacacttag tatattacta gaataaagtc 44640agctgcagac aaccccttgc acagctggaa agcaagtgtc caagcatcaa atcggtttcc 44700aatcaatgaa gtgcctgtga gaggaaatct caactctctt tagaagtaaa caacaaagtc 44760gattgcctca gctatgcggt atccgcagag tgagtcctaa atttaaaatc tgactacatg 44820tagaaaagcg tttcgtgtga cccatgacca ggaaataaat cgggtaatac aaacaggctc 44880aggaatgaga gaaatgatta gaattgcgtg aaaatttgaa atatcagtat gataactgat 44940ttcaaatatt taaaaaaaca acatgcaaga aagcagatat catatcaaga gaaattaaca 45000gtacagaata gccaaattaa attaaagagc tagtataaaa aaagtatgtc ttaattgaaa 45060aaaattactg tatggccggc tgatcaattt agacgtttca gaggaaaaca ttacccaaca 45120cacaattcta gagaacctac agaatgagct acacacacac acacacacac acacacaaac 45180tgaaaacaca cccatactca cacacacgca gaaactcaca agttctaaca cacacagaca 45240cgcgcacccc tgaagaaaca gtgaaatata aaattaagcg agcctcacag acatgtagga 45300aaatatgaaa agatttcctg catgtgggaa gcaagtcaca gtaaagagca agggagtttg 45360gaatagaaac aaataccaga atcaaggatg gctgataact tttcaattac gaagaacatt 45420aaaaaaaatc acagaatcgt gaaactcaag ggatcacata gggaatttcg gaaaaaaaac 45480ccaacctgta tgatgtactt ttgtacatca cagttcgaag gtaacaaggc aaagatataa 45540taagaagaaa cctgtcacga gaaactggag gaaaaagagc tgtgtcttcc tacaagtaca 45600ctgatacaaa ttgccaatgt gttcacctca gaaacactgg aagccagata ccagggaata 45660ttgttaaaat gataatcagg aacaaaaaga gatcaaccgg gaatgctgaa tccagcaata 45720aaatgccttg aagatcatcc atgtcggata aatgcatatt gtgcactgcc ccaaagaaag 45780aaaccggaaa ctgtaagaat tggaaatcag caggcttatg taacaagaga ggtgacccga 45840aggaattagg tagaagaaga attgaacaag aaaggaactt tctgcagccc acgtaatgaa 45900gaatccagca attggcaaat gtagatagat gtaaatgcaa aatattttct tgatcaaatt 45960tctatatctt tgtaaatgag agttgactac ttgaaacaaa atgatagcaa gatatttaac 46020ttcagcatat gtagaggtaa gaatttgaaa tggtagcata aatcacgaag ggattaattc 46080gaagtgtacc gttgtaagtt tctttacctc atgcacgatg gtgtgtcata ttaataaaag 46140ggtactgtgc gggttcgaag ggatattgca aatcctagag caatcacaaa ggtttgaact 46200ctgaggtttt tggtataata agaatagtcc atgcattcaa aagagggaag ccaaggaaga 46260actagaagtc tttcaagagc tcaggctctt atacatccag ttgctcattg aaccagcttc 46320ctggaatgga gggtctgggg ttgagactag gccacaagtc tagagtctct agagagacag 46380tgttggaacc ccatggccca taatacattt cccattttct caggcagcca gaggtcatga 46440atgtgaggat actgggaggt tggagcaacg ttcttgggag gcataaggaa gagcgaatgc 46500ttcaagatcc ccgcagccca aactactcgc ctgctttgcc ccctaatgca tttttctctg 46560ctgctccgta gctgtccgac ctcttcagat ctcttagtcc accctgccgt cttcctttat 46620gccatgggtc ccactgttct ttcaactcat ccccctttcc ctcagtcccg gagtagctgc 46680ggccagcaga gggtagactg agagcaggag agaaggacct gcctaggaac cccttctaga 46740gatactgcat cctgcctggg agcaagtttt ccagggcagc tttgagaagt cttggagaaa 46800caaacctact aaacctgaca gacagtaata ctatttgcac aatgcttttc tgtgggaaag 46860gtagagcctt ttcactacgt attgagtaca tagagtgtga gggttgacct ggaacggcta 46920tcctcctgga tgacgtgtgt tttctgaaga actacatgtt cgttgcaact cccacattag 46980aatatgaagt cctaccgaga gagatacgga gactagacag atacagatgc atttgcatgt 47040gaatacacaa tcccacaata cagacgtcaa aacccatacc agttattcca gagagatgga 47100ttgggcagaa ggcagaagga gaatactctg atcgtttttc ggccacgtgt gtgtgttatc 47160tcagtgtttc taagaagcgt ttgctacttt agatttttta tttaaaaaaa atagtaataa 47220tctattaagt atgagagatg tgcagagagg attagtgatc gagagccatt tttgctggtg 47280gcaatcatat ggtactttta atgggaatat tagaaaggca ccggtaatga ccttgttgca 47340gcacaaagga gagagtgtgg ggtgcccctg catgttgtcc cacctcttgt gacgtgtatc 47400gttttggaat ttccagtggc ttgatcatga actactgcag gaatccagat gctgtggcag 47460ctccttattg ttatacgagg gatcccggtg tcaggtggga gtactgcaac ctgacgcaat 47520gctcagacgc agaagggact gccgtcgcgc ctccgactgt taccccggtt ccaagcctag 47580aggctccttc cgaacaaggt aaggagtctg tggccagaca tctacacgct tcgatgctgg 47640gatgaaaagc catggaaatt cccactgatg cagccgcctt caatggtaaa cggatgctcg 47700agtgttgcct gagttctacc atgtaggagg aagcctccgt gcactctctg ggggagccag 47760cggagtgatt tctggtgcaa cgtggttggg ctttgtcttt aggatgggca caaaccctcc 47820agggggatcg acttcaaaat tcaccttgtt gtaaaacggg ctacctcagt gtcccagcca 47880aaatttttat tgtaacatgc tgtcaggtgt gtcactcttt ccaagccagt aagcttttcc 47940ggggatttct tcaagtagcc agcattcaga gcaatcttca gcattgcaga ttctgagaaa 48000tgtggctctg gagcctgtca ccctcgagaa acctaagagg gctgcattga ttccatgtgg 48060ccctgggtct atggagcagt acatgagctc ccagtgctct aaggctcttc agccctaggc 48120tttgaaggga gtgatttctc agtattctta aacctctttc tgatgacact tgtacctgtg 48180aggggtctag agagaaagag tagtagactc ctactttact acaattcagg atgcagggca 48240tgagaggatt ccctctctcc tccaagggaa gaagcttttg gcgtgcacac atccctgaga 48300agcaaagtgt ctttgtcttc agtcagatac ataggaccgt tttctgcccc atggcccgga 48360agccaaaggc cttggctttc atgatcaacg gtctagggaa acatgcaaaa tttccatgtc 48420tgtcccaaac tcttcccccg acagccaatt accacctgca gcccgcattg ccaaatgcgg 48480tgccgtttgc atgaagattc agtagagttt cctagaaagg tgctacctcg tgagctcact 48540ttccaatgag gaatctgatc tgttgtgttt ctctaaggtg tcaggtgaaa tatttccaag 48600aacttactac agttctagaa tgggaggaat ctgttgcttt ggtgtttgtt tgttggtcgg 48660ttttctcaca tccatctgcc tatggataag gaaaagagaa cggtcgtaat tctcatagac 48720tcctttctgg ttgtgtcaca aatggcttca catgtttctc tatgctcaga gatactcagc 48780ttgatttccc gtgttttcat ttcagcaccg actgagcaaa ggcctggggt gcaggagtgc 48840taccatggta atggacagag ttatcgaggc acatactcca ccactgtcac aggaagaacc 48900tgccaagctt ggtcatctat gacaccacac tcgcatagtc ggaccccaga atactaccca 48960aatgcgtatg tctttgttct ttaccataag agaagaaagg gccaagtgaa gtttctgtta 49020caagagatgt gtctcaagct gagttctccg aactcaactt gtgacagatg cagatggcgt 49080agcaaaatgt ctcaggatga ttgccttgga gctaagggtc tgagagaagg gaaatgttaa 49140gctccctctc cttcctccta gttctattga gcagaaggga aatctggagg tgagaagatc 49200acattatgaa gaaagtcaga atgacaaagg accagacact tagattaccc ttccacaaca 49260ccaactaaac gtcaatggag actttccagt tggaattccg ttattctggc ttccacttcc 49320tgaagggaag gttgcgtttg ccttttctct ctgggttcaa gaggaaagaa taggtgctta 49380tttatggaca ggtgaattga tctgtttcta tatctacgta tattccgatt gtcagaaaaa 49440cactcgttcc taagtaccag tggcctgaag ggatacaggt tcccagcaag agaagatcca 49500aggaaggaag gcagatgaga gtcagcacag agagggatgc tgaaaagtaa aagggatggg 49560tggatggaga gaagcccggg tctgaccacc caatggccaa tattttggcc acaagcgact 49620accagagaca tggaaaaatg gtttctacat gtgggacaac agatggtaga ggacctagag 49680aattgagaga ggggcaatga tgggctccac tccgcagatg ccttggcttt cttcctggat 49740acccttcctg cactgaatag caaggagatg gagcccaagc agactgtagc catcttgctg 49800aatggaggag agggattgga gtttgggatg actgtggtag ctgaaatttt tctaggtctg 49860ctagaaataa gaactggttt gtgtggagga aaagagctct acaaatacgc atagaagtct 49920cctccagtcg ttggcctgac atgacgctgc ctgtgcacag gaaatggttc cacgagaaag 49980tgtggcaaag aacatttact gagaaacagc aagtacaaga gcacaggaag ctcaataaag 50040aagagagaga tcacatagca ctctgggata ctggagttct tcccagctag accagagagt 50100cctcacggag cacattgcca attcagtgga gaccccagaa cagccgtaat ttaaaggtac 50160acttagtata ttactagaat aaagtcagct gcagacaacc ccttgcacag ctggaaagca 50220agtgtccaag catcaaatcg gtttccaatc aatgaagtgc ctgtgagagg aaatctcaac 50280tctctttaga agtaaacaac aaagtcgatt gcctcagcta tgcggtatcc gcagagtgag 50340tcctaaattt aaaatctgac tacatgtaga aaagcgtttc gtgtgaccca tgaccaggaa 50400ataaatcggg taatacaaac aggctcagga atgagagaaa tgattagaat tgcgtgaaaa 50460tttgacatat cagtatgata actgatttca aatatttaaa aaaacaacat gcaagaaagc 50520agatatcata tcaagagaaa ttaacagtac agaatagcca aattaaatta aagaggtagt 50580ataaaaaaag tatgtcttaa ttgaaaaaaa ttactgtatg gccggctgat caatttagac 50640gtttcagagg aaaacattac ccaacacaca attctagaga acctacagaa tgagctacac 50700acacacacac acacacacac acaaactgaa aacacaccca tactcacaca cacgcagaaa 50760ctcacaagtt ctaacacaca cagacacgcg cacccctgaa gaaacagtga aatataaaat 50820taagcgagcc tcacagacat gtaggaaaat atgaaaagat ttcctgcatg tgggaagcaa 50880gtcacagtaa agagcaaggg agtttggaat agaaacaaat accggaatca aggatggctg 50940ataacttttc aattacgaag aacattaaaa aaaatcacag aatcgtgaaa ctcaagggat 51000cacataggga atttcggaaa aaaaacccaa cctgtatgat gtacttttgt acatcacagt 51060tcgaaggtaa caaggcaaag atataataag aagaaacctg tcacgagaaa ctggaggaaa 51120aagagctgtg tcttcctaca agtacactga tacaaattgc caatgtgttc acctcagaaa 51180cactggaagc cagataccag ggaatattgt taaaatgata atcaggaaca aaaagagatc 51240aaccgggaat gctgaatcca gcaataaaat gccttgaagg tcatccatgt cggataaatg 51300catattgtgc actgccccaa agaaagaaac cggaaactgt aagaattgga aatcagcagg 51360cttatgtaac aagagaggtg acccgaagga attaggtaga agaagaattg aacaagaaag 51420gaactttctg cagcccacgt aatgaagaat ccagcaattg gcaaatgtag atagatgtaa 51480atgcaaaata ttttcttgat caaatttcta tatctttgta aatgagagtt gactacttga 51540aacaaaatga tagcaagata tttaacttca gcatatgtag aggtaagaat ttgaaatggt 51600agcataaatc acgaagggat taattcgaag tgtaccgttg taagtttctt tacctcatgc 51660acgatggtgt gtcatattaa taaaagggta ctgtgcgggt tcgaagggat attgcaaatc 51720ctagagcaat cacaaaggtt tgaactctga ggtttttggt ataataagaa tagtccatgc 51780attcaaaaga gggaagccaa ggaagaacta gaagtctttc aagagctcag gctcttatac 51840atccagttgc tcattgaacc agcttcctgg aatggagggt ctggggttga gactaggcca 51900caagtctaga gtctctagag agacagtgtt ggaaccccat ggcccataat acatttccca 51960ttttctcagg cagccagagg tcatgaatgt gaggatactg ggaggttgga gcaacgttct 52020tgggaggcat aaggaagagc gaatgcttca agatccccgc agcccaaact actcgcctgc 52080tttgccccct aatgcatttt tctctgctgc tccgtagctg tccgacctct tcagatctct 52140tagtccaccc tgccgtcttc ctttatgcca tgggtcccac tgttctttca actcatcccc 52200ctttccctca gtcccggagt agctgcggcc agcagagggt agactgagag caggagagaa 52260ggacctgcct aggaacccct tctagagata ctgcatcctg cctgggagca agttttccag 52320ggcagctttg agaagtcttg gagaaacaaa cctactaaac ctgacagaca gtaatactat 52380ttgcacaatg cttttctgtg ggaaaggtag agccttttca ctacgtattg agtacataga 52440gtgtgagggt tgacctggaa cggctatcct cctggatgac gtgcgttttc tgaagaacta 52500catgttcgtt gcaactccca cattagaata tgaagtccta ccgagagaga tacggagact 52560agacagatac agatgcattt gcatgtgaat acacaatccc acaatacaga cgtcaaaacc 52620cataccagtt attccagaga gatggattgg gcagaaggca gaaggagaat actctgatcg 52680tttttcggcc acgtgtgtgt gttatctcag tgtttctaag aagcgtttgc tactttagat 52740tttttattta aaaaaaatag taataatcta ttaagtatga gagatgtgca gagaggatta 52800gtgatcgaga gccatttttg ctggtggcaa tcatatggta cttttaatgg gaatattaga 52860aaggcaccgg taatgacctt gttgcagcac aaaggagaga gtgtggggtg cccctgcatg 52920ttgtcccacc tcttgtgacg tgtatcgttt tggaatttcc agtggcttga tcatgaacta 52980ctgcaggaat ccagatgctg tggcagctcc ttattgttat acgagggatc ccggtgtcag 53040gtgggagtac tgcaacctga cgcaatgctc agacgcagaa gggactgccg tcgcgcctcc 53100gactgttacc ccggttccaa gcctagaggc tccttccgaa caaggtaagg agtctgtggc 53160cagacatcta cacgcttcga tgctgggatg aaaagccatg gaaattccca ctgatgcagc 53220cgccttcaat ggtaaacgga tgctcgagtg ttgcctgagt tctaccatgt aggaggaagc 53280ctccgtgcac tctctggggg agccagcgga gtgatttctg gtgcaacgtg gttgggcttt 53340gtctttagga tgggcacaaa ccctccaggg ggatcgactt caaaattcac cttgttgtaa 53400aacgggctac ctcagtgtcc cagccaaaat ttttattgta acatgctgtc aggtgtgtca 53460ctctttccaa gccagtaagc ttttccgggg atttcttcaa gtagccagca ttcagagcaa 53520tcttcagcat tgcagattct gagaaatgtg gctctggagc ctgtcaccct cgagaaacct 53580aagagggctg cattgattcc atgtggccct gggtctatgg agcagtacat gagctcccag 53640tgctctaagg ctcttcagcc

ctaggctttg aagggagtga tttctcagta ttcttaaacc 53700tctttctgat gacacttgta cctgtgaggg gtctagagag aaagagtagt agactcctac 53760tttactacaa ttcaggatgc agggcatgag aggattccct ctctcctcca agggaagaag 53820cttttggcgt gcacacatcc ctgagaagca aagtgtcttt gtcttcagtc agatacatag 53880gaccgttttc tgccccatgg cccggaagcc aaaggccttg gctttcatga tcaacggtct 53940agggaaacat gcaaaatttc catgtctgtc ccaaactctg cccccgacag ccaattacca 54000cctgcagccc gcattgccaa atgcggtgcc gtttgcatga agattcagta gagtttccta 54060gaaaggtgct acctcgtgag ctcactttcc aatgaggaat ctgatctgtt gtgtttctct 54120aaggtgtcag gtgaaatatt tccaagaact tactacagtt ctagaatggg aggaatctgt 54180tgctttggtg tttgtttgtt ggtcggtttt ctcacatcca tctgcctatg gataaggaaa 54240agagaacggt cgtaattctc atagactcct ttctggttgt gtcacaaatg gcttcacatg 54300tttctctatg ctcagagata ctcagcttga tttcccgtgt tttcatttca gcaccgactg 54360agcaaaggcc tggggtgcag gagtgctacc atggtaatgg acagagttat cgaggcacat 54420actccaccac tgtcacagga agaacctgcc aagcttggtc atctatgaca ccacactcgc 54480atagtcggac cccagaatac tacccaaatg cgtatgtctt tgttctttac cataagagaa 54540gaaagggcca agtgaagttt ctgttacaag agatgtgtct caagctgagt tctccgaact 54600caacttgtga cagatgcaga tggcgtagca aaatgtctca ggatgattgc cttggagcta 54660agggtctgag agaagggaaa tgttaagctc cctctccttc ctcctagttc tattgagcag 54720aagggaaatc tggaggtgag gagatcacat tatgaagaaa gtcagaatga caaaggacca 54780gacacttaga ttacccttcc acaacaccaa ctaaacgtca atggagactt tccagttgga 54840attccgttat tctggcttcc acttcctgaa gggaaggttg cgtttgcctt ttctctctgg 54900gttcaagagg aaagaatagg tgcttattta tggacaggtg aattgatctg tttctatatc 54960tacgtatatt ccgattgtca gaaaaacact cgttcctaag taccagtggc ctgaagggat 55020acaggttccc agcaagagaa gatccaagga aggaaggcag atgagagtca gcacagagag 55080ggatgctgaa aagtaaaagg gatgggtgga tggagagaag cccgggtctg accacccaat 55140ggccaatatt ttggccacaa gcgactacca gagacatgga aaaatggttt ctacatgtgg 55200gacaacagat ggtagaggac ctagagaatt gagagagggg caatgatggg ctccactccg 55260cagatgcctt ggctttcttc ctggataccc ttcctgcact gaatagcaag gagatggagc 55320ccaagcagac tgtagccatc ttgctgaatg gaggagaggg attggagttt gggatgactg 55380tggtagctga aatttttcta ggtctgctag aaataagaac tggtttgtgt ggaggaaaag 55440agctctacaa atacgcatag aagtctcctc cagtcgttgg cctgacatga cgctgcctgt 55500gcacaggaaa tggttccacg agaaagtgtg gcaaagaaca tttactgaga aacagcaagt 55560acaagagcac aggaagctca ataaagaaga gagagatcac atagcactct gggatactgg 55620agttcttccc agctagacca gagagtcctc acggagcaca ttgccaattc agtggagacc 55680ccagaacagc cgtaatttaa aggtacactt agaatattac tagaataaag tcagctgcag 55740acaacccctt gcacagctgg aaagcaagtg tccaagcatc aaatcggttt ccaatcaatg 55800aagtgcctgt gagaggaaat ctcaactctc tttagaagta aacaacaaag tcgattgcct 55860cagctatgcg gtatccgcag agtgagtcct aaatttaaaa tctgactaca tgtagaaaag 55920cgtttcgtgt gacccatgac caggaaataa atcgggtaat acaaacaggc tcaggaatga 55980gagaaatgat tagaattgcg tgaaaatttg acatatcagt atgataactg atttcaaata 56040tttaaaaaaa caacatgcaa gaaagcagat atcatatcaa gagaaattaa cagtacagaa 56100tagccaaatt aaattaaaga gctagtataa aaaaagtatg tcttaattga aaaaaattac 56160tgtatggccg gctgatcaaa ttagacgttt cagaggaaaa cattacccaa cacacaattt 56220tagagaacct acagaatgag ctacacacac acacacacac acacacacac acacaaactg 56280aaaacacacc catactcaca cacacgcaga aactcacaag ttctaacaca cacagacacg 56340cgcacccctg aagaaacagt gaaatataaa attaagcgag cctcacagac atgtaggaaa 56400atatgaaaag atttcctgca tgtgggaagc aagtcacagt aaagagcaag ggagtttata 56460atagaaacaa ataccagaat caaggatggc tgataacttt tcaattacga agaacattaa 56520aaaaaatcac agaatcgtga aactcaaggg atcatatagg gaatttcgga aaaaaaaccc 56580aacctgtatg atgtactttt gtacatcaca gttcgaaggt aacaaggcaa agatgtaata 56640agaagaaacc tgtcacgaga aactggagga aaaagagctg tgtcttccta caagtacact 56700gatacaaatt gccaatgtgt tcacctcaga aacactggaa gccagatacc agggaatatt 56760gttaaaatga taatcaggaa caaaaagaga tcaaccggga atgctgaatc cagcaataaa 56820atgccttgaa ggtcatccat gtcggataaa tgcatattgt gcactgcccc aaagaaagaa 56880accggaaact gtaagaattg gaaatcagca ggcttatgta acaagagagg tgacccgaag 56940gaattaggta gaagaagaat tgaacaagaa aggaactttc tgcagcccac gtaatgaaga 57000atccagcaat tggcaaatgt agatagatgt aaatgcaaaa tattttcttg atcaaatttc 57060tatatctttg taaatgagag ttgactactt gaaacaaaat gatagcaaga tatttaactt 57120cagcatatgt agaggtaaga atttgaaatg gtagcataaa tcacgaaggg attaattcga 57180agtgtaccgt tgtaagtttc tttacctcat gcacgatggt gtgtcatatt aataaaaggg 57240tactgtgcgg gttcgaaggg atattgcaaa tcctagagca atcacaaagg tttgaactct 57300gaggtttttg gtataataag aatagtccat gcattcaaaa gagggaagcc aaggaagaac 57360tagaagtctt tcaagagctc aggctcttat acatccagtt gctcattgaa ccagcttcct 57420ggaatggagg gtctggggtt gagactaggc cacaagtcta gagtctctag agagacagtg 57480ttggaacccc atggcccata atacatttcc cattttctca ggcagccaga ggtcatgaat 57540gtgaggatac tgggaggttg gagcaacgtt cttgggaggc ataaggaaga gcgaatgctt 57600caagatcccc gcagcccaaa ctactcgcct gctttgcccc ctaatgcatt tttctctgct 57660gctccgtagc tgtccgacct cttcagatct cttagtccac cctgccgtct tcctttatgc 57720catgggtccc actgttcttt caactcatcc ccctttccct cagtcccgga gtagctgcgg 57780ccagcagagg gtagactgag agcaggagag aaggacctgc ctaggaaccc cttctagaga 57840tactgcatcc tgcctgggag caagttttcc agggcagctt tgagaagtct tggagaaaca 57900aacctactaa acctgacaga cagtaatact atttgcacaa tgcttttctg tgggaaaggt 57960agagcctttt cactacgtat tgagtacata gagtgtgagg gttgacctgg aacggctatc 58020ctcctggatg acgtgcgttt tctgaagaac tacatgttcg ttgcaactcc cacattagaa 58080tatgaagtcc taccgagaga gatacggaga ctagacagat acagatgcat ttgcatgtga 58140atacacaatc ccacaataca gacgtcaaaa cccataccag ttattccaga gagatggatt 58200gggcagaagg cagaaggaga atactctgat cgtttttcgg ccacgtgtgt gtgttatctc 58260agtgtttcta agaagcgttt gctactttag attttttatt taaaaaaaat agtaataatc 58320tattaagtat gagagatgtg cagagacgat tagtgatcga gagccatttt tgctggtggc 58380aatcatatgg tacttttaat gggaatatta gaaaggcacc ggtaatgacc ttgttgcagc 58440acaaaggaga gagtgtgggg tgcccctgca tgttgtccca cctcttgtga cgtgtatcgt 58500tttggaattt ccagtggctt gatcatgaac tactgcagga atccagatgc tgtggcagct 58560ccttattgtt atacgaggga tcccggtgtc aggtgggagt actgcaacct gacgcaatgc 58620tcagacgcag aagggactgc cgtcgcgcct ccgactgtta ccccggttcc aagcctagag 58680gctccttccg aacaaggtaa ggagtctgtg gccagacatc tacacgcttc gatgctggga 58740tgaaaagcca tggaaattcc cactgatgca gccgccttca atggtaaacg gatgctcgag 58800tgttgcctga gttctaccat gtaggaggaa gcctccgtgc actctctggg ggagccagcg 58860gagtgatttc tggtgcaacg tggttgggct ttgtctttag gatgggcaca aaccctccag 58920ggggatcgac ttcaaaattc accttgttgt aaaacgggct acctcagtgt cccagccaaa 58980atttttattg taacatgctg tcaggtgtgt cactctttcc aagccagtaa gcttttccgg 59040ggatttcttc aagtagccag cattcagagc aatcttcagc attgcagatt ctgagaaatg 59100tggctctgga gcctgtcatc ctcgagaaac ctaacagggc tgcattaatt ccatatggtc 59160ctgggtctat ggagcagtat atgagctccc aatgctctaa ggctcttcag tcctaggctt 59220tgaagggagt gatttctcag tgttcttaaa cctctttctg atggcacttg tacctgtgag 59280gggtctagag agaaaggtta gtagacttct cctttactgc aattcaggat gcagggcatg 59340agaagattcc ctccctcctc caagggaaga aggttttggc gtgcacacat ccttgagaag 59400caaagtgtct ttgccttcag tcagatatat aggatcgttt tctgccccat ggcctggaag 59460ccagaggcct tggctttcat gatcaacgat ctagggaaac atgcaaaatt tccatgtctt 59520tcccctcctc tgccctcgac agccaattac cacctgcatc ctgcattgcc aaatgcagtg 59580ccctttgtat gaacattcag tagagtttca tagaaaggtg ctacttcgtg agcgcacttt 59640gcagtgagaa ggagtctgtt ctgttctgtt tttctaagga tttcaggtga aatatttcct 59700agaacttact acagttctag attggtagga atctgtaggt ttgctgtatg ttttttggtt 59760ggttttctcc catccatctg cctacaggta agggaaagat aacgttcata attctcatag 59820actcctttct ggttgtgtca taaatggctt cacatatttc gttattctca gagatactca 59880gtttatttct tgtgttttca tttcagcacc gactgagcag aggcctgggg tgcaggagtg 59940ctaccacggt aatggacaga gttatcgagg cacatactcc accactgtca ctggaagaac 60000ctgccaagct tggtcatcta tgacaccaca ctcgcatagt cggaccccag aatactaccc 60060aaatgcgtat gtctttgttc tttaccataa gagaataaag ggccaactga agtttctgtg 60120acaagagaca tgcttcaagc tgagttctcc gaactcaact tgtgtcagat tcagatggtg 60180tagcaaaatg tctcaggatg atttccttgg agctaagggt ctgagagaag agaaatgtta 60240agctgcctca ccttcctcct agttttgtgg agcagaaggg aaatgaggag gcgaggagat 60300caccttatga agaaagtcag aatgacgaac caccaaacac ttagattacc cttgcccaac 60360acccactaag cgtcaatgaa gactttccag ttggaattcc gttattctga cttccaattc 60420ctgaagggaa gattgtgttt gccttttctg tctgggctca tgaggaaagt ttatgtgctt 60480acttatggac aggtgaattg atctgtttct atttctacct gtattccaat agggagaaaa 60540tctcttggtc ctaagtacca gtggcctgaa aggatagagg ttcccagcaa gagaagatcc 60600aaggaaggaa ggcagatgag agtcagcaca gagagggatg ctgaaaagta aaagggatgg 60660gtagatggat agaagccctg gtctgaccac cccatggcca atcatttggc cataatcaac 60720aaccaaagac atggaaaaat ggtttctaca tgtgggacaa cagatggtag aggacctaga 60780gaattgagag agggccaatg atgagctcaa ctccatagat gccttggctt tcttcctgga 60840tacccttcct gcactgaata gcaaggagat ggagctcaag cagcctgtag ccatctagct 60900gagcagagga gagggattgg agtttgggat gactctggta ttttctaggt ccgctacaaa 60960taagaactgg tttgtggagg aaaggagctc tacaaatacg catagaagtc tcctccagta 61020gttggcctca catgacactg catgtgcaca gaaaatggtt ctacagaaag tgtggcaaag 61080aacatttact gagaaacagc aactacaaga gaacagcaag ctcaattaag aagatagaga 61140tcacatagca ctctgtgtta ttggagttct taccagctag atgagagagt gctcacggaa 61200cacattgcca attcagtgga gaccccagaa cagccataat ttcaaagtac aattagtata 61260ttactagaat aaaggcagct gcagacaacc ccttgcacag ctgaaaagca agtgtccaag 61320catcaaatgg gtttccaatc aatgaagtgc ctgtgagagg aaatctcaac tctcttcaga 61380agtaaacaac aaagtcaatt gcctcagcta tgcggtatcc ccagagtgag tcctaaatta 61440aaaatttgac tacgtgtaga aaagaatttc gtgtgatcca tgaccagaaa ataaatcagg 61500caatacaaac aggctcagaa atgacatcga taattagaat tgcatgaaaa tttgacatat 61560cagtatgata actgatttca gatatttaaa aaaagtgcaa caaagcaggt atcatatcaa 61620gacaaattaa tagtatagaa tagccaaatc aaattaaaga actattatac aaaaagtatg 61680tcttaaatga agaaattact gtatgtccgc ctgaaaaatt tagatgtttc agaagaaaaa 61740attaaccaaa aacaattctg cagaacctac agaatgagcc acacacacac acattcaaaa 61800cacacccata cacacacaca tgcaaaaact cacaagttct aacacacaca caaacacaca 61860cacacatgca catccctaaa gaaataggga aatataaaat taaccgaccc tcagagacat 61920gcaggaaaat ataagaagat ttcctgcatg tgggaagcaa gtcacagtaa agagcaaggg 61980agtttggagt agatacaaat accggaatca cggatggctg ataacttttc aattatgaag 62040aacgttagaa aaatcacaga ttcatgaaac taaagggatc aaataggaaa tttcgagaaa 62100aaaaactaca tgatgcactt ctctacatca cagttcaaag gtaacaaggc aaggatataa 62160gaagaagaaa catctcacga gaaactggag aaaaaagagc tgtgtcttcc tagagtacag 62220tgatacaaat tgctaatgcg ttcacctcag aaacactgga agccagatac cagggaatat 62280tattaaaatg ataatgagga acaagaagag atcaaccgag aatgctgaat ccagcaataa 62340aatgccttga agatcatcca tgttggataa atgcatattg tgcactgccc aaaacaaaga 62400aactggaaag tgtaagactt tggaatcagc aggcttatgt agcaacagag gtgacccgaa 62460agaattaggt ataagaagaa tagaagaatt gcatgaaaat ttgacatatg actaagataa 62520ctatttcaaa tatttaaaaa aagatgaata tgtaataaaa cagataaaat atcaaaagaa 62580agtaacagta ttgactagcc aaatcaaatt aaagacttag tgtaaaaagc tatgtcttaa 62640aagaaaaaat tactggatgg ctgcctgatc aatttagaca tttctgaata ggaaactaac 62700caaaaatcaa ttctacagaa ccaactacac acatatatac acatacaaca cacccataca 62760cacccacgca aaaactcaca agttcacaca cacacacaca cacacacaac cctcaagaaa 62820tagtgaaata gaaaaccaac cgaacctcac agacatgttg caaaatagga aaagatttcc 62880tgcatatggg aagcaagtca cagaaaagag aacgggagat tggaaacaga aacaaatacc 62940ggaatcaagg atggccgaaa acttttcatt gatcaagaat attaacaaaa tcgcaaaaac 63000acgaaattca atgcatcaaa taggcgtttc gaaaaaaaga aaaaatctgg tatgatgcac 63060ttttgtactt cacattttca cggtaagaag acaaagatat aataacaaga aacttcttat 63120gagaaactgg ggaaaaacaa gctgtttctt gctagaagaa cagtgataca aattgctaat 63180gcattctcgt caaaaacact ggaagccaga taccgggaat gttattaatg tggtaaacag 63240gaacaagaag agatcaacca agaatgctaa atccagcaat aaaatgcctt gaagatcatc 63300catgctgcat aaatgtatgt tgtgcactgc cccaaacaaa gaaaccggaa actgtaagaa 63360tttggaatca gcaggctgat gtaacaagag aggtgaccca aaggaattag gtagaagaag 63420aatagtacaa gaagggaact ttctgcagcc catgtaatga agaacccagc aattggcaaa 63480tgtagatgta aatgcaaaat attttcttga ccaaatttct atatattttt aaatgagcgt 63540tgactactgg aaacaaaatg atagcaatat atttaatttt agcatatgta gaggtaagaa 63600tttgaacaag tagcgtaaat catgtaggga ataattagaa gtgtaccatt gtaagtttct 63660tacctcatgc acaatggtat gtaatattaa taaaatgtta ctgtgtgggt tcaaggagat 63720attgcaaatc ctagagcaat cacaaagttt tgaactctga ggtatattgt ataataagaa 63780tattccatgt attcaaaaga gagaagccaa ggaagaaaga aatttgtcac gagtttgggc 63840tcttagtaca tcctgtagct cattgaacca gcttcctgga atggagggtc tgggattgac 63900actaggccac atgtatagag tctctagaga gacagtgttt catccccatg gcccgtaata 63960catttcccat tttctcaggc agccacaggt catgaatgtg aggatagaga gaggttggag 64020caacgttctt gggaggcata aggaagagca aatgcttcaa gatccccgca gcccaaactc 64080ctacctgctt tgccccctaa tgcagtgttc ctccgtagct gtccgacctc ttcagatctc 64140ttagtctacc ctgccatctt cctttatgcc atgggtccca ctgttctttc aactcatccc 64200cctttccctc agtgcagagt agctgcggcc agcagagggt agactgagag caggagagaa 64260ggtcctgccc aggaacccat tctagagatg ctgcattctg cctgggagca agttttccag 64320ggcagctttg agaagtcttg cagaaacaaa cctatttgac ccacatgata tgggaatgac 64380agaaagtaat acaatttgca cagtgctttt ccatgggaaa agtagagcct tttcgcgagg 64440ttttgagtac atagagagtg aaggttgacc tggaaaggtt atcctcctgg atcccatgtt 64500ttttctgaag aactacctgt tagttgcaac ttgcacatta gaatatgaag tcctaccgag 64560agagatacgg agaactagat aaatacagat acttttgtat gtgaataaac gattccacaa 64620tacacacatc aaaatccata ccagttattc cagagagatg gattgggcag aaggcagaag 64680gagaatactc tgatcgtttt ttgcccacgt gtatgtatta tctcagtgtt tctaagaagc 64740gtttgctact ttagattttt ttttataata ataatctttt aagtatgaga aatgtgcaga 64800caggattagt gattgagagc catttgtgct tgtggcaatc atatggtact tttatgggaa 64860tattagaaag gcactggtaa tgaccttgtt gcagcacaaa ggagagggtg tggggtgccc 64920ctgcatattg tcccacctct tgtgacgtgt atcgttttgg aatttccagt ggcttgatca 64980tgaactactg caggaatcca gatcctgtgg cagcccctta ttgttatacg agggatccca 65040gtgtcaggtg ggagtactgc aacctgacac aatgctcaga cgcagaaggg actgccgtcg 65100cgcctccaac tattaccccg attccaagcc tagaggctcc ttctgaacaa ggtaaggagc 65160ctgtggccag aaacctacac gtttcgatgc tgggatgaaa agccatggaa attcccactg 65220atgcagcagc ctccaatggt aaacggatgc tcgagtgttg actgagttct gtcatgtagg 65280aggaagcctc cgtgcactct ctgggggagc cagcggattg atttctggta caacgttggg 65340tgggctgtgt ctttagaatt ggcacaaacc ctccagggtg atcgacttca caactcacct 65400cgttgaaaaa tgggctatct cagtgtctta gccaaaattt ttattgtaac atgctgtcag 65460atgtgtgact ctttccaagc cagtaagctt ttcctgggac ttcttcaatt agccagcatt 65520cagtgcaatc ttcagcattg cagattcaga gaaatgtggc tctggagcct gtcacccttg 65580agaaacaggg ctaacagggt tgcattaatt ccaaatcacc ctggttctat ggagcagtac 65640atgaactccc aatgatctat gtttcaggac ttcctcagtc ataggtgggc tctgcagccc 65700taggttttta agtgagtgac tgccccgtgt tctggtggca gttgtacctg tgagcggtct 65760ggatagaaag agtcggagac ttctgtatta ttgcaactca ggatgtgggt catgagagga 65820tttcatctct cctgcagggg agtaagctgt tcgcctccac ccatccctga taactgaagt 65880gtctttgtct gcagtcctag acgaaggact gttgtctctc ccatggccca gaagctgaag 65940accttgcctt ttgttatgaa acgttcattg ttttcatgtc tgtccgtttc tctgccccta 66000acacccaatc accatgtatg gcctgtaccc ccaaatgcat cgtgctttgc tgtttgctgc 66060cccatagtcc tcatgaacat tcagtagaaa ttcccataaa tgtgcttgca cgtgagcaca 66120gtttccattg agaagccctc tcatttgtcc tttttttcta agcttttatg tgaaatattt 66180ctaagaactt actacagttc taaagtgtta ggaatttgtt tctttggtgt ttttgtttgt 66240tggttggttg ttgcttttct caagtccatc tgcctacaaa taaagaaaca agaatgttac 66300ttgtcatatt ctcctgaggt cataattctc agagactttt ttctggtttg tgccataagt 66360ggcttcacat gtttgtctct tcttggaaac actcagtttg atttcttttc ttttcatttc 66420agcaccaact gagcaaaggc ctggggtgca ggagtgctac cacggaaatg gacagagtta 66480tcaaggcaca tacttcatta ctgtcacagg aagaacctgc caagcttggt catctatgac 66540accacactcg catagtcgga ccccagcata ctacccaaat gcgtatgtct attttcttta 66600ccataagtga aggaagggtc agtggaaatt tctgttagta gagtcatgct tcaagctgag 66660tgttcaggac tcaagttgtc tcagatgaac agtgcatagc aaaatgtctc aggaacattg 66720tctttgagca aagagtctaa gagaagacaa atgttaatct ggctctcctt cctcctagtt 66780taatggagca gaaaggtatc tggaggcaag gatatcacat taagaaacaa gtcaagatga 66840caaatgatga aactcttaga gtacccttcc acaacaccca ctaaggttca atgcagcctt 66900ttctccttgg aattctatta aactaaactc caattcctga agtgaaggtt ctgttggggt 66960tttctgtttt ggcttacaag gaaagtatat atgtatatct atggagaggc aaatctatct 67020ctttctatat ctacgtctat tccaatatgt agaaacacag tcggttctga ccaccagtgg 67080tctgaaggga tactggttgt tagagaataa aaatggcagg aaggcagatg agagtcagca 67140aagagagaga tcctgtaaag taaaagggtg gatagatgga cagaagccca ggtctgacca 67200gcccatggcc aggctttagg ccataagtga caccaaagac atggaaaaat ggtttctaca 67260tgttggacaa cagacagtag tggaccaaaa gaatagtgac agggggaaca atgagatcaa 67320ctccatagat accttggctt tcttcctgga ggcccttctt gcactgaaga gcaaggtgat 67380ggagcccaga tggactgtag ccatcttcct gaatgcagga gagagattgg aatttgggac 67440tactgtggta gctaggattt tataggcctg ctgagaatga gaatggattt gtggatgaaa 67500ggagctccag gggcacgcat agtagtctcc tcgaatcttt ggctaaacat gacgttgcat 67560gtgcccagaa aaaggttcca caagaaagta gagaaaagaa tatatcctga ggaatagcaa 67620ctgcgattga acagtgagct caataaagag gacagagccc tcatagcatt ctgggatact 67680ggagttctga ccagctggag gagagacctc actgaacctc ttgggaatac agtagagact 67740ccagaaaagt catactttag gagtagaatt agtaaatttc tagaaaaaaa ggcagctcta 67800gacaaaccct ggcaaaactg aaaagcaagt ctccaagcat taaaatcatt tccaagtcaa 67860ttaactgcct gggagaggaa aaccctcttt agaggtaaac aacaaagtca agtggctcag 67920ctatgtggtg ttcacagtgt gagttctaaa tttaaaactt gactacacat agagaagctt 67980ttagtatgaa ccatgaccag gtgaaaaatc agtcaataca aatagaccta gaaatgacag 68040aaatgattag aatggcaaaa aatttgacat atcaatatgt caactgagtt ttaggtttta 68100agaaaacatg aatacggaat gaagcagata ccatatcaag agacagtaac agtatagaag 68160agccaaatta aattaaagaa ctagtataag aaggtatgtc ttaaatgaaa aaattactgg 68220atgtattccc aatggagtga gatgtttcag aagtaaaaac taactgaaaa acaattttat 68280accacctaca gaaccagcta cacatacaca aatgacacac acatatacac acatactcac 68340acatgcacag gcttagaaac atgcacgcac acacacacac acacacacac acacctccac 68400aaatactaaa aaatgaaatc cactgatcct cacagacagg cgggaaaata taaaaagatt 68460tcctgcatgt gggtaggaag tcacagaagg agaggaagga gagattgcta caggaacaaa 68520tactggaagc aaggatagct aaaaactttt caaataagaa gaatattaaa aaccacagat 68580tcaagaagct gaatgaatca gacagggaat ttccaaaaaa aaaaaaaaaa aaactgtatg 68640attcactttt gtacatcacc gttcaacagt cagaaggcaa agatataata acaagaaaca 68700tctcatgaga aactggagga

aaaagagctg tgtcttgcta gaagaacagt gatacaaatt 68760gctaatgcat tctcatcaga aacactggaa cccagttaac aggggatatc attaaaatga 68820taaactagaa aaaaaagaga tcaaatgaga atgctacatc cagcaataaa atgccttgaa 68880gatcatccat gttggataaa tgcatattgt gcactgcccc aaataaataa accaaaaact 68940aataatttgg aatcagcagg cttgtgtaac aagagatgtt gcccaaagaa aattagctag 69000aagaagaata gttcaagagg agaactttct gcagcccacg taatgaagaa cccagcaaat 69060ggcaaatgta gatgtaaatg caaaatattt tcttgatcaa atttctatat ctttttaaat 69120gagagttgac tacttgaagc aaaatgatag caatatattt aactttagca tatgtagagg 69180taaaaatttg aacatataga ctaaatcatg tggggaataa ttggaagtgt accattgtaa 69240gtttcttacc ttatccacga tggtatgtaa tattaatgaa aggttgaatt tgtgggtcca 69300aagggatatt gtaaatccta aagcaatcat aaaattttga attctgaggg atattatata 69360ataagaattt tccatgtatc caaaagaggg aagccaagga agaaaaagaa gtctttcaag 69420tactcaagct ctgagcacat ccagttgctc attgaaccag cttcctggaa tggagggtct 69480gggcttgaga ctaggtcaca tgtgtagagt ctctagagag acagtgttgg atccccatgg 69540cccataatac atttcccgtt ttcccaggca gccacaggtc acgaatggga ggattctgag 69600aggttggagc aatgttctta ggaggcataa ggaggagtga atgctctgag atttccccag 69660cctgaggtcc tccatagctg cccgacctct tcagacctca tagtctgccc agctgtctcc 69720ctttatgcca tgagtgccac tgttctttca actcatcccc cattccctca gtcccggaat 69780tgctgtggcc agcagaggat ggactgagag caggagagga agtcctgacc aggaacccat 69840cctagagata ctgcatcctg cctgaaagct aggtttccag ggcagctttg agaagtcttg 69900cagaaagaaa cccacttgac ccacctgata cggtatcgac agacaggaat actttttgtg 69960caatggtttt acatgctgaa catagagcct tttggctaca ttttgagtac attgaatgag 70020actgctggcc tgggaaggat atcatgctgg atgccatttt tttctctgga gaactatgtg 70080ttagttccaa ctcgcacatt actatatgaa gtcctacaca gagagatacg gagagctaga 70140cagatagaga tacttttgta tgtgcataac caattccaca atacacacgt caaaatccat 70200accagttatt ccagagagat ggattgggca gaaggcagaa ggaggatatt ctgatccctt 70260tttggccaca tgtatgtata atctcagtgt ttctaggaag tgtgtgctgc attagatttt 70320ttttctttaa aaaaagtgat aatatattaa gtatgagaaa tgtgcagaga ggattagaga 70380ttgagagcca tttgtcattg tggcaattgt atggtatctc ttttgggaat atttcaaagg 70440caccagtaat gaccttgttg tagcaaaata tacagtgttc ctgcatatgt acccattttt 70500tgtgatgtgt attcttttgg aatttccagt ggcttgatca agaactactg ccgaaatcca 70560gatcctgtgg cagccccttg gtgttataca acagatccca gtgtcaggtg ggagtactgc 70620aacctgacac gatgctcaga tgcagaatgg actgccttcg tccctccgaa tgttattctg 70680gctccaagcc tagaggcttt ttttgaacaa ggtaagaagt tgtgccagac atttacctgc 70740ttggatgctg ggatgaaaag ccatggatac ccccactgac gcacaaccct tcagtgctac 70800actggttctc gtgtgttggt tctgggtctg ccatgtggga ggaagcctta gcgcactctc 70860tgggggagcc agaggtgtga tttttggtgc aacctgtgcg agctgtgtct ttaggatggg 70920cggaaaccat tctgggtgct cgacttcacc actcccctca ttgtaaaagg ggctatctca 70980ttgtcctaga caaaattctt attgtaatat gctgtcagat gtgtgtgtct ttccaagcca 71040gtaaactttt ccagggattt cttcaagtag acagcattca gtgcaatctt cagcattgca 71100gattccgaga aatgtggctc tagatcctgt tatccttgag aaacctaact gggttgcatt 71160aattccatat ctccctgggt ctgtggagta gtacatgagc tcccgaagct ctatctctca 71220ggtctttttc agtccgaggc aggttgtgca gttcttagct ttgaagggag tgattttttc 71280gtgtgctttt gcctctttct gatggaactt gtacctgcgg ggggtctgga gaaaaagagt 71340agtagacttt tgctttattg caatgcatta tgctgggcac gagaggattc cctatcttat 71400tgtaggtgat aagcttttgg cctccactca tccctgagaa gtgaagtgtt gttgcctaca 71460gttttagctg caggactgtt gtctgcccca tcaccaggag tttaatgctt tcttttttga 71520gcaatcatct agggacacat gcaaggtttt tatatgtcct tgcctcctcc ccaaaaaacc 71580attttaatgc ttggagactt gcttttcagc tttgccaaat gcatcaccct ttcttctatg 71640ctgttccatg tcgtcatgaa cactctgtag agattcctag aaatgagctt ccatgttagt 71700ggagtttccg atgagaagca atctgatatt tcttttccac taagttttac atgaaatatt 71760tctaagaact tactacagtt ctagaatggt aggcatctct tactttcgtg tttgtttgtg 71820tgttttctca tgtccatttg cctattaata aagaatagag aatggttgta aatctcagtg 71880actctttttt ggtttatgtc ataaatggct tcctgtattt ttctgttcta ggaaataata 71940agcttgatgt cttctgtttt aatttcagca ctgactgagg aaacccccgg ggtacaggac 72000tgctactacc attatggaca gagttaccga ggcacatact ccaccactgt cacaggaaga 72060acttgccaag cttggtcatc tatgacacca caccagcata gtcggacccc agaaaactac 72120ccaaatgcgt acgtctttgt tctttaccat aagcgaagga agggccaatg gaagtttctg 72180ttagaagagt catgcttcaa ggtgactgct caggactcaa cttggctcag atgcagagga 72240acatttcctg tgagcaaaag ttcttagaga agactttgtt tttttgagac agagtcttgc 72300tttgttgccc aggctggagt gcagtggcat gatctcggct cactgcaagc tccgcctccc 72360gggttcacac cattctcctg cttcagcctc tctagcagct gggactacag gcacccacca 72420ccacacccgg ctaatttttt gtatttttag tagagacagg gtttcactgt tctagccagg 72480atggtcttgg tctcctgacc tcgtgatccg cctgcctcag cctcccaaag tgctgggatt 72540acaggcgtga gccaccgtgc ctggctgaga agacattttt taagctggct ctccttcctc 72600ctagttttat ggaagcagaa ggatatatgg agttgagaag atcttattaa taaaacagcc 72660gggatgacaa atgaccaaag agttagagta tccttctaca acatcggctg agggttaata 72720caaccttttc accttggaat tctatcattc taagctctag tccctgaagt gaatgttgtg 72780ttggcctttt gcatcttggg tcacagggaa ttgatacttg cacatctatg gagaggcaaa 72840tctttttcta tctacttctt tttcaatggg tacaaacaca cttggtcctg agcaccagtg 72900gtctgaagag atacggtctg cccagaggag aagaacaaag gcaggaaagc agatgagagt 72960cagcaaaggg gcgatgctga aaagtaaaag gggcgggtag atggacagaa gccatgatct 73020ggccattcta tggccagtct ttcggccata agtgactacc aaagacacgg caaaacggtt 73080tccacatgtt gaacaacaga tgctagagga ccaagagtat tgcaagaggg agaaaatgag 73140atcaacccat caatgccttg gctttcttca aggagaccct tcctgcactg aagagcaagg 73200agatggagcc caagctgact gtagccatgt tgctgaacag aggagagtga ttggactttg 73260ggattactca ggtagttagg attttctagc catgctaaga gtaagaatgg acttgtggag 73320gataggagct ccaggcatag aagtctcctc aagtgttagt ctaaacataa agcagcactt 73380gcatagaaga ttttccacaa gaaaatatgg caaaaaaaca ccatatattg aggaacaaca 73440actacaaggg aacagtgagc ttaataaagg tgacagagct cacatagtgc tctggaatat 73500tggagttttg accagctaga gagaagagac ctcattgaaa atcttgggca ttcagtagag 73560acctcagaaa agtcagactt tatgagtaga ctttgtatat tcctagaata aaggcagctc 73620cagaaaaaac ctagcaaagc tgaaaagcaa atctccaagc attaaaatgg tgtcctagtc 73680aattaactgc cttctagaag aaaactcaac actctttaca ggtgaacaac aaagttaagt 73740tgctgagcta tgcaatatcc acagtgtgag tcctaaattt ataactttac tacacataaa 73800aaagcattta gtgtgaacca taaccaggaa aataatcagt caataaaaat agaaccagga 73860atgatagaaa tgatttaaat ggcatgagaa tttgacatat tagtatcata actgcattgc 73920tggatttaag aaaacataaa catggaacgt aacagatatc atatcaaggg aaagtaaaag 73980gataaaagag tcaaatcaaa ttaaaggact attaaaaggt atatcttaaa tgaaaaattc 74040actggatggt ctcccaatca ggttagttgt ttccagggaa aaaattaact gaaaaataat 74100tcaatagaat ctacagaaat agctgcacat atatacacac aatggcacac gtgcacacac 74160ccacacccac acaggtgtga atcctagagc cacacgagca ttgaaacata gagaagtaaa 74220aattgttcat tgaggaatat gtagcaatgc tcaatgtgtt ttaccctaat aagagctttt 74280gtgatgtatg attgaaaaac tgacacaact gaagagagaa atagataagc ccacactctg 74340agttagagat ttccttgatt ctctcactat ggttataaat ctttcccaaa cacaacaggc 74400tagaacaaat atgcagaaaa ttagacatag tatctttgtt ctcaataaaa acgtcgacct 74460atttaacatt ataccgaact accgagtaca cattaaagtg tgcatggagc attcactgag 74520gtgtactcta cacatgacct tccagcaagt ctccatagat ttaaaagaat taaagtcata 74580cagagtgtgt cactttattc tcccagaata aagtgagata tgaataatga gaagtttgcc 74640agcttctcaa atatttggga gtcatacggt gcatttcaaa atactctttg ggacaaagaa 74700aacatcacta aggaatttag aaaagttttg aactgagtaa gaatataaca caatttatcc 74760aaacttagga gatgcagtga atgtctttag gcttttacat aattttagat gctcttaggg 74820aaaaacagaa gcatgtaata atcaagattt caaactgcaa ttctcaaagt gtagtctaga 74880gaaacctgag gacctttgag taccttcaga gacagtccat gaggttaaag gactttgcta 74940cgtgaaaagt aagatgctat tggccctttt tactttcatt ttccaacaag agaagagggg 75000agttttccag cagttacata atatgtaatg gcatcatgtc tctgatggct aagaaaatgg 75060gcaattgttg actttgtgtg ttaaaaaaat tctcagtgtt ggtttcttat actataaata 75120ttcatcttgt gttttgaaaa agaaaagctc tttggaatcc cctatgaaca aagactttga 75180cagttgttga tctaagacca cagcttaaat atctacacaa gaaaaaaaaa aaaagcaaat 75240aagagccaag gaaagcagat ggaaggaagt agtccaaacc agtgacattc agtgaacaag 75300aaaagagacc aacaagggag taaactcttg aaacagaaag ttgattcttt gaaaagatcc 75360atatgattga acacagtctg gctaaacaaa tgacagacca atgagggtgc acaaccatca 75420ccatctggag taacagagga gaggtgccat tactatagca tcttccagtt ctgaaagctg 75480aaaagaagat tttgagaaca attgtatgtg aataaattca ggaatgttaa tcatgtgggc 75540caattcctga ggaagacaac aaatcagcaa accagatgct gaatagttag tgtagtcctg 75600tagagagaca tacagagagg ctgacagaga aatatttgta tgtgcataaa acaatctaca 75660agacacactt caaaatcaat ctcagttaat ctggaggaac atatttcaca gaaggtggaa 75720ggagggtatt ctgatcctct tgtacattgt acaacattgt acaatgtaca gagtataatt 75780gtacaagtac aattgaagtt gtacaagtac aagtgcaact tgcacaatgt acagagtaaa 75840cattgatgtt tactctcaat tttcttatgg agcacagatg actttggatg tgttacaata 75900tgaatgataa tttgtctttg agatgttcgc agttgtttag aagttgagga ccatttgtgc 75960atattatggg acctttagtg aaaatatttc aaagtctctt tttacacttt gttacagcaa 76020aatgtagagg gcgctaagtg cccttgaatc ttctcccatc tctggtgacc tgtgttgttt 76080tgaaatttgc agtggcctga ccaggaacta ctgcaggaat ccagatgctg agattcgccc 76140ttggtgttac accatggatc ccagtgtcag gtgggagtac tgcaacctga cacaatgcct 76200ggtgacagaa tcaagtgtcc ttgcaactct cacggtggtc ccagatccaa gcacagaggc 76260ttcttctgaa gaaggtagga agtctatggc cagacaacca caccctagga cgttgggatg 76320aaaagagttg caaaatctta gtgatataga agccttccat gctcacacaa ttccaagtag 76380aatgtggact cagggtcagc cactgggaag gaacactcag cgccttctct gggagaacca 76440gagctgtgat gtttggtacc ctgtgaaagg gtggtatcta taggaagggt gcagaccctc 76500tagggcactg gacttaccac tcccctggtt attcaaagga tcattttagt gtcttagcca 76560gaagaatatt ctaacatttt gccaaatttg tgaagattta ccaagctcat gataagcctt 76620tcatggtatt tcttcaagta gtcagtgttc attgcatctt tggctttgcg gtttcggagg 76680aatgcggttt ttgagtctgt catccttgag aaacctaata tgacttttct tagttccata 76740tacttctggg tccaggtagc agtacatagc caacaaatgc tccatcgttc tggcctatct 76800ccatcttaag ccagtcctgc acaactaggc tttgatggga gggatctctc agtgttcttg 76860cccctccttc tcatggaaca tatatctgtg ttggtctctg agaagaagag tagtggatat 76920ctactttgtt gcaatgcaga atcctgggcc aaagatacca gccatccctc caagggaata 76980aaattttggc cagtagccct ctctgagaga caatttgtct ttgcctacga gtcctagatg 77040caggaccgct tcctgcccca tcttcaagaa gctgaaggct ttggctttgg aggatcagca 77100gtctagggaa atgtgtgacg gtttcatgtc tgtccccact gacagtcaat caccacctac 77160aacctgcaca gcctgatgca tagcagtcta gtttcctgcc ttattctcag gaacacccag 77220aagatgtcta tattaaagag catgcacatg agtgcaattt tgactgatag gcactctgat 77280ctttcctttg gtgcctgtgt tttaaaggaa atctttctaa gaactcgtta aagttctaga 77340atgctatgaa tctttgggtt ttattattgg tatgtccatc tgcctgctag tacagaacag 77400agcatggtag tctttctcag agacaatgat cctgtttcag tcacagattt cttctgatgc 77460ttctgtgttc tagaaattac tcagcttgat ttctcctctt tgaatttcag caccaacgga 77520gcaaagcccc ggggtccagg attgctacca tggtgatgga cagagttatc gaggctcatt 77580ctctaccact gtcacaggaa ggacatgtca gtcttggtcc tctatgacac cacactggca 77640tcagaggaca acagaatatt atccaaatgg gtacaacctt gagttttctt caaagacaga 77700cagcagcccc cttacatttc tcttggaagg gccatgcttc caactaactt cttatgacaa 77760atttatctca gatctggaat gttgggtaga atgtctcagg cttctttctt caggcacagt 77820gtctgaaagg agagaaatgt caggccagct ctcttttctc atagttgaca gaagcaggag 77880gatatttgaa ggtggtgagt tctcatgaat agaaagctca ggacacatgg ccacgtgctt 77940agaaatagca ccattccaca atgcccacta aagaccaatg caatagttca accagggatt 78000tctgtcattc taatctccaa gtcctgaagt gaaggttgta ttagccatgt tcatcttggg 78060caacaaataa aggatatcta tgttgacatc cagatcttcc aatcactttc tcctctaacc 78120tgtacctggg ttctgagaac aaggtatctg aagagctatg tgttgccagc acatgagggg 78180caaaagtagg aaggcagctg agagtcagga agtataaaga ttctgaagag ttacacatgc 78240aggaagatgg acagaaaccc agttcagacc acgtcagcgt ttctgccatg aaggactatc 78300aaatacatag gaaaagtgtt ttcataggtt ggacaacaga catgacaggc ctgagaaaat 78360tcagaaaggg aatcaaagga gatcaacctt atcatgtccc tggcatcctt ccttgagacc 78420cttgaagggc aagcagatgg agcccagctg accacagcag tcttgcttaa ctgaggagag 78480agactggagt ttgtgatgcc tcaggcatct gacgtattct aggctggcta agaatgagag 78540gggatttgtg gaggaaagga gctccaagaa tacacaccga agtcttctca aggctttggc 78600taaatacaaa gctgcgtatg cacaaggaga gttttcacaa agaaagaaca ataaagaaaa 78660gctactgggg aaagaacaac tgcaagggaa cagtgagctc aatggagatg ctagagctca 78720catagcactg ggggatattt gagttctgac cactcagagg agagacacct cactgaacat 78780cttgggcatt cagtagaggt caaagaaagc cataatttgg gagtaggatc ttcggattcc 78840tagaaataag gtgactccag aaacactcca gcaacccttc ttccaagcca gtctaaaagg 78900atccaaatga tttccaagta aattaactgc cttccagaaa aaagtaaact caaccctcct 78960tagaggtaag gaacgaatac aagtttctca gttatatgac atccccagag tgcaacttgc 79020atttaaaaat ttactagaca caaaagaagt tttcactgtg atccataact gggagaaaaa 79080tcactcaaca caaataggcc cagaaataat agaaattatg gcattggcaa gaacatttaa 79140aatgcacctc tgagaactgt gtttcaggaa aatgtcagca aaagctgacc atgagagaaa 79200tgaatgcata atatcagaaa agaaaagaat tgaagagcca aatggaaatt taaaaactga 79260gaaaagttat atctgtaatg aggaattcac tggatggcct tataaccagt ttagatatta 79320tggtaggaaa aggtgaacga gaaaatgatt caattaaagc tagacaaacc acaagacaga 79380cagacagaca caaatacaca tacacacaat gactgaacca attaatcaac agagcctcaa 79440ggacatctag gaaaacatcc acacatttaa tatatgtgtt aggcaagtca cagaaagaga 79500ggaaaaagat aatgtgacag aagttatact tgaagccatg acggctgaca aatttccaaa 79560catacagaaa atgagaaatt catagtcatg aagctcaatg actcaggtat agatttttaa 79620agagcaaaac tctgatttac tggggtacat catagttaaa ttgtctgatt tcaaagctaa 79680gaagaaaaaa agggggttcc tatgaacaaa cattttgaca gttgatctaa gaccacagct 79740taaatatcta ggcaaggaaa agcaaataag acacaaggaa aggggatgga tggaaatagt 79800ccaaaccaat gacattcagt gaacaagaaa atagaccaac aaaggagtaa atccatgaaa 79860cagaaagttg gttctttgaa aagattcatg tgattgacca cagtctggct gaacagatga 79920cagaccaagg agggagtaca accatcacca tttgaagtaa caggggagag gagccattgc 79980tataccatac tccaggtctg aaagctgaca agaagatatc aagaaaaact gtatgtgaat 80040aaattcatga atgtagatca tgtggatcaa ttccttaggt aaacaacaaa tcagcaaacc 80100agatactgaa tagattgggt actcctatag aaagacatac agatagccag acagagaaac 80160atttgtacgt gcataaaaca atctacaaga ctcacttcaa aatctctcag ttaatccaaa 80220gtaacatatt tggcagaagg tggaaggagg gtattctgat cctttcttgt acacattgat 80280gttttctctc ggttttctta tggagtatag acgagtttgg atgtgttaca ataagaatga 80340taatctgtct ttgaaatgtt cacagttgtt tagaagttga ggacgatttg tgattgttac 80400aggaccttta gtgagaatat ttcaaagtca ctttttacca ctttgttaca acaaaatgta 80460gaggatgtct ggtgcccttg tatcttctcc catctctggt gaactgtatt gttttgtaat 80520ttgcagtggc ctgaccagga actactgcag gaatccagat gctgagatta gtccttggtg 80580ttataccatg gatcccaatg tcagatggga gtactgcaac ctgacacaat gtccagtgac 80640agaatcaagt gtccttgcga cgtccacggc tgtttctgaa caaggtaaga agtctctggc 80700cagacaacca cacccttgga cgttgggata aaaagagttg caaaatctta gtgatacaga 80760agccttccat gctgcacggg aatctgaatg tggactcagg gtcagccaat gggaaggaag 80820cctcagcgcc ttctctgggg gaaccagggc tgagattttt ggcaccccgt gacagggtgg 80880tgtctttagg aagcgtgcag accttctagg gcactggatt taccactccc ctggttattc 80940aatagattat ttcagtgtcc tagtgaaaat ggatattcta acatcctgcc aaatttgtga 81000tgatttacca agctcatcat gagcctttcc tggtatttct tcaagtagac agtactcatt 81060gcaaacttca gctttacagt ttcagaggaa tgtggttttt gagtctgtca tccttgagaa 81120acctgatatg actttactta gttccatatc ctcctgggtc taggtaacag tacatagcca 81180gcaaatgctc tatctccctg tctaccttaa tcttaggcag gtgctgcaca cctaggcttt 81240gatggaaggg atttcttagt gttcttgccc ctccttctca tggaacacgt atctgtgttg 81300ctgtttgtga agaagagtag tggatgtcta ctttgttgca atgcaggatc ctgggcccaa 81360gatttcccgc cgtccctcca agggaataaa attttggcca gtacccctct ctgagagaca 81420atgtgtcttt gcctggaagt cctagatgga ggaccacttc ctgccccatc ttccagaaac 81480ttaaggcttt ggctttggag gatcagtgct ctggagaaat gtgtgacggt ttcatgtctg 81540cccccactga caaccaccac ctacagcctg caccgcctga tgcatggcac tctggtctcc 81600tgccttgttc tcaggaacac ccaaaagaga tctttgccaa agaacaggca catgagtgca 81660attttgactg ataggcactc tgatctgtcc tttggtgccc aggttttaaa gaaaatcttt 81720ctaaaaactc attgaagttc cagaatgcta tgaatctttg agctttgtta ttggcatgtc 81780catctgccta ctaatgtaga acagagcatg gtcgtcattt tcagagatga tgtcctgttt 81840ctatcatgga ttttttttct catgcttctg tgttctggaa attactcagt ttgttttctc 81900ctctttgaat ttcagcacca acggagcaaa gccccacagt ccaggactgc taccatggtg 81960atggacagag ttatcgaggc tcattctcca ccactgttac aggaaggaca tgtcagtctt 82020ggtcctctat gacaccacac tggcatcaga gaaccacaga atactaccca aatgggtatg 82080tctttgagtt ttctcccaag agaaacagcc acccacttaa atttctcctg gaagagccat 82140gcttccagct aacttcttat gacccaattt ctctcagacc cagaatgttg gacagaatgt 82200ctcaggcttc ttgctttggg cacagggtct gagaggagag aaatgtcagg ccagctctct 82260tttctcatag ttgatagaag taggaggata cttggaggtg gtgaggtctc atgaatagaa 82320agctcagaag aacatatgac catgtgctta gaaatagcac cattccacaa tgcccactaa 82380agaccagtga aatagttcaa ccagggaatt ctgtcattct aatctccaag ccctggagtg 82440aaggttgtgt ttgccatgtt tgtcttgggt aacaagtgaa ggatatctat attgacttcg 82500agatcttccg atcactttct cctctaacct gtataaacac attgggttct gagaacaagg 82560tgtctgaaaa gctatgtgtt gccagcccat gaggggcaaa aggaggaagg cagctgagag 82620tcaggaagta tagagatgct gaagagttac acattcagga agatggacag aaacccatgt 82680ctggctatgc cagcctttct gccatgaagg actatcaaat acatgagaaa acagttttca 82740caggttggac aacagatatg gtaggcttga gagaactgag aaagggaatc aaaggagatc 82800aacttcatca ttaacctgtc ttccttcctg gacacagtgt tggattgaag gacaagcaga 82860tggagcccag ctgaccacag cagtcttgct taactgagga gagagactgg agtctgcgat 82920gcctcaggca gctgatgtgt tctaggctgg ctaagaatga gaagggattt gtggaagaaa 82980ggagctccag gaatacacac agaagtctcc tcaaggcttt ggctaaatac aaagctgcgt 83040atgcacaggg agagttttca taaagaaaga acaacaaaga aaagctactt gggaaagaac 83100aactgcaggg gaacagtaag ctcaatggag atgccagagc tcacatagca ctgggggata 83160tttgaattct gaccactcag aggagaaaca cctcactaca ttttgggcat tcagtagaga 83220ccaaagaaag ctgtattttg ggattgggat catcttattc ctagaatcaa ggtgactcca 83280gaaaaactcc aacaaccctt cttccaagcc agtctaaaag gatccaaatg atctccaagt 83340aaattaactg cattccacaa gaaaaaaaaa actcaacccc ccttagaggc aagggacaaa 83400tacaagttgc tcagttatat ggcattccta ttgcgttact tctatttaaa aatttaatag 83460agacacaaga agctttcact gtgatacata actgggagaa aaaatcactc aacacaaaca 83520ggcccagaaa ttatagaatt gatgacattg gtgagaacat ttaaaatgca cctctgagaa 83580ctgtgtttca ggaaaatgtc agcaaaagct gaccatgaga gaaacaaaag cagaatagca 83640agagaaaaga aaagaaccgg agagccaaat gaaaattaaa gaactgagaa aaggtacatc 83700tctaatgaag aactcactgg atggccttat catcacttta gacattacgg taggaaaggt 83760gacctagaaa ataattcaat

aggagctaca caaatcacag gacagacaga cagaccaaca 83820gacagaaaca cacacacaca cacacacaca cacacacaca cacacacaca cacacaaaga 83880ctgaacctat taatcaacag agcctcaagg gcatctagga aaaatccaca catttaatat 83940atgtgttagg caagtcacag aaggagaaga aaaagatatc atgacagaca ttatacttga 84000agcgatgatg gctcgcaaca cgccaaatat acagaaaaca agaaactcat agtcaagaag 84060ctaaatgact caggtataga attttaaaga gcaaaactct atgatttact gggatatatc 84120atagttaagt tgcctcaatt caaagctaaa aagaaaaaaa gggggttcct atgaacaaca 84180gctttgacag ctgttgatct aagaccacag cttaaatatc taggcaagga aaagcaaata 84240aggcacaagg aaagaggatg gaaggaaata gtccaaacca atgacattca gtggaaaaga 84300aaatagacca acaaaggagt aaatccatga aacagaaagt taggttcttt gaaaagtcta 84360tatgattggc caaagtctgg ctaaacagat gacagaccaa ggagggagca tatccatcac 84420catcatgagt aacaggagag agatgccatt gctatagcat cctccaggtg tgaaagctga 84480gaagtagata ttgagatcaa ctgtatgtaa ataaattcat gaatgtagat catgtggatg 84540gattgcttag gtaaataaca aatcagcaaa tcaaacactg aatagatcat gcagttttat 84600agagacttac agacagcctg acagataaac atttgtatgt acgtgaaaca atctccaaga 84660cacacttcaa aatccctctc ggttaatcca aaggaatgta tttggcagaa ggtagaagga 84720gggtattctg atcctttctg gtacacattg atgttttctc tcagttttct tataaagcat 84780agattacttt gaatgtgtta caataagaat cataagctgt ctttgaaatg ttgacagttg 84840tttagaagtt gaggaccatt tgtgagtgtt atgggacttt agtgagaata tttcaaattt 84900gcttgtttac actttgttac aagaaaacat agagggtgcc aggtggtgct gtatcttctc 84960caatctctgg tgacctgtat tgttttggaa tttgcagtgg cctgaccagg aactactgca 85020ggaatccaga tgctgagatt cgcccttggt gttataccat ggatcccagt gtcagatggg 85080agtactgcaa cctgacgcaa tgtccagtga tggaatcaac tctcctcaca actcccacgg 85140tggtcccagt tccaagcaca gagcttcctt ctgaagaagg taagaagcct gcagtcagac 85200aaccataccc tcggacattg ggataaaaag atttgcaaaa tctttgtgat gcagaaaact 85260tccatgctgc acaggaagtc gaaggtgaag tcatggacag ccaatgggaa ggaagcttca 85320gtgccttctc tggggggacc agagctggga tgttgagtgc cttgtgaggg atggtgtctt 85380taaaaggggc acagaccctc taggacactg gatttatcac ttccctgtta tcaaacgaat 85440catattagtg tcctagccaa gatggatatt ctaacatcct gccaaacttg tgaagatata 85500ccaagctcct aagcctgtcc agccctttct tcaagtaggc agtgtttatt gcagtcttca 85560gctttaccat tttgaaggaa tgccattttt gaggctgttg ttcttgagaa acctaacatg 85620tcttcattag atccgtattg tcctgagact ttgaagcagt acatagccac caaattgttt 85680atctccccag cctaccttca tcttgggcat gccttccaca cctaggattt gagggaaggg 85740atttctcagt gttctcatcc ctgcttctca tggaacattt atctccgttg ttttttgaga 85800agaagagtag tggatgtcag ctttcttgta atgagggatc ctgggcccaa gattccctgt 85860ctcccctcct aggctataaa attttggcct gtactccttc tccctgagag gcaatgtgtc 85920tttacctaca agtcctagat gcaagatcct tttctgcccc acaccccaga atctgaaggc 85980ttttgctttg gaggagcagt ggtctagtgt gcaagggttt catgtatacc ccccactaac 86040agccaatcac cacctatagc ctgaacagct tgatgcatgg caccctggtc tcctgccttg 86100ttctcatgaa cacccagaag aggtgtaagc aaaagaccat tcacatgagt gtaattttga 86160agtataggca ctctgatctg ttttttgttt gtttctttgt ttgtttgttt tccagggttg 86220aattaaaata tttatgacta cttattaaat ttctagaatc ctataagtct atttgtattt 86280ttattctaca tttcaatttg catgctaata tagaagagtg taaattgtta atcctcagat 86340tattccactt tgtgtgtcat aatttttttc acatttccct tttctaggca atactgagct 86400tgattttctc ttttaatttc agcaccaact gaaaacagca ctggggtcca ggactgctac 86460cgaggtgatg gacagagtta tcgaggcaca ctctccacca ctatcacagg aagaacatgt 86520cagtcttggt cgtctatgac accacattgg catcggagga tcccattata ctatccaaat 86580gcgtatgtct atcatgttag ccataaaagg aacaatagtc aactaaaatt tctcttagct 86640ggcccatgct acaagctcac ttcctaggtc caaatttctc atagactcag agtttgtagc 86700aaaatgtctc aggaaactta cttttgagca aaaggtctga atgaagagaa gttttaggat 86760tgctatcttt cataacaatt tgatggaagc agcaggatat atggaggtgg tgaagtctca 86820ttaatgtaaa gctaaggaga tcaaatgacc aaatgctgag acaaagtatc attccacaat 86880gcccactaaa ggtccatgca gtctttcaac catgcaattc tatcattcta tcctccattc 86940cctgaagtga aatttgtgtt tgccattttt gacacgaatc agaagtaaca aattcaggct 87000gggtgcagtg gctcaggcct gtgatcccaa cactttggga ggacaagacg ggcagatcac 87060cagaggtcag gagttcaaga ccagcctggc taacatggca aaaccccatc tctacgaaaa 87120attaaaaaat tagccggtca tggtggtggg tacctgtaat tccaactact tgggaggctg 87180aggcaggaga aacacttgag cctgggattc agagtttgct gtgagccgag aacatgccac 87240tgcactccag cctgggtgac agagcaagac tcaatctcaa aaaaaaaaaa aaagaagaag 87300aagaagaaaa gaagaagagg aagaagaaga agaggaagaa gaagaagaag aagaagagga 87360agaggaagag gaggaggagg aggaggagga agaagaagaa gaagaagaag aagaagaaga 87420agaagaagaa gaagaagaag aagaagaaga agaagaaaat agaaatgagt gcatatattt 87480atatatgagt actagcctgt atgaacacac tgggttctaa gcaccagttt tctgaaggga 87540tatgggttgt caggcagagt aaaagcagga atgcagatga gagtcaggaa gtaaacagat 87600gtggtgatta aaatgggcag gtacatggac aaaaaaatgc atgtctgaca aaaactggcc 87660tcttgccata agtgagtatg aataatatgg aaaaactgtt tgcacatgtt gaacagcaga 87720cagtacaacc tgagatagtt tagaaaggga aacaaataag atcaacccca taattaccct 87780tcctagactt aagggcaaag agttttaacc aaagcattcc acagcagtct tgctaaactg 87840gggagagaga ctggagtttt gtttactaat aaaaccgaga ttttctaggt taggtaataa 87900tgagaaagta tttgtggaga aaaggagctc caggaataca cacagaagtc tcttcaagtc 87960tctggctgaa cagaaagctg tgtatgcaca gaaagagttt ccagagagaa aggagaacaa 88020agaacagcta ctggggaaag aacaactgct ggggaacagt gagctcaatg aagatgccag 88080agctcacata gcactgggag gtatttgagc tctgaccagc ctgaggagag acacttcatt 88140gaacatcttg ggcattcagc aaagacccca aaaaaccata cttcaggagt agaattaatg 88200cattcctaga ataaagtcta ctccagaaac accctagaaa agcttagaaa ccaagtctaa 88260aaagatccaa atgatctcca agtaaattaa ttgcctgtca gaagaaaaca acctcttcag 88320aggtaaacaa caaaattaaa ttgctcaatt atatagtatg cacaatgtgt ggcatacatt 88380taaaaatttg ctaaacatac aaaaagcatt tagtgtgacc cataaccagg agaaaaatca 88440gtcaatacaa atagacccaa aaatgataaa aataacagaa ttggcaagga gatttaaaat 88500gtatgtatca taattgtgtt caaggattta aagaaagcgt ggacaagaaa taaataaatg 88560gataatatca acagaaagaa aaattgtaaa aggaccaaat ggagagtcaa gaactgaaaa 88620aaaagacatc tctttaatga gaaaatcact acatggcctt ataatcatat tagatagtac 88680agatgataaa gctaactaga aaatattagg gtggtgcaaa ccatagcacg cttatacaaa 88740gcctgagaag ataaacagag cctcaaggac atctatgaaa atatcaaaat atttaatatt 88800tgtttaaagc aagtcacaga ggaagggaaa gagatattgg aacagaaaaa atacttgaag 88860cagtgatggc tgatgacttt ctaaatatgg aaaaaatgat aaactcacat agtcaagaag 88920ctcaatggat cagatatagg attttaaaaa gtaaagctgt atgatttatt tggacacatc 88980ataattaaat tgtccataat caaagataga aagtaaaatc ttatttgaag cccaagggaa 89040aaaacatacc tttacataga gtaacagtga cacaaatgac tgatgccttc tcatcagaaa 89100caacacaaat cagaaacaat agaataacac ctttagagtg gtaagaagaa aaaaagatca 89160aatcagaaac aacaaaataa cacgtttaga gtggtaagga ggaaaacaag atcaaatcag 89220aaacaatgga ataacacctt tagagtgtaa gaaagaaaaa aagatcaaat caggaacaac 89280agaataacgc cttcagagtg gtaagaagga aaacaagata aaatcagaaa caatgaaata 89340acacctttag agtagtaaga agaagaaaag atcaggtcag aaaaaatgga ataatatgct 89400aagaagaaaa aaaaagatca agtcagaaac aatggaataa cacctttaga gtgaaaagaa 89460ggaaaaaaac ccagcaagct taaacgctat gcacagcaaa caattccact gaaaatgaat 89520gttacgtaag tacatattct gtcctcctaa aaacaaagaa caaataaaag aatgtttcat 89580cagcaggatt atgtaataaa agatgtgaaa gaatgctatg taagtagaag aaaaataata 89640ccatatggga attggcatca aaaccacaaa atactatcaa aacaaaaaaa ctttattgat 89700aaatttaaca caatatgcaa aagaactata ccatgtatac tacataacat tggtgagaag 89760aaaattagaa gatctaaata aagacacatc atgcttatag attaaaaaat ccaatgtcac 89820ttttcacaaa actgatcttt agtttcaacc cacacccaag cagaattcct gcagtctttt 89880cttgaaaacc taacagaatg tatatgctag aatcaccaag acaatcttta aaaagaataa 89940aaaacttgga ataaaatcac aagtttgtgg gatagatgca tatggtaata tggaaattct 90000cataaagaca cagtaatcaa gacatgtggt attggctggg acgcttggct gtaatcctaa 90060cactttggga ggccaagatg agaggattgc ctgagatgag gagttgcaga caagcctggg 90120caacatagca agaccctcat ctctacaaat atttaaaaaa attagccagg tttggtgcca 90180tgtgcctgta gtcccagcta ttcaggaagc tgaggtggga ggatcactgg agcccatgag 90240gtggaggctg aaatgagcca tgattgtgct actgaacttt agcctgggag acagattaaa 90300accttccctc tctctctcaa acaaacaaac aaaaaataca tagtattggg caaaacatat 90360gcaaacaaaa acagaaaagg gtcagcataa atttacatat atggtcaatt tattttcaat 90420acaggtagca aagcaattta atgaggaaat ttttttccaa aattggtctg aaacaactgg 90480atagccatag aaaaaaacta taacaaatgt gacgcttgaa tcctactgta tgactcaaat 90540taaattaatt tgagatagct cttagacctc aatgtaacag ctaattctga ggctgaaata 90600taagactgct atgaaaaagt atagtatctt ataaccttgg agaaggaaaa attttttgag 90660ggaagaacca gaaaacacta actgtaaaag aaaacaaatg ataatgtgga cattcattga 90720ataaaaactt atgctcacca aatatgactg ttaagaaaat aaataagtaa gtaacacact 90780ggaagaaaaa cactctcatc catatatctg acaaatggcc tgtatccaga gtatagaaac 90840atttctccca ctcactaatc agaggacaaa caacctaatc aaaatgggca acaggcttga 90900atagtcattt cttaggagaa gatgcacaca gagccaacaa tcacctgaaa aagtgcacaa 90960catcttagcc atcaaaaatc aagagttata accctcataa gatgacactg aacatccagt 91020gtacatggat atcattaaga agacacaata ataagtggtg tcaccgattt ggagctagaa 91080tgtgccactc tctcatatgc tggtggaagt tcaaaatcat acaacaaatt aaaaaatcag 91140tctgatgctt tcttataaag ttcgataaat atgcatctat cctacaaacc tgtaattcta 91200ttcttgaata tttacccccc aaaatgaaaa cataagtcca caaaaatcta tataaatatt 91260catagcagct ttatgtttta taaactcaaa ataaaaacta tttcaatgtt ttcatcaaaa 91320gaaaatgaaa actatttaaa tggtttcatc aaaagaaaat gaaaaaagaa tttccagtat 91380atttatacaa aggaatacta ttcatcaaca aggaacaagt tactgatagt ctcagaagca 91440tgaacaaacc tcaaaaatat attaaggaaa gaagccagac gtcaaagtgt atagtctgta 91500tgagtccatt catgtgagtt tatagaaaac acaatttatg gtgaaagaaa ccaatagcat 91560ttgacactgg ccgtgggaag agggtagcag agattgattg agcagccaca caagggagtt 91620tctggggtgg tgaaaatgtt ctgcattgtg agggcagtgt gggctacaca agtatatgta 91680tttatcaaat ctcatccagc tacatttaag atctgtgcat ctcactctat gtgaaaatat 91740actcaactga aaaacagagc aggtatctgt ttcaggtgct acatcacttg atacgtccag 91800ttgtgttaaa aaccactgcc taacatcctc aaatggggga tctgggcttg agactaggtc 91860acatgtgtag agtctctaca gagaccgtgt tggattccca tgctccataa tacgttccaa 91920gttttctcag acagccacag gtcatgaatg tgaggattct gagaggttgg agcaacgttc 91980ttgggaggca taatggggaa ggcattctcc aagattcctc cagcctgggg tcttcacctg 92040ctgtgcctct tactgcattg ttttctgact catccatagc cacttgaccc cttcagatcc 92100catagtctac ctagccgtct ccctttatgc cttgggtccc gctgttcttt caactcatca 92160cccattcctt cagtcccaga gtggctgcag ccagcagagg atggactgag agcaggagag 92220gaggtcgtgc ccatgaaccc atcctagaga agcagcatcc tgcctgggag ctagttttcc 92280agggaagctt ttataagtcc tgtagaccca aacccacttg ctctaccaga tacagtattt 92340atagtaatac tattttcatg attattttat attgcaaatg tagagcattt atgctacact 92400atgagtaaat agagtaaggg ggctggcatg ggaattatat aatcttggat gccacttctt 92460ccttggggaa atgtatttga gttccaactt acatattact atatagtctt atagagagag 92520agacaaagag ctagacagac agagatatct ttgtatgtgc attaaaaaat ctaagataca 92580tatttcaaaa tctgtgtcat ttattctgga ggaaagtatt tggcagaagg tgaaaggaag 92640atattctgat cctttcttgt acagacatgt attatctcag ttttcataga gagcatatac 92700tacttttgat gttttaaaac aaaaattata atctgtgatg tgtccacagt tgtttaaaag 92760ttgaagctga agaccatttg tgcttgtggc aatattattg tggtataatg ggaatatttc 92820aaaggcactt gttaacactt tgttacagca aaatgtagag ggcgctaagt gcccttgaat 92880attctcccat ctctggtgac ctgtgttgtt ttgaaatttg cagtggcctg accaggaact 92940actgcaggaa tccagatgct gagattcgcc cttggtgtta caccatggat cccagtgtca 93000ggtgggagta ctgcaacctg acacgatgtc cagtgacaga atcgagtgtc ctcacaactc 93060ccacagtggc cccggttcca agcacagagg ctccttctga acaaggtaag aaatttgtgg 93120ttagacatct atatactggg atgaaaaacc atggaaaatc ttactgatgc agaagccttc 93180agtggtacac tggagggttg gttgagggtc tgcaatgtgg aggaaagcct cagcgccctc 93240tctgggggat ccagaactgt gatttttggc acgctgtgag gaggcagtgt ctttaggaag 93300ggcacggtgt ctttaggaag ggcacagacc cgccagggca ctggacttac cactcccctg 93360gttattaaat gggtcatttc agtgtcctag ccaaaatgga tattctaaca gcctgccaaa 93420tatgtgaaga tttccaagcc aataagcctt tccagtgatt taaagtagac ttttttcatt 93480gcaatctaca gtttgcagtt tcttaagaac atggcctttg agtatgatat cctagagaaa 93540cctaaggaga ctgcattatt tttctattgt cctggggctg catagcagga ggtaaccaac 93600gaatgctgtc tctccctggc ctatctcagt ctttcacagg ctctgttcac ctcagctttg 93660aagttagaaa tttctaggtg ttcttgcctc ttcttctcat gaaacctgca ttggcagtga 93720gtctacagaa gaagaggaag agaattctgc tttgttacaa ttcaggactc tgggcactag 93780aagattccct atctctcctc caagggaata agttgtttgt ctctaaccct ccttgagaaa 93840caatgagtct ttgcctgcac tcctaaatgt aggatgattt cctgcccaaa ttttcaaaag 93900attaagcctt ttgccttggt atgagcaatg gtctagggaa atgcgcaagg gtcttgtgtc 93960ggcccctgac tgaccaccag tcacctccta cagcctgcac caaggaatgc attgcattct 94020ggtcttctgc cctgtggttc tcatgaaaac cagcagagat tcatatgatg gagctgcaca 94080tgaatgtaat ttccaatgtc cagcattctc ctctgttctt tatctttaga tttaaaaata 94140atgtttctat gaacttatta aaattctaga atactatgaa tctactgggt cttttcacat 94200ccttttgcta ctagtagaaa aaagaatagt aataattttc agaggctact gtccagtatg 94260tgacataaat tgtctcccat gtttctctgc tcatgcaatt actgagtatg atttatttta 94320ttttaatttc agcaccacct gagaaaagcc ctgtggtcca ggattgctac catggtgatg 94380gacggagtta tcgaggcata tcctccacca ctgtcacagg aaggacctgt caatcttggt 94440catctatgat accacactgg catcagagga ccccagaaaa ctacccaaat gcgtatgtat 94500ttgattaaaa ccataagagg agcaacagcc aactcaaata ttggttagaa gacccatgct 94560ttaagctcac ttcctaggga caaatttctc ttagactcac attttggcaa aatgtctcag 94620gacctttgct tttgagcaaa gagtctaaga gaagagaaat tttaggcctg ctatttttcc 94680taatagtttt atggaaggag tagaatatac ggaagtggcg aagtcatatt aatgtaaagc 94740tcagaagata aatgaccaaa gcttaaacac agcaccattc cacaatgccc actaaaaatc 94800aatgtcatct ttcactcgtg caattctgtc attctaaatt tcaattcccg aaggtttgtt 94860tgccattttt gtcatgggta ataagtaaaa aaaaaaaaat taagatgtgt atatatatat 94920atatatatat atatatacac acacacacac acacacaaac atctgaatat ttatatatat 94980gtctgaatat ttatatactt gtgtataaaa cttatattta aatttttgca taaatttata 95040tatttttaat atttcattaa aaattatatt gtttcactat gtatgtctga gtatttttat 95100atattttaat ataacatttt aaatatttat atataaatat tcaggtatgt aactgaatat 95160tcatttacac acacaaatat atgtgtgcat gtgtgtatat atatatatac ccatatatat 95220atatatatat atatatacat atatatatat atatatatat gtatatatat atatatatat 95280atatatacac acacacacac acacacatac atacaggtat aaacacactg ggcctgaagc 95340accagtggtc tgaaaggaca tgtgttgcca ggacttgaag agcaaaagca ggaaggcgga 95400tgagagtcag gaggtacaca aacgctgaaa agtaaaatgg acaagtacat ggacaaaaag 95460caggtataag cataacagcc ttttggaagt aaatgactat aaaatatatg aaaatactgt 95520tttcacaagt tgcacaacag atagtagtgt attgagataa tttagaacag aaaacaaatg 95580tgatcaaccc cataagtgtg ctgtatttca tcatggattg aaggaaaaag agatggagcc 95640caagaagacc acagcagtct tgatgaactg agagacacca gagtttggga ttacaaaggc 95700agctgggatt ttctacactt ggtaataatg agaaagaatt tgtggagata aagagctaca 95760gtcatgtacc tagaagtcac ctcagtgtaa tataaatctg catatgcaca gggagtgatt 95820ccacaatgaa agtaggacaa agaacagcta ctggggaaag aataactaca agggaacaat 95880gagttcaatg gagatggcag agctcacaaa gcactggggg atatttgagt tcttaccagc 95940tagaaaagag acctcattgc aaatcttggg cattcagtag agaccccaga aaagccactc 96000tttggaaaca gagttgatgt attttaagag caaaatctac tccacaaaaa tcctagcaaa 96060attgaaaagc aagtcagaaa gaccaaaatc ctctcaacat aaattagttg cccatcagaa 96120gaaagcttaa cctcttcata ggtaaacaat aaaatcaaat tgctcagtta tctggcatcc 96180acaatatgtg acataaattt aaaaatttac tagacataca agaagcattt agtgtgatcc 96240ataaccagga gaaaaatcat tcaatacaaa tagacccaga aatgacagaa atgatagaat 96300tagcaaaaac atttaaaata tacatatgat catttgatct tgtgatcaga tatcacaaga 96360gaagaaagag atacttgaac agaaaaaatg cctgaagcaa tgatggctga aaactttcca 96420aatatgaaga aaaaaaagct cacagattca agaaaactaa tcaatcagaa atatgatttt 96480gaaaagtaaa aatgtatgat ttactttggc aaatcttctt ggttaaattg tctaaaatca 96540aagaaagcta ggaaaatttt ataagccaga ggaaaaaaga ttgtttatat aaaggaacag 96600ttacacaaat gactgatgcc ttctcatcag aaacaatgaa agtcagaaac aataaagtaa 96660catctttaaa gtaatagaag aaaaacccaa gaggtgaggg atcgtggcag acaggaggca 96720ggactagatt gcagctctgg acagagcagc atgcagaggc tcatattgtg aattttagcc 96780ccatattgac tgcaagaaca gaccagcaat cctgagagga cccacagacc gtgtgaagga 96840agcagactgc tcctgcagga taagggagac accccaaata ctgtgagttc cccaactgca 96900gaagtggaaa agggaggcct tactccctca aacacacccc acaactggag aagctgaaag 96960tctgtttgca ggagaagttc ccaactttac ctgggcctca gtaaatttag agagctgagc 97020caagcaaaat ataggggtag aggaagcagc agagaagacc tcagagcttg ctggatcccc 97080aagcagctca ttcctgcctg gcaccacaga gatccatcag aagtgtggcc aaaggaacag 97140agggtaaaac tccacatgga ggactgctct acctgaactt tctaacaatt tgaacagggg 97200gagaagcctc ctggccagaa cttgggggag ggcatgaatc tggtttgcag acttcacagg 97260tgggggaagg actaaagccc ttttctttca cagctgggag gtggaaagcc tcaggcaagt 97320tttcaagcct gactttcccc ccacctggaa acagacttgg agctgttgcg gggttggggg 97380catggtggga gtaagaccag cccttcagtt tgcatgggtg ctgggtgagg cctgtgactg 97440acagcttccc tccacttccc cgacaactca gatgactcag cagaggcagc cataatcctc 97500ctaggtacac aactccagtg acctgggaac ttcaccccca caccatacag aagcttcagt 97560aagacgtgcc caaggaaagt ctgagctcag acacgcctag tcccaccccc aactgatggt 97620ccttccctac ccaccctggt agcagaagac aaagagcata taatctttgg agttctaggg 97680cccacccacc tctagtccct ctccacacta gtatagctga tgcaggaggc caaccagcac 97740aaaaatagag cattaaacca ccaaagctag gaacccctat ggagtccatt gcaccctcct 97800ccacctccac cagaacaggc actggtatcc acagctgaga gacccataga tggttcacat 97860cacaggactc tgtacagaca gtccccagta ccagcccaga gctgggtaga cttgctaggt 97920ggcaagaccc agaagacagg caataatcac tgcagttcag ctcacaggaa gccacatcca 97980taggaaaaga gggagagtac tacatcaagg gaacacccca tgggataaaa acatctgaac 98040aacagccttc agccctacct tccctctgac acagtctacc caaatgagaa ggaaccagaa 98100aaccaaccct ggtaatatga caaaacaagg ctcatcacac tcccagttca ccagcaatgg 98160atccaaacca agaagaaatc cctgatttac ctgaaagaga attcaggagg ttagttatta 98220agctaatcag ggagggacca gagaaaggca aagcccaatg caaggaaatc caaaaaaaaa 98280aaggtataag aagtaaaagg tgaaatattc aacaaaatag atagcttaat aaaaaaacaa 98340taaaaaattc agtagacttt ggacacacct ttggaaatgt gacatgctct ggaaagtctc 98400agcaatagaa ctgaacaagt agaaaaaata aattcagagc tcaaagacaa ggacttcaaa 98460ttaacccaat ccaacaaaga caaagaataa aggataagaa aatatgaaca aagccttcaa 98520gatgtctggg attatgttaa atgaccaaat ataagaataa tcgtggctcc tgaggaaaaa 98580gacaatacta aaagcttgga aaacatattt gggggaataa ctggggaaaa cttacctggc 98640cttgctggac acctagacat gcaaatacaa gaaacacaaa gaacatgtaa atacaagcag 98700cacaaagaac acctgggaaa ttcatcacaa aaagatctta gcctaggcac attctcatca 98760ggttatgcaa agttaagacg aaggcaagaa tcttaagagc tgtgagacag aagcaccagg 98820taatgtataa aggaaaccct

atcagattaa cagccagttt ttcagcagga actgtacaag 98880ctataaagga ttggagccct atcatagcct cctcaaacaa aacaattatc agtcaagaat 98940tttgtatcca gcgaaagtaa gcatcatata tgaaggaaag atacagtcgt ttttggacaa 99000acaaatgcta agagaattca ccattaccaa gtcaccacta gaagaactgc taaaaggagc 99060tctaaatctt gaaacaaatc ctagaaacac atgaaaacag aatctcttta aagcataaat 99120cacacaggac ctataaaaca aaagtacaag ttaaaaaaca aaaacaaaaa acaaaaccaa 99180agtacggagg caataaagaa tatgatgaat gcagtggcac ctcacatttc aatgctaaaa 99240ttgaatctaa atggcctaaa tgctccactt aaaggataca aaaagagttg gtggctggca 99300agatggctga ataggaacag ctccagtctg ccgctccccg tgagatcaac acatagggtg 99360ggtcatttct gcatttccaa ccaaggtacc cggctcatct cattgggact ggttagacag 99420tgggtgcagc ccacagaggg tgacctgaag cagggtgggg tgtcacctca cctgggaagt 99480ggaaggggtc agggaactcc ctcccctagc caaaggaagc cgtgagggac tgtgccgtga 99540agaccagtgc attctggcac aaatactatg cttttcccac ggtctttgca acctgaagac 99600caggagattc ccttgggtgc ctacaccacc agggccctgg atttcaagcc caaaactggg 99660ctggcatttg ggcagacact aagctagctg caggagtttt ttttcatacc ccagtggtcc 99720ctggaatgcc agcaagacag aaccattcac ccccgtgaag aaagggctga agccagggag 99780ctaagtggtc tttctcagtg gatcccaccc ccatggagcc cagcaagcta agctccactg 99840gcttgaaatt cttgctgcca gcacagcagt ctgaagttga cctgggacgc tcaagcttgg 99900tgggaggagg ggtatccaca aatactgggg cttgagtagg aggttttccc ctcacagtgt 99960aagcaaaacc gctaggaagt ttgaactggg cagggtgcac tgcagcttgg caaagccatt 100020gtagcaagag tgcctctcta gattcctcct ctctgggcag ggcatctctg aaagaaaggc 100080agcagcccca gtcagaagct tatagataaa actcccatct ccctgggaca gagcaactgg 100140aggaaggggt ggctgtgagt gcagctccag cagacttagt ttcctgcctg ccagctctga 100200aaagagcacc agatccccca acacagcact agagctctga taagggacag actgcctcct 100260caagtgggtc ctggtttcag aagataataa gaaactcctc tgagctaaag gagcatgttc 100320taacacaatg caaggaagct aagaaccttg aaaaaggtca gaggaattgc taactacagt 100380aagcagttta gagaagaaca taaatgacct tagggagctg aaaaacacag cacgagaact 100440tcatgacaca tacacaagta tcaatagcaa aatcgatcaa gtggaagaaa ggatatcaga 100500gattgaaaat caacttaatg aagtaaagcg tgaaaacaag attaaggaat aaagaatgaa 100560aaggaatgaa caaatcctcc aagtatggga ctatgtgaaa agattgaacc tacgtttgat 100620tggtgtacct gaaagtgatg ggagaatgga accaagttgg aaaacactct tcaggatatt 100680atccaggaga acttccccaa cctagcaaga caggccaaca ttcaaattaa ggaaatacag 100740agaataccac attcaaattc aggaaataca gagaacacca caaagatact cctcaagaag 100800agcaacctga agacacataa tcgtcagatt caccaaggtt gaaatgaagg aaaaaaatgt 100860tgagggcagc cagagagaaa gtttgggtta cccacaaagg gaaccccatc agactaacag 100920tggatcttcc tgcagaaact ctacaagcca gaagagagtg ggaggccaat attcaacatt 100980cttttttact attattatac tttaagttct agggtacatg tgcacaaggt gcaggtttgt 101040tacatatgta tacatgtgcc atgttggtgt gctgcaccca ttaactcttc atttacatta 101100ggtatatctc ctaatactat ccctccccac tccccccatc ccatgacagg ccccggtgtg 101160tgatgttccc cactctgtgt ccatgtactc tcattgttca attcccacct atgagtgaga 101220acattcggtg tttggatttc tgtccttgtg atagtttgct gagaatgatg gtttccagct 101280tcatccacat ccctacaaag gacatgaagt catccttctt tatggctgca tagtattcca 101340tggtgtatat gtgccacatt ttcttaatcc agtctaccat tgatggacgt ttgtgttggt 101400tccaagtctt tgctattgtg aatagtgccg caataaacat atgtgtgcat gtgtctttat 101460agcagcatga tttataatcc tttagatata tatccagtaa ttgtatggct gtgtcaaatg 101520gtatttctag ttctaaatcc ttgaggaatc accgcactgt cttccacaat ggttgaacta 101580gtttacagtc ccaccaccag tgtaaaaatg ttcctatttc tccacatcct ctctagcatc 101640tgttgtttcc tgacttttta atgatcacca ttctaactgg tatgagatgg tatctcattg 101700tggttttgat ttgcatttct ctgatggcca gtgatggtga gcactttttc atgtgtctct 101760tgactgcata aaagttttct tttgagaatt gtctgttaat atcctttgcc aactttttga 101820tggggttgtt tgattttttt tcttgtaaat ttgtttatgt tctttgtaga ttctggatat 101880tagccctttg tcagatgggt agattgtaaa aattttctcc cattctgtag cttgcctgtt 101940cattctgagg gtagtttctt ttgctgtgca gaagctcttt agtttaatta gatcccattg 102000gtcaattttg gcttttgttg ctattgcttt tggtgattta gtcatgaagt ccttgcccat 102060gcctatgtcc tgaatggtat tgcttaggtt ttcttctagg gtttatatgg ttttaggtct 102120aacatttaag tctttaatcc atcttgaatt aatttttata taaggtgtaa ggaagggatc 102180cagtttcagc tttctacata tggctaggca gttttcccag caccatgtat taaataggga 102240aacctttccc tatttcttgt ttttgtcagg tttgtcatag atcagatggt tgtagatgtg 102300tggtattatt tctgagggct ctgttctgtt ccattggtct atatctctgt tttggtacca 102360gtaccatgct gttttggtta ctgtagcctt gtaatgtagt ttgaagtcag gcagagtgat 102420gcctccagct ttgctttttt ggcttaggat tgtcttggca atgcatgctc ttttttgttc 102480catatgaact ttaaagtagt tttttccaat tctgtgaaga aagtcattgg tagcttgatg 102540gggatggcat tgaatctata aattacctta ggcagtatgg ccattttcac aatattgatt 102600cttcctatcc atgagcatgg aatgttcttc catttgtttg tgtcctcttt tatttcatta 102660agcagtggtt tgtagttctc cttgaagagg tccttcccat cccttgtaag ttggattcct 102720aggtatttta ttctctttga agcaattgtg aatgggagtt catccatgtc cctacaaagg 102780acatgaagtc atgtatggga atgcttgtga tttttgcaca ttgattttgt atcttgagac 102840tttgctgaag ttgcttatca gcttaaggag attttggtct gagaagatgg ggttttctaa 102900atatacaatc atgtcatctg caaacaggga caatttaact tcctcttttc ctaactgaat 102960accctttatt tccttctcct gcctaattgc cctggccaga acttccaaca ctatgttgaa 103020taggagtggt gagagagggc atccctgtct tgtgccagtt ttcaaaggga atgcttccag 103080tttttgccca ttcagtatga tattggctat gggtttgtca taaatagctc ttattatttt 103140gagatatgtc ccatcaatac atagtttatt gagagttcag catggagagc tgttgaattt 103200tgtcaaaggc cttttctgca tctattgaga taatcatgtg gtttttgtct ttggttctgt 103260ttatatgatg gattacattt attgatttgc atatgttgaa ccagccttgc atcccaggga 103320taaagccaac ttgatcatgg tggataagct ttttgatgtg ctgctggatt cggtttgcca 103380gtattttatt gaggattttt gcatcaatgt tcatcatgga tgttggtcta aaattctcat 103440ttttgttgtg tctctgccag gatttggtat caggatgatg ctggcctcat aaaatgagtt 103500agggaggatt ccctcttttt ctatgattgg aatagtttca gaagaattgg taccagctcc 103560tctttgtatc tgtggtagaa ttcggctatg aatctctcct ggactttttt tggttggtag 103620gctcttaatt attgcctcaa tttcagagcc tgttattggt ctattcaagg attcaatttc 103680tttctggttt agtcttggta gggtgtatgt gtccaggaat ttttccattt cttctagatt 103740ttctagttta tttgcacaga ggtgtttata atattctctg atggtagttt gtatttctgt 103800gggattggta gtgatatccc ctttatcatt ttttattgca tctatttgat tcttctctct 103860tttcttcttt attagtcttg ctagtggtct atcaattttg ttgatctttt caaaaaacca 103920gctcctggat tcattgatgt tttgaaggtt tttttgtgtc tctatctcct tcagttctgc 103980tctggtctta gttatttctt gccttctgct agctttttaa tgtgtttgct cttgcttctc 104040tagttctttt aatggtgatg ttagggtgtc aattttagat ctttcctgct ttctcttgtg 104100ggcatttagt gctgtaaatc tccccctaca cactgcttta aatgtgtccc agagattctg 104160gtatgttgtg tctttgttgt cattggtttc aaagaatatc tttatttctg ccttcatttc 104220gttacatacc cagtagtcac tcaggtgcag gttgttcagt ttccatatag ttgagcagtt 104280tttaatgagt ttcttaatcc tgagtcctag tttgattgca ctgtggtctg agagacagtt 104340tgttataatt tctgttcttt tacatttgct gaggaatgcc tcacttccaa ctatctggtc 104400aatttcagaa taagtgcgat gtggtgctga gaagaatgta tattctgttg atttggggtg 104460gagagttctg tagatgtcta ttaggtctgc ttggtgcaga gctgagttca attcctggat 104520atccatgtta actttctgtc tcattgatct gtctaatgtt gacagtgggg tgttaaagtc 104580tcccattatt attgtgtggg agtctaagtc tctttgtagg tctctaagga cttgctttat 104640gaatctaggt gctcctgtat tgggtgcata tatatttagg atagttagct cttcttgtta 104700aattggtccc tttaccatta tgtaatggcc ttctttgtct cttttgatct ttgttagttt 104760aaagtctgtt ttatcagaga ctaggattgc aacccctgct ttttttgttg ttttccattt 104820gcttggtaga tcttcctcca tccctttatt ttgagcctat gtgtgtctct gcacgtgaga 104880tgtgtcttca gaatacagca cactgatgga tcttgactct ttatccaatt ttccagtctg 104940tgtcttttaa ttggagcatt tagcccattt acatttaagg ttaatatttt tatgtgtgaa 105000tttgatcctg tcatcatgat gttcgctggt tattttgctc attagttgat gcagtttctt 105060cctagcatcg atggttttta caatttggca tgtttgtgca gtggctgata ccgattgttt 105120ctttccatgt ttagtgcttc cttcaggagc tcttgtaagg caggcctggt ggtgacaaaa 105180tctctcagca tttgcttgtc tgtaaaggat tttatttctc cttcacttat gaagcttagt 105240ttggctggat atgatattct cagttgaaaa ttcttttctt taagaatgtt gaatattggc 105300tgccactctc ttctggcttg tagagtttct gctgagagat ctgctgttag tctgatgggc 105360ttccctttgt gggtaacccg acctttctgg tgaatctgac aattatgtgt cttggagtta 105420ctcttctcga ggagtatttt tgtggcattc tctgtatttc ctgaatttga atgttggcct 105480gcctttgtag gttggggaag ttctcctgga taatatcctg aagagtgttt tccaacttgg 105540ttccattctc ctcgtcactt tcaggtacac caagcagatg tagatttggt cttttcacat 105600agtcccatat ttattggagg ctttgttcat ttctttttac tccttttttt ctctaaactt 105660ctcttctcgc ttcatttcat tcatttgatc tttaatcact gatacccttt cttccacttg 105720attgaatcaa ctactgaaac ttgttcatgt gtcacgtagt tctcgtgcca tggttttcag 105780ctccattaga tcatttaagg tcttctctat gctgtttatt ttagtctgcc attcatctaa 105840actttttcaa ggtttttagc ttctttgcaa tgggttcgaa catccttctt tagctcggag 105900aaatttgtta ttacagatcg tctgaagcct tcttctctca actcatcaaa gtcattctct 105960gtccagcttt gttctgttgc tcgtgaggag ctgcgttcct tcggaggaga agaggcaccc 106020tgatttttag aattttcagc tgttctgctc tggtttctcc ccatctttgt ggtttatcta 106080cctttggttc ttgatgatgg tgatgtacag atggggtttt ggtgtggatg tcttttctgt 106140ttgttagttt tccttctaac agtcaggacc ctcagctgca ggtctgttgg agtttgctgg 106200aggtccactc cagtccctgt ttgcctgggt attaccagtg gaggctgcag aacagcaaat 106260attacagaac agcaaatgtt gctgcctgat tcttcctctg gaagcttcat ctcagagggg 106320cacccagctg tatgaggtgt cagttggccc ctactgggag gtgtccccca gttaggctac 106380tcgggggtca cggacccact tgaggaggca gtctgtccat tctcagatct caaactctct 106440gctgggagaa ccactactct cttcaaagct gtcagacagg gatgtttaag tctgcagaag 106500tttctgctgc cttttgttca gctatgccct gcccccagag gtggagtcta cagaggcagg 106560caggtctcct tgagctgtgg tgggctccac ccagtttgag cttcctggtc gctttgttta 106620cctactcaag tctcagcaat ggcagacgcc cctcccccag ctttgctgcc gccttgcagt 106680tcggtctcag actactgtgc tagcagttca atctcagact gctgtactag cagtgagcaa 106740ggctctgtgg gcatgggacc ctctgagcca tgtgcaggat ataatctcct ggtgtgccgt 106800ttgctaagac cattggaaaa gtgcaatatt agggtgggag tgtcccgatt ttccgggtac 106860atctgtcatg gcttcccttg gctaggaaag ggaattccct gaccccttac acttcccggg 106920tgaggcaata tcccgccttg cttcggctca ctctccgtgg gctgcaccca ctgtctgaca 106980agccccggtg agatgaaccc agtacctcag ctggaaatgc agaaaccacc catcttctgc 107040tttgctcatg ctgggaactg tggactggag ctgttcctat tcggccatct tgaaacctcc 107100cctctctcac gatcacaagg tcccacaata ggccgtctgc aggctgagga gcaagaaaag 107160ccagtctgaa ttccaaaact gaagaaattg gagtctgatg ttcaagggca ggaaacatcc 107220agtgccaaag aaagatgtag aatattcaac attcttaaag aaaataattt tcaacctaga 107280atttcatatc cagccaaact aagctttata acaaaggaga agtaaaatcc tttacaaaca 107340agcaaatgct gaggaatttt gtcaacacca ggcctgcctt acaagaggtc ctgaagaaaa 107400cactaaatat ggaaaggaaa aaccagtaac agctactgca aaaacatacc aaattgtaaa 107460caccatcaac actataaaga aactgcatca actaatgggc aaaatagcca gctagcatca 107520taatgacagg atcaaattca cacataacaa tattaacctt aaatgtaaat gggctaaatg 107580ccccaattaa aagacacaga ctgggaaatt gaataaagag tcaagaccca ttggtttgct 107640gtgttcagaa gacccatctc agggtgaaaa gacatacatg ggctcaaaat aaagaaatga 107700aggaatattt accaagcaaa tggaaagaaa aaaaaagcag cggttgcaat cttagtcttt 107760gatgaaacag actttaaacc atcaaagatc aaaagagaca aaggagggca ttacctaatg 107820gtaaaagtat caatgcaaca agaagatctg actgtcctac ttatatatgc acccaataca 107880ggagcaccca gattaataaa gcaagttctt agagacctac aaagagactt agacttccac 107940acaaaaatag tgggagactt taacacccca cagccaatat tagatcgacg tgacagaaaa 108000ttaacaagga tattcaggac gtgaattcag ctctggacca agctgaccta atagacatct 108060acagaactcg acaccacaaa tcaacagaat atacattctt ctcagcacca cattgcactt 108120attctaaaat tgaccacata attggaagta aaacacttct cagcaaatgc cgtagaatgg 108180aaatcataac aaacagtctc tcagaccaaa gtgcaatcaa actagaactc aggattaata 108240aactcactca aaaccacaca actatatgga aactgaacaa cctgctcctg aattactact 108300gggtaaataa caaaattaag gcagaagtag ataagttctt agaaaccaaa gagaacaaag 108360acacaatgtg ccagaatctc tggtacacag ctaaagccat gtttagaggg aaatttatag 108420cactaaatgc ccacaggaga aagcgggaaa gatctaaaat caacacccta acatcacaat 108480tcaaagaacc agagaagcaa gagcaaacaa atacaaaagc tagcagaaga caagaaataa 108540ctaagatcag agcagaactg aaggggataa agacacgaaa accctttaaa aaattaataa 108600atccaagagc tggttttttg aaaagattaa caaaatacat agaagcctag ccagactaat 108660aaagaagaaa atagagaaga atcaaataga cacaataaag aataataaag gggatatcac 108720caatgatgcc acagaaatac aaactaccat cagagaatac tttaaacacc tctatgcaaa 108780taaaatagaa aatctaaaag aaatggataa attcctggac acatacaccc tcccaagact 108840aaaccaggaa gaagtcaaat ccctgaatag accaataaca agttctgaaa tcgaggcagt 108900aattaatagc ttaccaacca aaaaaagccc agaccagagg gattaacagt caaatcctaa 108960cagaggtaca aagaagagct agtactattc cttctgaaac tattccacac aatagaaaaa 109020gagggactcc tgcctaactc attttatgag gccagcatca ttctgatacc aaaacctggc 109080agagacacaa caagaaaaga aaatttcagg ccaacatccc tgatgaacat caatgtgaaa 109140atcctcaata aaatactggc aaactgaatc cagcagcaca tcaaaaagct tatccaccat 109200gatcaagttg gcttcatccc tgggatgcaa ggctggttca acatattcaa atcaataaac 109260ataatccatc acataaacag aaccaatgac aaaaaccgta tgattatcgc aatagacgca 109320gaaaaggcct ttgataaaat tcaataccca atcatgctaa aaactcttaa taaactaggt 109380attgatggag catgtctcaa aataataaga gctacttatg acaaatgcat agccaatatc 109440atactgaatg agcagaagct ggaagcattc cctttgaaaa ccagcacaag acaaggatgc 109500cctctctcac cactcctatt caacatagta ttggaaattc tgtccagggc aatcaggcaa 109560gagaaagaaa taaaggtatt caagtgggaa gagagggagt caaattattt ctctttgcag 109620atgacatgat tgtatattta gaaaactcta tcatctcagc ccaaaatctc cttaagctga 109680taagcaactt cagcaaagtc tcaggataca aaatcaatgt gcaaaaatca caagcattcc 109740tatacaccaa taagagacac agagccaaat cctgagtgaa ttcccattca caattgctac 109800aaagagaata aaatatacct aggaatccaa cttacaaggg atgtgaagga cctcttcaag 109860gagaactaca aaccactgct caaggaaata agataggaca caaacaaatg gaaaaacatt 109920ccatgctaat ggattggaag aatcaatatt gtgaaaattg ccatactgcc caaagtgatt 109980tatagattca atgttatccc catcaagcta ccattgattt cttcacataa ttagaaaaaa 110040ctactttcaa tttcatatgg aatagaaaaa gggcctgtat atccaagaca acctaagcaa 110100aaagaacaaa gctggaggca tcatgctatc tgacttcaaa atatactaca aggctacagt 110160aacaaaaaca gcatggtatg gtactggtac caaaacagat atatagacca atagaacaga 110220acagaggcct cagaaataac accacacatc tacaactatt ggatctttga caaactggac 110280aaaaataagc aatggggaaa ggattcccta tttaataaat ggtgttggga aaactggcta 110340gccatatgca gaaaactgaa actggatccc ttccttacac cttatacaca aattaactca 110400agatagatta aagaattaaa tgtaagacct aaaaccataa aaaccctaga agacactttg 110460ggaggccgag gtggatggat cacgaggtca ggagatcgag accatcttgg ctaacacagt 110520gaaagcccat ctctactaaa aatacaaaaa attagctggg tgtggtcgtg ggcacctgta 110580gtcccagcta cttgggaggc tgaggcagga gaatggcatg agctgaggag gttgagcttg 110640cagcaagcca agattgtgcc actgcactcc agcctgggca acagagtgag actccatcaa 110700aaaaacaaaa acaaaaacaa aaaatcaaac cctagaagaa aacataggca ataccattca 110760ggacataggc atgggagaag acttcatgac taaaacagca aaaccaatgg caacaaaagc 110820caaaatttac aaatcagatc taattaaaat aaagagcttc tgcacagcaa aaaactctca 110880tcagagtgaa aaagcaacct atggagaaaa attctgtggt ctagccatct gacaaagggc 110940taatgtttag aatgtacaag caacttaaac aaatgtacaa gaaaaaaaaa acaaccccat 111000caaaaagtgg gcaaaggata tgaacagaca cttctgacag gaagaccttt atgtggctga 111060caaacatgaa aaaagctcat catcactgtt aattagagaa atgcaaatcg aaaccacaat 111120gagataccat ctcatgcccg ttagaatggc gatcattaaa aagtcaggaa acaacagatg 111180ctgaagagga tgtgtggaga aagaggaaca catttacact gttggtggga gtgtaaatta 111240gttcaaccat tgtggaagac agtgcggtga ttcctcaagg atctagaacc agaagtacca 111300tttgacccag caatcccatt actgggtata tacccaaagg attataaatc attctacaat 111360aaagacacat gcacacgtat gtttattgta gcactattca caatagcaaa gacttggaac 111420caactgaaat gcccatcaat gatagactgg ataaagaaaa tgtggcacat atacactgtg 111480gaatactatg cagccataaa acaggatgag ttcatgtctt ttgcagggac atggatgaag 111540ctggaaacca tcattctcag caaactaaca caagaacaga aaaccaaaca ccatatgttc 111600tcactcataa gtgtgagttg aacaatgaga acacatggac acaggaaggg gaacatcaca 111660cacaggggcc tgttggggag ttgaggctag gggagggatt ggattaggag aaatacctaa 111720tgtagatgat gggttgctgg gtgcagcaaa ccaccatgac acgtgtatac ctatgtaaca 111780aacccacaca ttctacacat gtatctcaga acttaaagta taataataat aagatacaga 111840actgcagaat gaataagaac tcaccaacca tctgctgcct tcaggagact catttaagac 111900ataaggactc acataaactt aaagtaaatg ggtggaaata ataataagtg gtgtcactga 111960tgtggaggta gattataaaa ctcttatcat atgctggtgg aagatcaaaa tgataaaacg 112020aattaaaaaa tcagtcagat ggtttcttaa aaagttccat caatatgcct ctatcttaca 112080aacctgcaat tctattcctg aatctttatc ccaaggaaat gaaaaagtaa gtccacaaag 112140agttctatat gaatatttat aggagcttta tttattataa ttcaaactgt aaaaataatt 112200tcaatgttca tcaataacaa aatgaaaaaa taatttgcaa cctactggta cacttgaata 112260ctattcagca ctgagtatct taaatagcat ggatggagct caaaaatata ctcaggaaag 112320aagccatgta tattctgtat gagttcattt acatgagatc atttacattt cctccaaaag 112380aggaaaaact aatttctgtt gaaagaaacc aatgtatttg cctctggcag tggtaagggg 112440gtagcacaga ttaattgggt agggactcaa gagagtttct ggggtcacag aaatgttccg 112500tgtggtgatg ggagtttggg ctccacaggt ataggtgttg atccaaaatc atcaaaaaaa 112560caacattgca gatctgtgca tctcactctg tgggaaagta tatctcaact gtaaaaaggg 112620cagaaattgc ttttaaacgc tcagcctttt agcacatcca gttgcttgga gaaccagctt 112680actcaaatgg gggtctaggc tggagactag gtcacaggca tagagtctct aaactttccc 112740atggcacata atacgtttca ggttttctca gagagctgca ggttagtaat ctgaggattc 112800tgacaagttg ggtcaacgtt cctaggaggc atgaatggga gtgcattctc taagatccct 112860ccaccccagg gtccttgctt tctgtgcctc ttactccatt gttttctgac tcctctgtag 112920ccactcgacc tcttcagatc ccattgtcta cccagccatc gccctttatg acttgggtcc 112980cactgttctt tcatctcatc ctccattccc tcagtttcgg agtggctgcc gctagcagag 113040gatggactga gagcaggaga ggtggtcctg cccaggaacc catcctagag aaatggcatc 113100ctgtctggga gctagttttt tagggcaggt tttataagtc ttgtaaagcc agacacactt 113160gatctacctg gtatgttatt tacagtaata ctattttcat aattgctttt cactctaaaa 113220gtagagcctt ttagctacac tgtgagtaaa taaaggggct ggcctgggaa tggtatcatg 113280ttggatgttg tttcttccct gaagtaatat atatcagtta caatttacat gttactgcag 113340agtcctagag agagacacag agaatgagac agataccaat acatttttat gtgcattaaa 113400aaaatctaag gccaggcgca gtggctcaca cctgtaatcc cagcactttg ggaggccgag 113460gtgggtggat cacgaggtca ggagattgag accatcctgg ctaacacggt gaaaccctgt 113520ctctactaaa aatacaaaaa attagccagg cgtggtggcg ggcgcctgta gtcccagcta 113580ctcaggagac tgaggcagga gaatggcttg aacccaggag gcagaccttg cagtgagccg 113640agattgcgcc actgcactcc agtctgggcg acagagcgag actccgtcac aaaaaaaaaa 113700aaaaatctaa aatgcactct tcaaaatcta tgtcatttat tctggaggaa tgcagttggc 113760agaaggagga agatattccg aatttttctt gtatacattt atgtatgatc tcagtttttt 113820tatggatcat agaccaattt tgatatttta aaataaaaat tataatctat cttggaaatt 113880tacatggttc tttagaactt

gaggaccgtt tttgcttttc ggaatattat tgtacctaaa 113940atgggaatat tacaacgtca ctttttaaca ctttgttata acaaagttta gacagcgctg 114000ggtgcccctg aattttttcc cgcctcttgt gacctgtgtt gttttggaat ttgcagtggc 114060ctgaccgaga actactgcag gaatccagat tctgggaaac aaccctggtg ttacacaacc 114120gatccgtgtg tgaggtggga gtactgcaat ctgacacaat gctcagaaac agaatcaggt 114180gtcctagaga ctcccactgt tgttccagtt ccaagcatgg aggctcattc tgaagcaggt 114240aagaagtctg tggccagata tctacacatt tgaacattgg gatgaaaaga gatggaaaat 114300ctgactgatg cagaagcctt ccatgctaca cagaaacttg agggtatggc aggtggaaag 114360aagcctcagc actctctctg gtggagcaat ttttggcgca acgtgcgtgg gcggtgactt 114420caggaatggt gcaaacccac ctgggcactt gacttaccac tcactttgtt atgaaagggg 114480ttatctcggt gttccagaca aaattccaat tctaacatca ggccaaattt gtgccaaatt 114540tcacactagt gagtgtttcc aggcatttat taaaatggac agtgttcatt gcaatcttca 114600gcattgcagt tgctgaggta tgtggccgct gagtttgtca tcctggggaa acctaatatg 114660atgatattta ttccatctaa tcctggggct atttggcagt aaataccaca gaatacacta 114720tttctctggc ttatttcagt cttaggtagg ctctgcacac ctatgcttgg aaggcaggaa 114780tttcttggtg ttcttgtgcc ttcttctcat ggaacgtgca tctttggtgt gtgttgagag 114840gaagggtagt agacttctgc tttgttgcaa tgcaggatgc tggaacaaga ggattccctg 114900tctctactgt aagggaataa gattttagcc tccatccttc tctaagaagc aatgtgtctt 114960tgcctccaag tactagatgc aggaccatga actgccccgt ccaccagaag cttaaggctt 115020tggcttttca ggagcaatca tctagggaac tgtgcagggt tttcatgtct gtcccctact 115080gacagccaat caccatacag cctgcataac ctaatccatc atcgtctggt ttcctgcctc 115140attgttttca tgaacaacca gtagagagcc atacgaaaga gcttgcacat gagtctttgt 115200tccaattgta agagcactga taggtccttt tcccaccagg ttttgaatat aaaatttcta 115260agaacttatt aaaatattag aatgttatta atctattgtt tttgcttcag catgtccttc 115320tgcttgtgag tatactaaag agaacagtca taattctgaa actactgtcc tgtttgtgtc 115380ataaattgct tcacatgttt ctgcatacta gtagttactc agcttgattt tgtctatttt 115440cagcaccaac tgagcaaacc cctgtggtcc ggcagtgcta ccatggtaat ggccagagtt 115500atcgaggcac attctccacc actgtcacag gaaggacatg tcaatcttgg tcatccatga 115560caccacaccg gcatcagagg accccagaaa actacccaaa tgagtatgtc tttgatgtta 115620cttgtaagag gagcaacagc caacttaagt tcctcctaga agagccttgc ttcaagctaa 115680cttgttagga caaatttccc ttagacccag aaggtgtgtc aaaatgtcca gacaactttg 115740cttttgatca aagagtctga gagaataggt attttaggct tgctatcttt tctaatagtc 115800tgatggaagc agaaggctac atggagctga tgaggtcttt ttaatataaa gctcaagaga 115860tcaaatgatc aaatacttag agtgccattc tacaaggctc ataaaagatc aatgcactct 115920ttcacccatg caattctatc attctaacct cccttctctg aaatgaaggc tttttgccat 115980ttttgtcatg ggtcacaagt aaataattca catgtatatg agtatatata taaccaggtg 116040tgtttattca gactagtatg tatatatata catatatatg ttcatataag ttagtattca 116100tatatatgtt catatatata tgttcataca gactagtatt catatatata tacatatata 116160tatacacaca catatatata tatatatata tgttctaggg aaacatgcaa ggtttttatg 116220tctgtccctg actgatgacc aaatacccta tagcctgcac agctgcaagc tgtatagcca 116280tacaatttgc aggacacaca cacatacaca cacacacaca cacacacaca cactaacata 116340taatataata taatataata taatataata taatataata taatataatt aatatatata 116400aacctgtgtg aacacactgg gttctaagct ccagttttct gaagggatat gggttgccag 116460gagaggaaga gcaaaagcaa gaatgtagat gagaattagg aagtaaacag atatggagat 116520taaaatgggc aggtacatgg acaaaaaacc aggtctgaca aaaactggct ttctgccata 116580aatgactata aaagatatta aaaaacactt tccacatgtt ggacaagaga cagtacagga 116640ctgagataat ttagaaaagg aaatgaatga gcgcaactcc gtaactatta tgactttctt 116700cctggagaac cttcctggac tgaagggcaa ggaattggag ccaaagccaa ccacagcagt 116760cttgctgaac tgaggaaaga gactggagtt tgggatagct aagaaaatgt gtattttcta 116820tgctaggtaa taatgagaaa gaatttgtgg tgaaaaggag ctgaaggaat atgcatggaa 116880gtctaatata aactgcatat gcacagggag aaattctaca aagtgggaca gagaaccact 116940actggggaaa ggacaaattc agggaaacag tgagctcaat ggtgacgcca gagctcacgt 117000agcactgggg gataccgggg ttctgatcag cccgaggaga gacacctcat tgaacatctc 117060gggcattcag tagagacccc agaaaagtca tactttagga gtaggattta tgccttctta 117120gaataaagac taccccagaa acaccctagt aaagcttaaa aaccaagtct aaaaggaccc 117180aaatgatctc caagtaaatt aactgcctga cagaagaaaa ctcaaccatc actggaggta 117240aataacatga ttacagtgct ctgtaatgtt gcattcacaa ggagtgacat catttaaaaa 117300tttatgaggc aggaaaaagc aattagtgtg atccataact aggagaaaaa ccagtcaata 117360caaatagacc aagaaatagt agaaacgatg gaattgacaa agaaattaaa actgtatata 117420tgataattgt gttcaaagat ttaaagaaaa catgaacatg agggaaacaa atgcagaata 117480taaaaaaaag caaatgcgta aaacaaccaa atggaaatta aagaactaca aaaaagtata 117540accttaataa aatactcact ggatggcctt aatattagtt tatacattac agaagaaaaa 117600gtgaaccaga agataactca atgaaagcca tacaatctgt aagacacaca cacacgcaca 117660cgcgcgcgcg cgcacacaca cacacacaca gagagagaga gagagagaaa gagagagaga 117720gaaaggctga aaaaaataaa tagaacctta aggatatcag tgaaaatagc aaaagattta 117780atatatgggt aaagcaagtc acagaaggac gggaaggaga tattgggaca gaaaaaaata 117840ctcaaagcaa tgatggctga agactttaca cgtatgaaga aaatgataaa ctcacagtca 117900agaagctcaa tgaatcagaa atagtatttt taaaagcaaa actctatgat ttacttgggt 117960acattataga taaatcgtcc aacatcaaag ataacaagga taatcttata agccagagga 118020aaacaatatc atttacatag agggacagta atgaaagtga ccgatgcctt ctccttggaa 118080acaatggcat aacatcttta aagtgataaa gagaaataaa aacagatcaa cctaggacga 118140catgtccagc caaaacaaac aaataaacaa aaaaaccctt taaaataaac gtgatgtaaa 118200tacgtattct gccacctcca gaggaaacaa gcaaaaaaac aaaagaatgt ttccaaggca 118260ggcttctgta ttaaaagatt ttaaggaaag ttattcaggt agaagaaaaa taataccaga 118320tgggaacttt aatccatact aagtaatgaa gagccctgga aatggcaaat ggcaatgtca 118380atataaaata ctcttattta tctaattttt aaatgtattt aaaggacaat ttgtgatatt 118440aattaaaata ataggaatat attgttgttt caacgtatgt agtagtaaaa ttcataaaaa 118500cagtagcaca aataatgcag atgataactg gaagtatact gttaatgagt tttttgcatt 118560atccatgaag ttatataata ttaatagatg gttgaatgtg atagtttaag gtgggatatt 118620ataaatccta ggacaaccaa aaaaatttaa actgagagga atggatagta agaggaatag 118680tccttttatg caaaagaagg aagaaaaaga ggaataaaga atataaaaga tatggtgtaa 118740acagaaaata catagcatta ttgtagacac aaactgaact accttatgag tatattaaat 118800ataaaaggat taagcattac aaataaaagg cagagattgt aaattgaata aaaaccacag 118860ctaagtgtgt tctttttaga ataaatactc tttaagtgta aagatctact ttaaacacca 118920aaatatgaaa aaggatatat accatgaaaa cctgaatcat aaataagctg gagtggtgat 118980taatggatgc aggcactcct aaagactaat aagtgaatgt ggtcaaattg aagaaacaaa 119040agtatatacg tgctcaatgt gcaaaaactt tttctgtata catgctatga tcctttggaa 119100aattaaagtt ttaaagcaat atcactgaca atagtatcaa aaccaaaaaa tatttagtga 119160taaatttcac acactatgct caaggactat acaccttgca ctagaaaaca atgttgagga 119220aagaattaaa agatctaaat atacaccatg cttatagatt aaaagactcc atatcagttc 119280tcgtgaaatt gatctttgga tgaaacccac acccaagcac tattgcaaca gtcctttttt 119340ggaaaaaaaa attggaggac ttatatacct taatataaag acttataaaa gtacaggaat 119400caagacatgt ggtattggcc tggccccttg gctcatgcct gttaccccaa cattttggga 119460ggctgagtct ggaggatggc ttgagcccag atgttcaaga ccagccttag caacagagtg 119520agaccctctc tctacaaaaa ataaacaatt agatcgatgt gatgacttgc acatgtagtt 119580tcagctactc ggaatgctga ggtgagagga ttgcttgact caggaggtct agccatgagt 119640gagcattgat catgcctctg cattccagcc tggatgatgg aatgagacac tgtctcaaaa 119700aaaaaaaaaa aaaaggatat gtgttattgg ccaaaaaagt atgcaaacct aaaaagggat 119760ggcccaccac cagacccaca tacatatatg gtaaatggat tttccgtata gatggcaaag 119820caattcaatg gagacaaaaa tgttttacaa aatcattctg aaccatttgg atatccatga 119880tacaaaacaa aagcagaact tgacttttgc ttttcatctc aaattatttt gatatctctt 119940ccacctaagt gtcagagcta aaactgaacc tgaaatatga aagttccatg aaaaaatata 120000aaatcttcac aaccttggag aaggcaaact tttttgaggc aggagtctgt aaacactcac 120060tataaaataa aacaaattat aatgtgggct ttcatgaaaa ctcatgctta ccaaaagtca 120120ttgttaagaa aataaatagg caagtaacac atgagaagaa aaatgctctc tgtccatata 120180tctgacaaat ggcttgtgtc cagaatatag gaacatttct cccactcact aaacagagga 120240caaacaacta atgggcaaca gattgaatag gcatttcttg gggatagata gatgtacaca 120300tagccaataa gcacctgaaa aaatgtccag tatctcagcc atgaaaaata aagagttata 120360atcatcatga gatgtcacca aacacccaat ggacatggat attattaaga agacaccaca 120420gtaactgatg tcactgatgt agagcaagga tgtgaaactc tctcatatgc tggtgaaagt 120480gcaaaatgat acaaccactt ttgaaatcag tctgatagtt tctccaaaag ttcaataaat 120540gcacttttac cctacaaacc tgcaatcctg tttgtgaata tttaccccac agaaatggaa 120600acataagtcc acgaagacat ctccaagaat attcatagca gctttatttt ttataacccc 120660aaactgtaga caatttcaat gtcaatcaat aagaaaatga ataaataatt tgtgaactag 120720tcatacaatg gcatactgtt cagcaataaa agggagcatg tttttgatac tctcaaatag 120780tatggaagat gctcaaaaat attacattaa agaaagatgc cagataacaa aaatgaacat 120840tatgtatgag tctattgatg taaggttcca gaaaggtaaa actaatttct ggtgaaagaa 120900accaatatca tttgcctctg gccatgggaa gagagtagca gagattgatt gagcagtaaa 120960acgaagtttt tttctggggt gatgtaaatg tcctgtattg tgattgaagt gtgagttaca 121020caagtgtaca tgttcatcag aagtcatcaa actacatcta agatctgtgc atttgactat 121080acatgaaaat atacctcagt tgaaaataga tcaataacct ccctcatata ctatacttgc 121140taacacagcc agctgcttgg agaaccagct tgctggaatg gagaatctgg gcttgagact 121200gggtcacatg tatagagtct ctacagagac aatgttgcat tcccacggta cataatacat 121260ttcaaggttt ctcagacagc cacatgtcat gaatgtgagg attctgagag gttggagcaa 121320cattcctggg aggaacgaag gggagcacat tctccaagat cccccaccac cggggtcctc 121380accggctgtg cttttttttt tttttttctt gacagagtct cgctctgtcg ccaggcagga 121440gtgtaatggc ccaatctcgg ctgattgcag cctccaactc cagggttcaa gagattctcc 121500tgcctcagct tcatgagtag ctgggactac agatgtgcgc cactgcgccc agctaatttt 121560tgtattttta gtagagacgg ggttttgcca tgttggccaa gatggtctcg ctctgttgac 121620ctcgtgatcc acccgccttg gcttcccaaa gtgctgggat tacaggcgtg agccaaagca 121680cccagcctgt gcctctcact tactcaattg tttttctgaa ccctccatag ctggtggacc 121740ttttcagatc ccatagtcta gccagccctc tcactttatg ccttgggtcc cactgttcct 121800tcatctcatc ccccttctgt cagtcccgca gtggctgtgg ccagtagagg atggactgag 121860agtaggagag gaggttctgc ccaggaaccc atcctagaga aacagcatcc tgcctgggac 121920ctagtcttcc aggtcagctt ttataagtct tttagactca aactcacttg acccacctga 121980agtggtattg acaataatgc tattttcatg gttgtttttc actgtaaatg cagagccttt 122040tagctacacg actagtacag agagtaaggg aggctggcct gggaatgata tcatcttgga 122100tggcatttcc tccttggaga aatatatgtt agttccaact cacatgttac tatacagtcc 122160tgtagaaaga gatacagaga gttagacagg tatagacgca tttgtatatg cataacaatc 122220tataagacac acatcaaaat ccgtataccg gttcctctag gggtatgtgc ttggcagaag 122280gtagaaggag ggtattctgg ttcctttctt ttgcacattt atgtatgatc tcagttttta 122340tatggagcat tgatagggtt tggctatgtc cccacccaaa atctcatctt gacttgtaat 122400ctctataatc ctgataatcc ccatgtgtca agggcaggac caggtggagg taactggatc 122460atgggggcag tttctcccag gctgttctca tgacagtgag agagtctcct gagatctgat 122520ggttttgtaa gtgtctggca tttcccctac ttgcacttac tctgtcctgc cgcctgtgaa 122580gaaggtgcct gtttctccct tgccttctgc catgactgta aatttccaga ggcctcccca 122640gcaatgtgga actgtgagtc aattaaaact cttttctttg taacttaccc agtctgtctc 122700gggtatttcc tcatagcaat gtgagaacgg gctaatacaa gcatatacta cttttgatat 122760tttaaaataa aaattatcat ctatctttga aaggcatgca caaatgggaa gttgaggaac 122820atttgtgttg tggcaattgt atgatacctt taatgggaat atttcaaaga cacttgttaa 122880gactttgtta gaacaaaatg tagagggtgc tggatgtccc tgaatattct tccgcctcct 122940gtaacttgta ttgctttgga atttccagtg gcctgacaat gaactactgc aggaatccag 123000atgccgatac aggcccttgg tgttttacca tggaccccag catcaggtgg gagtactgca 123060acctgacgcg atgctcagac acagaaggga ctgtggtcgc tcctccgact gtcatccagg 123120ttccaagcct agggcctcct tctgaacaag gtaagaagtc tgtgtcttac cttgtctagc 123180acatacctct ctatgtgctt ggacaacggg atgaaaagac atgaaaaacc acactgatgc 123240agaagccttt agtgctacac gggagctcga gtgttggttg aggttctgcc atgaccaagg 123300aagtctcagt gccgtccctg ggaaagccag agctgtgatt tttggcacaa cttgtgggag 123360tagtgacttt aggactggcg caaaacctcc agggtgctca acttaaccac tcaccttatt 123420ctaaaatggg ttatttcagt gtcccagtca aattcctatt ctaacatgct gtcaactgtg 123480tgattatttc caagccaata agcatttcca gtaatttctt aaaatagtgt tcattgcagt 123540cttcagcgtt gtggctcctg agggatgtgg cccctgattc tgtcgtccta gagaagcctg 123600acatgactgc attgattctg tatcgtcctg ggtctatgtg gctgcctggc tgtctgtaat 123660catctgtttt atttttattt ttttctacag actgtatgtt tgggaatggg aaaggatacc 123720ggggcaagaa ggcaaccact gttactggga cgccatgcca ggaatgggct gcccaggagc 123780cccatagaca cagcacgttc attccaggga caaataaatg ggcaggtctg gaaaaaaatg 123840taagccactt tgatttggac tctttttccc tttgctgaca aatcttttca aacagaagag 123900gggcagagga aaatactgga aagacttcag gaggctaagc gtaattagcc ttagcatgga 123960aagtgcaagc agcacaggcc agcaaagccc cacgcgtgtg ggggttctca ggcctcttct 124020cttttgacat ttctttactg tttccattgt tgggtgctgt ttctcgtttc tagtgcttgt 124080cctctaagcc aggggtcccc actccagtac tggtactggt actggtactg gaactggtaa 124140ttatctgtgg cctgttagga actgggctgc acagcaggag gtgagcttcg ggggagcaaa 124200caaagcttca tctgtatttt ctgctgcttc ccatcactct catagctgcc tgagctctgc 124260cagctgtcag atcagaggca gcattagatt atcatagcac aaaccctatt gtgaactgca 124320catgtgagga atctagattg catgctcctt atgagaatct aatgcctgat gatctgtcat 124380gcttccatca cccccagatg ggaccaccta cttgcaggaa aattagctca gggctcccac 124440tgattttacc ttatggtgag atgcacattt atttcattat atattacaat gtaataataa 124500ttgaaataaa gtgcacgata aatggaaggt acttgagtca tcctttaacc atcgccccct 124560caccccaggt gcacagaaaa attgcctttt atgaaactgg tctctggtgc caaaaaagtt 124620ggggaaccac actgctctgg gttctagtag tcagagatgc cctctatgag gcttaagtca 124680gatttttcta gaaaagattt ggatgggcca tcaggtcacc atgagacttc ccttagcctc 124740atgcattctc tgtgatggtt tactttgggg cctatgaata gggaagactg agatatagga 124800aaaaccaaag tgtctgtgtt cccccactct cacacccatg taacataaca cttctcacac 124860cagatatggg gggatttctc ctcacacccc aagcgagtct ccagcagata ccagctgggt 124920gtcctacaat gtaactcggt cctgacactc tatctggaga cagtgtcaga tcccacaagt 124980taaggctcag tcctacaaga ctgccccact gcagatgcca atcccaagtt gcaggctgtg 125040acctgtactt ctgcccagct ggataaagat ctgtttttct atatgaccct ccatgggttt 125100gattactttg ctagagtggc tcacagaact cagggaaaca cgttactttt atttacccat 125160ttattataaa agatattaaa aaggatcctg gtgaacagcc aggtggaaga gatgcacagg 125220gcaaggcacg tgggaagggg ctcagagcct ctatgccctc tccagtgcac cagtccccag 125280taccctaagt gttcagcaac ccagaagctc tccaagtgca gtcttgttgg gtttttatgg 125340aggcttcatt acagaggcac agttgattac atcattggcc atcggtgatc ggctcacctt 125400cggcccctct tccctccctg gaggttggag ggtggggctg aacagttcca accctcaagt 125460cacatggttg gttcccttgg caaccagccc ctggggctat ccaggaaccc accaagagtt 125520gcttcattgc agctcccttc acccaggaaa ctccaaggga tttaggagct ctgtgttaag 125580aactgggggg cagagaccca atatacattt cttattctat cacaatatca caggaagcta 125640aggatgatac tgcctttgtg tgtcttggct gtggatggtg cataatgcat ggaagtaagc 125700atttctgaat caacagcaaa caggctttat caggtagaag acccctcagc gccccaggga 125760caaagctcat caatgatgtc ccactgtcct ctgaggctct agctctaaga cctccagtgg 125820gtcaagctcc tggagaagtg gcacattctc caaagaccct tcagggtcac cacaccctgg 125880ttaagggtgt ggcctcataa ctccttttga ctatgactga tggcttacag catagaaaga 125940aataactttg tcaaaaaata taataatgat agaaaggaag aaggaacgct cccttttgtc 126000ttctaagaat agatgtgaaa tgtgtgtgcc ttagaatatc ttctccctct cctgctccac 126060gtgagctgga gcttacatgc ctgcttgttt tcagtactgc cgtaaccctg atggtgacat 126120caatggtccc tggtgctaca caatgaatcc aagaaaactt tttgactact gtgatatccc 126180tctctgtggt aagttgcctt ctgttttggt aaggaaactg cttccttaat atggatttgg 126240aaaaaaaaaa gcaaaaaaaa cagaaaatgg cttttgagct gagtgcttct ggggaggaga 126300tggctgccct ctccaccaga gcctgctttt catcatggcc accttgaacc tgccctacta 126360ttggccccat ttgttaggaa aacacccgcc cctcccacca cacacacata aataaaataa 126420atgtcaaatt cccaaagggc aaacttagag gtgatctaat cagcccggga tagtcccacc 126480gaacccttct ttgtctagcg tgggatgcat gaaaaacaaa tttagagtca ttatgatgaa 126540aaactgtcct cttctgcagc tgagaagaaa aaaaaaatac gagcagcagg aaacagctaa 126600gcatgtaatg cacattgtaa acctcagatg gccatcctag gaaatcaatg aagggtagtg 126660cagctcttta gccccagatg gcctttctcg taagattact actcatgagt cccattagcg 126720acattgctta gagactgctt gttaggttcc ttcctcattg ctctgagact cttattggga 126780gtatgaggct tggatcaggg gaaggggaat tgacattaga tcttaaatga ttggggtaac 126840aaatccatgg gggaaaaaaa gccacttgta cttgttccct attttcttcc tgctgaccaa 126900tcaacttgtc tgtccgagtt acagaacacc accctggact tttcttttgt gtaatttggt 126960tgcttgtggt tgggtctgcc atgtgaaggg accttgagct gggggaagaa ggttggcctc 127020caagtccact gaagaccagc atcctgagat tgcctgggga ggtggtacag ggcagtgatg 127080aagatcatgg gagccacact gcccatcgtc acatttgggc cactcctggg gagagcaaga 127140gggaagaagg agaggttagg gtgataggaa agattctact tggccaatat tattataatg 127200tggcattgtg gtctctggat ttagtgtgag ttgatagctg acttttttct cgagtgggtg 127260cttttgttct attttgtcgg tgctattgca gaagcatctt ggtggttcct ctacctcaaa 127320gtctcttgat ggggtcagtt ccagttctcc gcttctggcc ccatctagta cacgccactg 127380cctctcactg cctgggctct ctatccttga caggctgcct tgaatttaag cccagtctga 127440cttacctgcc tcaaacaccc acagtagtgc ctgggactca tgcacctttg actcccatgg 127500aagggaagtg cagtagcttc ccaggtgcaa ttctgctgtc ctcacccaca ttgaggatgt 127560atgagaatca ggttcttaga gattggagaa agaaggaaga atgggaacaa gatttcttcc 127620aatggactgt gaggttcccc accttacttt gatgtaagac aagtgaggtt aaccccaagc 127680ctggtgagga gggttcccat cagacacttg gaaatcctga ggactgtttc ctgcagaagg 127740atgtggttgg tgggatattc aggtttgact catgattgag aaagttagag cctctggttg 127800gagaaagagt ttaataacta tttcatttcc accaacacat tcagtacgaa taataaataa 127860gtaaaaataa atagaaacat tcagttttat tttgaatagt aggagtaggg tataatttct 127920gtagttactc ttttagtaca atgatgcatg tttactgtat gtaaggcata ctagcagaaa 127980ttgagctcag cactagaaaa gatgattgca ttccatgcca tgcttctttt ttacaaaaga 128040cttctataga tagattctca aaacaaccca cagcaaatga aaagttattt ggaaaactca 128100ggttccagat tcactggagt gtagaatctc tggttggttg gggaggaatt tcctcttgca 128160gttgttatta ataattatat gaataattat taactatatt aatatttata gttttgaaga 128220ccttgaaggg ctggagacaa cagagaagca tttttgaaca ccctctgtag cccctgcact 128280gttgtaggca ttgatgggtg gtaccaaaga tgggacactt tccctacctc cagagacctt 128340gtgggcttgc tgcagagaga aggcagggag gaggaaaaga agaatagagg cacatgtgtg 128400taaattaccc ccacagcagt cagttagtca tgggaggctc cccagaagaa ctgtcctgaa 128460gctggctgag agaaggcaac atttcaacat aggacagtta tccttgctac ataaaatcac 128520atacacacat gcacatatgt ccacacacag agactcacat gcaaaagaat cctttgtgcc 128580tttcagtaaa ctttacatgg tttagaaaga acttatattt ccttgaaagg agagtgtcct 128640ttgttgttta ctaccacttt ttaaacttag aaagaaaaat ctaaagagtg tttatgattt 128700taccatttaa tttcaccttt gagatgtgaa aaactagtgc ttggaattcg tcctgaatta 128760aacgacacaa ttgctaactt ggactcaaat gcgacttctt ttcccacctt gtgccacagc 128820atcctcttca tttgattgtg ggaagcctca agtggagccg aagaaatgtc ctggaagcat 128880tgtagggggg tgtgtggccc acccacattc ctggccctgg caagtcagtc tcagaacaag 128940gtaagaacag gcccagaaac

catctatact gtccttccat gtaagcccca caaaaccctt 129000ctacatttac acagaaccca cacagctgat gcatcaatac ctgcctctct gttttctgaa 129060ggaggaaaaa atatagaaaa attaaaaaaa gttatattat tataggttct ctacttggaa 129120aatagccaaa atacaaatct ttttcttgat ctgggcagtt ccatcaaaat ctgtaggcac 129180agtgatttgc accaagttcc aatacttttg gaaaatattg aagatgctct gagggtttct 129240atggatatcc attgtctcac tgtcagatga aaagaaaggg aagtttttag aaatgtgaca 129300ctttgcagtg agggaggaca agagcaaact tacctacagt ctatcacagg cacagatttt 129360tttttacact tttgtgaatc attgaattca atgccgaggc tattcatcta ttcacaaaca 129420catgaacaaa ttatgggttg tgatccccat aaatgaagag taatcagtcc gaacccacag 129480aacctggaca ttttgggtat cgtttcagtg gaacatgcaa ttcgtaagtt cagtttgctt 129540gggtgtctct taggaagaac acataggaca cagacccatc tgcctgcatg ttttgcttcc 129600tcatctcctt tctacaccag ggcacctgtg ctcaattgct gttctcctct aaagagactt 129660ccttctgtaa gtttgtgaaa tgccatcgac aaacctgatc gcatcgcatt tcactctgct 129720gttgagttga tttttcttta ctttatcgtt tgtaacttct tgctctacag agctttcacc 129780ttccacatat ttcagattca ttctttccta aactgtgtgg tggtctatgt cctcactgac 129840tatcaacata ctgccatcat gcacttccta tctctattcc tcttcgttgc aatctggctc 129900caagtggctc acaccattat tctgatctat caactgccta cacagtccta gaaagtaagt 129960gagtcaagaa acatccccca aaagtaaact tttcaggtaa gatcagaaga ccctcatgag 130020tcactgctgc tcaggatcgt atctggctcc ttgaagagtg accttgcata gatcttgtca 130080taaaaaatga aagagacctt gggaaggtct tgggctggtc acttttgtca gagtccaggg 130140ctgtggggtg aaagccacag ctatagagct tcattctgga gtcacttagc tttgctctcc 130200tggggacagg ctgtgcctat tcttgcctca ggcatcaaaa aaagtggcac agatgggccc 130260ttctgaaaaa tctcactact ggagcacagc tcgaagtttc tactatcctg acgttgggcg 130320gtagtccttt gctttgggaa tatgaacatg atcaaaactg agtgaacttg tcttcctggc 130380tttctgtaca atgaagtaga acaaaccatc caatttgacc aaagccttgg catgttttct 130440ttctaggttt ggaaagcact tctgtggagg caccttaata tccccagagt gggtgctgac 130500tgctgctcac tgcttgaaga agtacgttta agggaaaact gacatggggt cttatcttca 130560agactttttt cctccctctc ttcctccatc ccttctttct tcccaccctc cccttccttc 130620ctccccacct ctcttccttt tctggaagga acactaggaa ccagggaatg catgcagaat 130680cctgaggcag aatttccagg gcaattggat gagagaggag ggaagtgttt ctagagggaa 130740tctgcagagg gaagacccag tgcaagtgat tttttggacc tgtataaacc gcaggacaga 130800gctgttcact accagaggca tcaatctgta ttgcattgct ctagagcaat atctgaggct 130860gaataattta taaagaaaag agtttaattg gcacatgttt ctgcaggctt tacaggaagc 130920aggatgctgt catctcctct gcttctgtgt gggcctaagg aagattacaa tcatggtgga 130980gggcaaagtg ggagcaggca tgtcacatgg ccagagcagg agcaagagac agagagagat 131040ggggtggggg tgctgcacaa taccaaatga ccagactttg caagaactaa gagtgagagc 131100tcactgatca ccatgaagat gtggcccaag ccattcaaga gggatgcacc tctatgatcc 131160aaaccccttt cacaggccat agctccatca ctggggacta cagttgaaca cgagatttag 131220gtggggacaa atatacaaac tatatcacag tctctgatga aacagattga gaacagacct 131280taactgtcag tttccagcaa attgtgaatt ttgtttcttg ccactcataa gtcactgatt 131340ctgggtggcc gagggtgtca gagggacagc gccaagttca tggcacagag gatacctgaa 131400ggggctggac catatttttc tcttgacatc ctcatctttt ctaggtcctc aaggccttca 131460tcctacaagg tcatcctggg tgcacaccaa gaagtgaacc tcgaatctca tgttcaggaa 131520atagaagtgt ctaggctgtt cttggagccc acacaagcag atattgcctt gctaaagcta 131580agcaggtact cgctcacctg tggtcttcac cccacgctgg tgaagatatt tgctttatgt 131640ctgggtttta tgggccatgg ccactgcatg gcagtgggga ggaactgtct atcacatgaa 131700aggctcaagg gctttgggga cagcatcaat cttcaacccc agccctgcca catgttagtt 131760gtgctcttta aaaaggcaga aggattcgtt tcctcacgtg gaaaaagaga taccctgtta 131820cccgtaaaac ttacttaatg ttcaccagtt catccacatt catgatcagg gaaaggttgt 131880tattccaggc taactattct cctttcataa taatatgctg gagagaatca aatgagattg 131940catttcaaag cgcttgaaaa accaccatat cgagccatgc ttagtgtggg cgcctctaat 132000cactgctatt caggaggctg acgaggaaga attgcttgag cccaggactt caaggctgta 132060ggcagctatg attgtgccac tgcactccag gctgggtgac agatcaagac cctgtctcaa 132120caaaagaaaa gaaaacaaaa caaatgaaca gaaatattcc acaatgtcaa aaaaaaaaaa 132180aacccacaca acatacaatt tacaaatgca aataataata ttattgttgt cttctttgat 132240tttctctttc ctggtgaaat tttgttttat taagcctgac aaagtgatac ctttgcttac 132300atcacttaaa gttagtctat ttggacctag gtgacagtac aatcagctaa gaaacagtat 132360ttgtaggaga ggcaggtttg ggacaggtga caaggcatgt ggggtgctcg ctgtgctggt 132420ggctctggaa ggcagggtgt caatgcagac agggatgagc atggcctggt tgggaaggca 132480tggggcaggc aggagcctga gctgctctcc tgggcctggt cacaagccca tggcagcttc 132540tctgggtctg tgaactgagg ggtgatgtcc tggaatcctc tgacactcta ggaaggagag 132600aagggccttt ctggctcagc ctttataaac agtagctgat ctccctcttg ctccccaggg 132660tcctccccac catcccagca aatgtgcaaa tacaagatct ctgctcctca tggtcctcag 132720agagctgggg tgttctgatg gcttgaacaa gtcacttagg aaatgtgggg ttttggaggc 132780attctctgat aggctgatac gttttgagtt tagagttccc accgcacatc cccacacccc 132840tagagtctag ggcatttagt gctccatgag ggaacctgta gagtgaggac atctgcatca 132900caggctgggc cttctagtgt ccagaagcag aaagtgtgtc tgcttcaaag ttggtgctaa 132960tgatgatttt tggtcagaat acggcatttc tcatttccat tcctttatcc ccttgaactt 133020actaaagtag aatcaggtct aaaaaccaga gttctaatct ttaagagtcc ctgggattct 133080aaggtatatg aatgtccttg gaaaacaata ccatttagtt catgcaaggt gcttatttcc 133140catcctcttt catttgatgt ctagcatttt actgcattct taccaccacg gtttagtaac 133200attcacgagg aggaagtgga ggatccagat ggagcaactt gctctgggca cacaaggcat 133260ttgcaatttt ataccctctt gatgatgtct cagccagaca ttctgcccag tcatcaatgc 133320cctcttcaat taatatgaaa ggacacactt ggcatgagat tccaatcgtg cacagaatat 133380acatgagaag tgtgcctttg tcatccctac tttcaaaggc taaggccacc ctcagtttct 133440tgcatgcaac tgatgccttt caaatgaaac cttacatctg tgtagtccat aggcaaccac 133500aggcaaatgt gagggtgaaa cgctgtgttc tacattgttc tgtgtcagtg aagcaaggca 133560gtgccagctc agagggctct ggggcttcaa ggcagggatg cctggttgta ggtactgcca 133620cttccagctg ggcagtgaaa cataactgct aatactttcc ttacaggcct gccgtcatca 133680ctgacaaagt aatgccagct tgtctgccat ccccagacta catggtcacc gccaggactg 133740aatgttacat cactggctgg ggagaaaccc aaggtgagat caattccatt gcccacgtaa 133800caaattgttt ttgaccttca gtgcatgtta caaaatgagc attttggaga tagttgtaca 133860aattcctacc catgaatgtg gtctacccac tcctgacttt gcctggacac ctgtctatgt 133920ctccataatc agtcttcaag ggacttgggc aaggggagcg gtgccatttc cttgagtctc 133980tctctttttt gttttcagaa tcttttaatt ttttttgtaa tgattgtatg tttcccttac 134040aacaaaaaca aacaccagta gaggtctttg agtctcttaa tcataatttc agcattcata 134100ttgcttcccc aggtaagtgg ggttttgacc cagccctcaa gttaagggtg ttagattatt 134160tttcatgtga aattagacag actgcgtttc taaacatggt gcaaaacagt aacgacaaaa 134220gttgtaatta aactattctt cttcccaaat acccacatgt ctaatgtgtg tgtgagggtg 134280ttaggcaggg gacctgaagc tgggggagag gcagacagtt cccatggccc caagtctagg 134340atggcatttg gtattggttg atgggtgaga gcaagagagg gaatattttt gtgcatgatg 134400tggtatcagc acctgtacta cattttatgg attccttctt ctctttgcgg tatgccctga 134460caataattat atccgtcagc cttaccccct tggcagtagg aaaactgaaa ctgtcttaaa 134520gtctcagctc tactttctca gaggtgcagg caagggcact gggagtctgg ggccctggaa 134580aactgttctg actctgccac ttgccagata gacctgaact agacacgtta cctctttgta 134640ccacttggct ctaatccctt atctgtaaaa ccagcatttt caaatggtgc tttgcacatc 134700agccttttgc ataagctttg atttgataaa atgttttttg tgtttttaaa aagattaaaa 134760accacaggtt tagataattt caaagtaggc ttcccttttt ctgtcatttt cctattattt 134820ttaaaacctc acctccttga ctccttgttc cctttttctg cactgctgag tctgggagca 134880ctgaggccag gtaaaaggaa acttggcaaa tgaggggcac ctatgggtgt gggaggctgc 134940tcctggtgtt tgcatatttt aaaatttaaa tgctacaaac cactgtgagt taggtattat 135000tgttcctatt ttaccattga ggaagctggg gctcagagaa ggtggagggt ggtacagaca 135060aacctgaatt ggaaccctgg ctcctgccta tgggctgtca ggacttagaa aagtcgtgag 135120ctctcgctga ttgtttcctc agctgatgtg ggctgcaggg ctgttatggg ggaaataata 135180agaaagtgca tcaagtgctg agcacatcct aagcactcca tcatggcagc tcctactact 135240aataaagaat agaattatat ctaacatgat tctttcttgc aagtgacaga aaatccaact 135300caaattggat taagcaaaac aagggaaatt cttagtgagc tgcaaagttt tcaggctcac 135360atgatggccc caaatcccag gtcctcccaa tcatggagta ggcactattt gggggcacaa 135420aggtgacatt cccatggctg cagatgctgt ggtgctgtgg ctgtaccggg aaagaataag 135480aaaggccact ctcccaatta tgtgaacaat agtctgccca ctctgagaag tcaaacttgg 135540gtcacagtcc tgcccctgaa cccatcactg actggctctg acctgcacca attgttccat 135600gttggaggtg aaggcaagac cccactaata cccataaggg gcaaaagtta gatagatcct 135660tcaagaggat tatgggaggt agggcaaaaa gctgctgggc agccagaaag caaacagagc 135720ctctatgata cctcaactga tgaaagcatg aagctaaaat cataaggatc tgggtgtgag 135780ttctggctct cccatcttcc atgtgacatt gggcagttat ttaatctctt ttagcctccg 135840ctttctcatc ttacatatga gataattgtg aggattaaga ttacacataa tcatcatcat 135900caccgtccac cactaccacc atcatcccca tcaacatcat cgccaccact atcatcattc 135960ttactggcac taccatcacc atcaccacca ttccaccacc atcaccaata tcatcactgt 136020caacatcatt accaccatca ccatcaccac caccatcatc attactacca ctaccactac 136080taccaccatc accatcacca ccattccacc accatcacca atatcatcac tctcaacatc 136140atcaccatca ccatcaccac caccatcatc atcattacta ccactaccac tactaccacc 136200atcaccatca ccactgtccc actactatca gcatgacatc accatcacca ccaccatcat 136260cattaccacc gctactacca acatcaccat caccacaatt ctactgccat caccattaac 136320attaccacca ccatcatcac tatcaccatc accaccatca tcaccactgc cattatcact 136380gccaccatca tcactatcct ctatatttcc tcatctgtat tatcattact accaccatca 136440ctatcaccac catcgtcacc atcataatca ccatcaacac catctccaat accaccatca 136500ctgtaaccat catcaccacc accatgatca ctatcaccat catcacaatg atcactgtaa 136560ccatcattac tacccaccac catcaccact actccaccac catcaccatt atcattacca 136620tcaccattat caccaccatc atcatcacca gcaccaccat catcaccagc accaccatca 136680ccatcaccat cattaacacc atcactatca ccattggttt aatcatcacc accatcatca 136740taaataaaca tcacataacc agggtgtagc tgggtgttga ccccagagcc cactcactgt 136800ttcctctctc ccacccccat ccacacattt ctaaccacca tcctgcactg ggctcccagt 136860ctcctctggt ctcacccaca tgtccactga gaaaaggatt ttcagaacac caactagacc 136920aggaggagcc acatacataa ctcaggcctg cttatcaact ttctacatgt taataatgac 136980atcagatcaa tgggtgttct cagcttctca gaaggaggtc aaaattctcc ccctctcccc 137040ttcatgtgtc cagaccttcc cggatttgga tgtaccaagt gcagagtggt gttgaggcca 137100aggggctcat ccatgtaagt ctcatctgca atcactgggc tgatcccgtg gccctgtctc 137160cagggcgcca tcagagaggg cttcaatcct caggttacct gtggcccacc ctgccctcag 137220aggtgccatc tctacattgg ccacgagatg gcagcacata ctcatagact gcattaattt 137280cccagcaact cctggtgggt tttccctctt atcaggatgt ttgccttgct cagagagcaa 137340atctgagagc agtgacacct aacttaactt tcagcaaaat attttgagaa gggtgcccct 137400ttacacatct gtgcagtcca ggtgatgcat cccatgccca atgctcggta gtcaggagga 137460gcttcctcca tgcagctctg cggaagagac tcttccacgc tgctcatgta aactccagat 137520tcggtgtcag ttttctgaca ccgaagacaa tgatctaagt gcagtcaagg gctttgggga 137580aagcaggaga gagtgcctca gttctagcct gtgccatgct tgcaaagttt tgcaaaattc 137640taatgagagc tgggcttgca acattggaaa cttggattat ttgtgagagc actgagaaat 137700ccctgggcat gtccatctgg aaaaacagca tttcctctgg cactttagca gaggttctgt 137760ttcaatttgg cgaaggaaat taagcagttt ttcacaaaag aagaactaca acgaggagaa 137820ttgtccctag tatttcttct ccctaattgt caaggaagtg taaattagaa aatgaatcag 137880gacaatttcc acctactatg ttagctaata ttttaaaaat tgaatatcac aagggtgagg 137940caaagtaatt gttttccagt gacattttcc actgtcacac ccttttagag aataatttgg 138000caatgttact gtgagataga aatatgtcta tataattatg ggaactgaga cttcagaaag 138060taataaggaa taagaatgaa atttatgaac aaacatgtgg aaggttggaa gcaagagtgg 138120ggccaacacg catggggagg aagcatttgg gcagcgactc cgcagaccca gactcaagct 138180gagctataca acctccttac gcctcagttt cctcaactga agaacaggaa tgacaagtgc 138240ctgtttcata ggaccgttgt gaggattaag tgagatatac cacattatga gcttgtgcct 138300ggaaaggttg attcttagta aatgatgact attctttttt attgcaataa aatttataca 138360acatagagtt actattttaa ccatttttgc aggtaccact gagtggcatt cagtacattc 138420acaatggtgt gcaaccgtca ccatatttcc aggacatttt tctcatcccc aaaggaaacc 138480tcatgcccat taagcagtca ctcctcatta aaatattagt tatgaagact gtagcatttt 138540tttaaaaact catgatataa cattgattga aaaaatcagt ataggaaatt gtgcattatg 138600atgtaatagt aaaagaagca tataaaaatc tgaaaaaagt atataaaaag aatagcaatt 138660gtatttctca gactctcttt acattgtaaa aatcattttg atagcttcaa aagaaaagca 138720aaaagtacac aaacaacaac caaccccaaa gcagcatgac aaagcccaga ttgttgaatc 138780caggtcttgg gaacataaaa tcttatatga catttgcact ttaatgggtc agagagtcca 138840gtggcattgg gagctgcctt gtgttctgca gcctcacgga cagacaggag gtccagctcc 138900actgctctgt tcttctggaa tttcctcgtg aacaagcttt ggcctcagta accatttctt 138960tcatcttttt aaacacaggt acctttggga ctggccttct caaggaagcc cagctccttg 139020ttattgagaa tgaagtgtgc aatcactata agtatatttg tgctgagcat ttggccagag 139080gcactgacag ttgccaggta agaaaagatc aatagatcaa agtcttgtgc tctcccgtct 139140cagtctcagt cccttagacg tcagtcccaa agtggcaaat tcaggaaggt tttgtcagtg 139200gaagacccca gtctaagtgt tgctcagaaa ctccccagat ctgtccctga atgcatattc 139260agatcatcta aggagacgtc ttggggcttg agttccagat ccatagcaag ggagccgtaa 139320gtgccataac tacctcaggc cactcacctt cctggtgtgt gctggtcacc agtgactgaa 139380gtggtggctt ttccagtaga gaggaaggta gagggtacag gaccgagaca aattacacac 139440acttaacaat gatgtccagg ctagcccagt ctaaaggaaa caccaagtta ggaagcaatg 139500catgcaggat tcacaaggga ttattttttt tcccaggaaa aaactaagtg atgtggtttt 139560gttgaataga ctttgctaag tacttaagca ctgcagatgc ttgagtaata tgctcataag 139620ttcctttctg atttgaatta ctgggaaaat gtacatatgg ataagagaag gatggcatcc 139680catattaaaa ggttggcagc ttaaagctca catgaatttt cccctacctc tgtttagggt 139740gacagtggag ggcctctggt ttgcttcgag aaggacaaat acattttaca aggagtcact 139800tcttggggtc ttggctgtgc acgccccaat aagcctggtg tctatgctcg tgtttcaagg 139860tttgttactt ggattgaggg aatgatgaga aataattaat tggacgggag acagagtgaa 139920gcatcaacct acttagaagc tgaaacgtgg gtaaggattt agcatgctgg aaataataga 139980cagcaatcaa acgaagacac tgttcccagc taccagctat gccaaacctt ggcatttttg 140040gtatttttgt gtataagctt ttaaggtctg actgacaaat tctgtattaa ggtgtcatag 140100ctatgacatt tgttaaaaat aaactctgca cttattttga tttgaattaa ttttggtttt 140160ggtcttcaaa attttcatgc tcttttcatc ccatctattt ttatttttat tttttagact 140220ttacgtcctg gggtacatgt gcagaatgtg caggtttgtt acatagatgt acacgtgcca 140280tggtagtttg ctgcacccat caacctgtca tctaattcgg tatttctttt agttctatcc 140340ctcccctagc cctccacccc ttgacaggcc caggtgtgtg atgttgccct ccctgtgtcc 140400atgtgttctc attgttcaac tcacacttat gagtgagaac atgccgtgtt tgtttttctg 140460ttcttgtgtt agtttgctga gaatgatagt ttccagcttc atccatgtcc ctgcaaagga 140520catgaactca tcctttttta tggctgcata gaattccatg gtgtatatgt gccacatttt 140580atccaatcta acattgatgg gcaattgggt tggttccaac tctttgctat tgtgaatagt 140640gccacaataa acatacgtgt gcatgtgttt tcatagcaga atgatttata atcctctggg 140700tatataccca gtaatgggat tgcagggtca aatggtgttt ctggtgctag atctttgagg 140760aatcaccaca ctgtcttcca caatggttga actaatttat gctcccacca acaatatcaa 140820ggcattccta tttctccaca tcctctccag catctgttgt ttcctgactt tttaatgatc 140880gccattctaa ctggcatgag atggtatctc attgtggttt tgatttgcat ttctctaatg 140940atcagtgatg atgagctttt ctcatatgtt tgttggctgc ataaatgcct tttttggaga 141000agcatctgtt catatccttt gcccactttt tgatggtgtt gtttttttct ggtaaatttg 141060tttaagttct ttgtagattc tggatattag ccttttgtca gatggataga tggcaaaaat 141120tttatcctat tatgtaggtt gcctgttcac tccgatgata gtttcttttg ctgtgcagaa 141180gctctttggt ttaattagat ctcatttgtc tattttggct tttgttacca ttgcttttag 141240tgttttagtc atgaagtctt ctcccatgct atgtcctgaa tggtattgcc taagttttct 141300tccagggttt ttatggtttt aggttttgca tttaagtctt taatccatct tgagttaatt 141360tttgtataag taatgccctt ctttgtctct tttgatcttt gttggcttaa agtatatttt 141420atcagagact agaattgcaa tccctgcttt tttttttctt tttgctttcc ttttgcttgg 141480taaatattct tccatccctt tattttgagc ctatgtatgt ctgcacatga gataggtttc 141540ctgaatacag cacaccaatg ggtcttgact ctttattcaa tttgccagtc tgtgtctttt 141600aattgggggc atttagtcca tttacattta aggttaatat tgttatgtgt gaatttgatc 141660ctgtcattat gatgctagcg ggttattttg cccattagtt gatgcagttt cttcatagtg 141720tggatggcct ttacaatttg gtagtttttg cagtggctgg taccaattgt tcctttccat 141780gtttagtgct tcgttcagga gctcttgtga ggcaggcctt gtggtgacaa aatctttcag 141840catttgcttg tctgtaaagg attttatttc tcctttgctt atgaagctta gtttcgctgg 141900gtatgaaatt ctgggttgaa aattattttc ttttagaatg ttgaatattg gcccccactc 141960tcttcgggct tgttgggttt ctgcagagag atccactgtt agtctgattg gcttcccttt 142020ccgggtaacc caacctttct ctctggctgc ccttagaaat ttttccttca tttcaacctt 142080ggtgaatctg acgattatgt cttgaggtgg ctcttctcga ggagtatctt tgtggtgttc 142140tctgtatttc ctgaatttga atgttggtct gtcttgctag gttggggaag ctctccttga 142200taatatcctg aagagtgttt tccaacttgg ttctattctc cccatcactt tcaggtacat 142260caatcaaatg tagatttggt cttttcacat agtcccatat ttcttggagc ctttgtttat 142320tccttttcat tctttatcct ctattcttgt cttcttgctt tatttcatta agttgatctt 142380caatctctga tatcctttct tttgcttgat cgatttggct attgatactt gtatatgctt 142440cacaaagttc ttatgctgtg tttttcagtc agatcaggtc atttatgttc ttctctaaac 142500tggttattct acttagcaat tcatgtaacc ttttttcaag gttcttagct tctttgcatt 142560gggttagaac atgctgcttt agctcggagg attttgttat tatacacctt atataatagc 142620ctgatataac tataagattt ttttgtaagc accatcgtaa ccacaaagca aaaacctaaa 142680gtagatatac aaaagataaa aaggaatcaa agcataccac tagagaaaat cacttaatca 142740caaataaaga tacgaagagt ggaataaagg aacgaagggt ctacaaaaca accagaaagc 142800aattaacaaa atggtgatag cagatcttac ctataaataa ttatcttgaa tggaaatgga 142860ttaaattttc caataaaaag acatacagtg gccaaataga ttaaaaaata agatccaact 142920atatgatgcc tataacacac tcacttcacc tgtaaggact caaacagact gaaagtaaag 142980ggatggaaaa aatattctat gcaaatggaa acaagaagat agaggggtag ttatacagat 143040tgagtatcac taatccaaac atctgaaatc tgaaatactc caaaattaaa aatgtttaag 143100tgccaacatg atgttcaaag gaaatgttct tcggagcatt ttggattttt gtgtttaggg 143160atgcaaaaac agtaaatata taatttgtat tagtccattc tcacactgct ataaagaata 143220ctacaaagag actgagtaat tataaaggaa agatgtttaa ttaactcaga gttccacagg 143280cttaacagga agcatggcta aggaggccac aggaaactta taatcatggc ggaagatgaa 143340ggagaagcag gcaccttctt cacaaggtgg caggacggag tgtgagtgtg tgaaggagga 143400actgtcaaac acttataaaa ccatcagatc ttgtgggaac tcactcactc tcacaagaac 143460agcataggga aaaccgcccc catgatccaa tcccctccca ctgggctcct cccttgacac 143520atggggatca tgagggttac aattcacgat gagatttggg tgggacacag ccaaaccata 143580tcataatgca aacattgcaa aaacaattca aaattcaaaa catttctggt ttcaggcatt 143640ttggataagg gaaactcaac tcaacatgag gtaaagcaga ctttaagtca aaaactgtaa 143700aaagagacga agaagaatgt aataataagg agatcagttc attacaaata tatagcaatt 143760ataaatatat attaatatat atacccaaaa ttgtagtacc tacatatagt aactaaaaca 143820aacattaata gatctcacag gagagctaca ctgtaatata atcatagtag cacacttgaa 143880tagctccact ttcactaatg gacagatcat ccagacagag aatcaatatg gaaacacgag 143940acttaaacta cactttagcc aagtagacct aacagaaata tatagaacat tccatccaac 144000agcagtagaa tacacattat

tctcaagtgc acagggaata ttctccagaa tagatcatat 144060gttaggtcac aaaactagtc aaaaaatgta agaagattga aatcatatca ggtttttttt 144120ttagatcata atcgtatgaa actagaaatc aataatgggg gaatattgga aaatccacaa 144180atagatagaa attaatcaat atgctcctga acaatcaatg agtcgaagaa gatattaaaa 144240gaggaaattt taaaaaatca agacatgagt tcatgtcctt tgcagggaca tgaatgaagc 144300tggaaaccat cattctcagc aaactatcat aaggacagaa atccaaacac cgcatgttct 144360cactcatagg taggaattga acaatgagaa cacttggcca cagggcgggg aacatcacac 144420accagggctt gtcagggggt gggaagctgg tgaagggata gcattaggag aaatatctaa 144480tgtaaatgac gagttgatgg gtgcagcaaa ccaacacggc acatgtatac ctatgtaaca 144540aacctgcacg ttgtgcacat gtaccccaga acttaaagta taataataaa aaaagaaata 144600tttgtttttg atttatatgc caatcagaca aaatgtgaaa agccctactg aaattaagta 144660tcaccatgaa agataaattc tggataattt tttcaagttt taacaatgta gctttaattg 144720gagaaagcta tcatttggaa tgagttaatc tatcctatac taaaataagt cacttgcttt 144780aaaacataat aaatatgatt ttgaattgaa aacaaaaaca actcaagaca aaggaaaatg 144840gacacactaa cataccaata atttatagta tgcagcaaaa gtggttttaa gagggaagct 144900tttaccaata aacacttcca ttaaaaaaga agatctcaaa taagcaacct aagattacac 144960ctcaacaaac tagacaaaga actaactaac ccaaaagtta gtagaaggaa agaaataata 145020aagatcacat cagaaatagt aaagactaaa aaactgatac caaaaagaaa taaaactact 145080agttggtttt caataaaata acaaaattga ccaactttta gctagattaa gaaaaacaga 145140gaatactcaa ataaaaccag aaagaggaga cattacaata gatactacag aagtacaaac 145200gatcataaga gactactatg aataattaca tgccaacaaa ttggataact tagaagaaat 145260ggatgaattc ctagagcaaa aaacctacaa agactgactc agaaagaaat agaaaatctg 145320aacagaccaa taatgtgtac atgattgtat cagtaataac aagtctccca tcaatgaaaa 145380ggccaggacc taatggcttc actgctgaag cataccaaac attacaaaga ctaatatcaa 145440ccctcctcaa actcttctta aaaactaaaa agaaggaatg ctttcacatt cattttatga 145500ggatagcatt acactgatac taaacacaga aaaataatac gctaataaaa gaacattaca 145560ggcaatatcc ctgataaaca tatgtgcaaa aatccgcaac aaaatactag aaaactgaat 145620ccagtagcac tttaaaaaga tcattcacca tgatcaagtg cgatttgttt cacgaatgca 145680agaatagttc aacttacaca aataaataaa tgaaaggatg gatgataaaa atgtgtatct 145740atatatatat gttttataca cacacacaca cacacacaca cacacacaca cagaggaata 145800ttattcagcc ttaatgaaga agaaaatcct gcctttgcat caacctggag gacattataa 145860taagtgaaat aagccagaca cagaaaggca aatactgtgt gatctcgctt acatatggaa 145920tctaagaaag tcaaattcct agaaatagag agtagcttag tgattgccag agccgtggaa 145980gggggaaatg gagagatgtt gatcaaagga tacaactgta tagctttgca agataaatag 146040gttctggaga tctaatgtgc agaatggtga ctagagttaa taatactgta ttgcatactt 146100gaaatttgct aaaagagttg atcttaagtg tcctcaccat atacacaaaa gtattatgtg 146160aggtggtgaa tattttaatt agcttatgat aataatttca cagtgtacat ctatattaag 146220gcattacatt gtacatctta aatatatata atttttattt gtgaagtgta cctcaataaa 146280actggaaaaa ataattgaaa agtaatgaaa aaaattaaaa gctattatgt gtcaaatgac 146340attatcaaga aagtgaaaag caacctactg atgaagcaaa cctattgaca aaggcctggt 146400gtccagaata tattaagatc tctaggctgg gagcagtggc tcacacctgt aatcccagca 146460cttggggagg ccaaggtggg aggatcactt gagcctggga gttcgacact gcagtgagct 146520atgattgggc cactgccctc caggctgcgt gacagagtga gactgccatc tcttaaccca 146580cttcttattt agaaaaagaa aatatgtagc ttgctgcctg catagtattc ttggggcaaa 146640tgggaaatga gttaaaaaaa aaaaaaagaa ctcttacaac tcaacaataa aaagaaaaac 146700aagaacgtga atagacattt tttccaaaaa agatatacaa ataggcaata agtacatgaa 146760atgatggtca acatcattag tcattaagaa aatgccaata aaatcacaat gaaataagac 146820ttcatatcca ttaaaatgtc tataatttaa aaaatggaaa ataacaagca tttgtgagga 146880tgtggagaaa ttagaatcct gtatattgct ggtgggaatg tacagggaaa atggtttggc 146940cactgtggaa aacaatttga cagttcctta aaatgctaaa catagaatta ccatgtgatc 147000taacaatttt actcttaggt gtatatatac aagaattgaa aacaagtgcc caaacagata 147060ccttgcatga gaatgttcat agcagcactg ttacaacagc cacacccaaa tgtcaatcaa 147120tagatgaggg gataaacaaa ttgtggttta tacagctaca aaaaggaatg aagtactggt 147180atccgctaca tggctgaaac ttgaaagcaa gggctgggat ggggtcatgg aaagtaccag 147240cttattgggt actgcattgt gctttggggt catgaaaatg ttttggaact ggatggaggt 147300ggtggttgcc aatgtgaaca tactaaatac aacgcattgt tcactataag actgctactt 147360ttcttatgag aatttcactt caattaaaaa ataccttcca tgtatccttt ctaaggatga 147420tactagaata tttgctttgg caaaatgagg aagtaacttt ttttaaaaag gaagatgtgg 147480gatccatgaa acgggatcaa atatcagaga ggaaaggggg tcttctggat gacagtccat 147540ggagatccca caactgcaca gcaggccggc tgtgcaccca ggccacacca gagcagagcc 147600ggtggttccc gaggagctct ctggaagaaa aacgctagat ggcctgattg gtttgggggc 147660atattgaaaa ggtatataac tgagaatttg gagtggaatt aggaaacaga cataaaagct 147720tacagaaaag aaaataatga attctaggga gaaatataaa aggatactac aggcctcagt 147780tacataaaca ctgaatattt acttaaccaa aattacaata taattacata attattttag 147840gtacatatgg caaaaggatg tgtgggtgta tgtagtatgt acggtgtgtg aagtgtatgt 147900gtgtggtatg tggacggtat gtgtatgctg tgtatgccaa taaaatcaca atgaaataag 147960acttcatatc cattaaaatg tctataattt aaatgtctat aattttaaaa atggaaaaca 148020cttctcatat ggcaggagca ggagcaaggg tgggggaggt accacacaca cttaaacaac 148080cagatctcct gagaactcac tatcaggaga acagcacctg gagaaggtgc taaaccattc 148140atgagttact gccctatgag ccaatcacct cccatcagac cccgcctcca cactaaggat 148200tacaatttga cttgaaattt gggcatgaac acagatcgaa accatatcaa taggtaatga 148260ctaaaactga aaaaagaagt accacagtca gaaagttatt tagagagctg aaggtaaatg 148320ccaataggat cagttgaaag aattggaggt ggccgggtgc ggtggctcag gcctgtaatc 148380ccagcacttt gggaggcgga ggtgggtgga tcgccctgag gtcaggagtt tgagaccagc 148440ctggccaaca tggtgaaacc cagtctctac taaaaataca aaaattagcc aggcctggtg 148500gtggacgccg tagtcccagc tactcaagag gctgaggcag gagaatcgct tgaaccaggg 148560aggtgaaggt tgcagtgaac cgagatcgtg ccactgcact ccagcctggg tgacagagca 148620aaactccatc tcaaaaataa atgaaataaa gaattggaag tgtttgcctc tggagagaag 148680gaaacgcagt aattctgtaa aaacagaact ttttactttt tttctttttt tttttttttt 148740tgagacagag tctccttctg tcacccaggc tggagtgcag tggtgcagtc ttggctcacc 148800gcaacctctg cctcttgggt tcaagcaatt cccgtgcctc agcctcccaa gtagctagga 148860ttacagatat gggctgctat atccagctaa ttttttttta tttttattag agatgaagtt 148920tcaccatgtt ggccaatctg gtctcaagct cctggactca tgatcctcct gcctcggcct 148980tccaaattgc tatgattaca ggtgtgagcc accatgcctg gacagaactt tttgactctt 149040taaactatgt gcatatataa agctgattta aaaaaaacca agtaaaataa ttttaaaatg 149100ttccaaaaca gattggatgg gtacacactt catcatgagt ggttgaggga gactgggtta 149160gagatgagga aattccaggg actggggaaa agttaaaatg acaaactgtt cacaattgtt 149220aactgcaggt tgtgggaaag ttggtaagtt gctacagtgt ttgttccctc tgtaggtttg 149280catatattta acatttctta aattagcata ataatgaact gtgtaatcag ctgtagagtt 149340gagggtgtgg agctggcaca ggacagctga gctactggtt taaaataaat gacatttaaa 149400aaaatggcta tttgtagaat taacagatat aagacaccct gatcaaggga tgataagaaa 149460ggactccagg gctctgtctc agctgtcttg gcaacacctg gaagacatgg gcctctgcaa 149520ggtctcatac tttcaggagg tgttgatgaa ggatatggac agatctgaag ctctgggcac 149580tgcatggtct gagaagagaa gctccggaaa cgcgggagct gagtgcagat gcagaagggc 149640tgtcatccag cagaggggta ggtgacaact ggcctagcga gtgaccctta tcatggctac 149700atttgttgat cactttcttt gtatgaggca ctgctgtgat tgcattaaat ttccacttac 149760ctaaatccaa cgttgtgcac ttgtgaattt ctactcttac aaaaaacaca acggcaacaa 149820cctcaaacca gtaatctagt caaaaaagca attcccaagg catgacattc agattcatca 149880gcactcacag agactacagt gattgctgat aacgccaact taatacctgg ccaacagcat 149940ggatcctgac ctccactttt cttgtgtgtt tacagaacca caaaaaggtg cagtgttttc 150000a 1500013138001DNAHomo sapiens 3ctctcccaaa ttgtcaaaga agtataaatt agaaaatgaa tcaggacaat ttcaacctgt 60tagattagct aatatttaaa aattgaacac tcatacaagt gtggtgaagt gattgttttc 120tagtgacatt ttacactgtc ataaccttct agaaaataaa ttggcagtgt tattgggaga 180cagaaatatg tctatataat ttatgggaac ttaggctcag aaaatattaa ggaataagaa 240tgaactttat gaacaaagat gtggagggtt ggaagcaaga ggggggccaa cgcgcacggg 300gaggaagcat ttgggcagtg actccgcaga cccaggctca ggttgaacta gacaacctcc 360ttacacctca gtttccttaa ctgtagagca ggagtgatgg aactgcctgt ttcataggac 420tgttgtgagg atgaagtgag atacaccaca ttataagctt gtgcctggaa aggataatgc 480ttagtaaatg atgactattc ttttttattg caataaaatg tacacagcgt aagagttact 540attttaacca tttttgcagg gtaccaccaa gtggcattta gtacattcac agtggtgtgc 600aaccatcatc atatttccag aatattttcc tcatccccaa aggaaacctc atgctcatta 660atcagtagct ctcctttaaa atattagtta tgaagatcat agcactatac aaaactcatt 720atgtaatgtt gagtgaaaaa atcagggtgt gaaattttgt gatatgatgt aattagtgaa 780agaagcatac aaaaagtctg aaaatataaa aacaatagca attgcatttc tcagactcta 840catttaaaca ttattcttta tggttttaaa agcaaagaaa aaggtaaaga aacaacaacc 900aaccgcaaag caccatgaca aagctcagat tgttaaatcc aggtttttgg aacatagact 960cttatatgac gtttacactc tccagggttc agagagtctg gcagcattgg gagctgcctt 1020gtgttctaca gcctcacgga cagacaggag gtccatcacc actgctctgt tcttctggag 1080tttccttgtg aacatgttgt ggacgtagtt accatttctt tcatcttttt aaacacaggt 1140acctttgggg ctggctttct caaggaagcc cagctccctg tgattgagaa tgaagtgtgc 1200aatcgctatg agtttctgaa tggaagagtc aaatccactg agctctgtgc tgggcatttg 1260gctggaggca ttgacagttg caaggtaaga aaagatcaag agaccaaagt tagtcttgtg 1320ctctcctgtc tcagtctcag tcccttagac ttgagtccca aagtagcgaa ttcaagtagg 1380atttaatcaa tggaagaccc cagtctaagt gttgctcaga aactccctag atctgtccca 1440aatgtatatt cagatcatcc aaggggactt cttggggctt gagttccaga tcagcagcaa 1500gggagccata agtgccataa ctacctcaga ccactcaccc tcctggggtg tcccggtggc 1560cagggactaa agtggtgatt tttctggtag ggaaggaggt agagggtaca ggacagagac 1620taactgcaca caatatctga gactggagct cagatattgc tgatgatcag agttggcgtg 1680tctccccaat tgatttacaa ctggggcttg gatactgttt taaacgggag gagcctccta 1740accatcttga cacaaccact gacgtgacta cactagagat agactctttc cacttaattc 1800taccactctt gctttacttc atgagaacga aaatgtaaga ttgcaccatg aattcatttg 1860cggaaagatt gatactatgc ttttatttta ttttatttta ttttatttta ttttatttta 1920ttttattgag actctcaccc cggttgaagt gcactgacgt gattttggct cactgcaact 1980tccacctcct gggttcaagt gaatactcca gcctccctag tagctgggat tacaggtgcc 2040caccaccacg cctggctaat ttttgtattt ttagtagaga tggggtttca ccacattggc 2100ctggctggtc tcaaactcct gaccttgtga tccacctgtc ttggcctccc aaagtgctgg 2160gattacagag ttgagccacc gcactcgacc ctatgtttta tttttaaaaa tatttattta 2220tttatttaag ccacaactac tagaatagga aggattgata ttttattaat tttatttggt 2280atttattatt tttttttctt tcctgagaca ttcttgctct gtcacccagg ctggagtgca 2340gtggcacatt cttggctcac tgcaacctcc atctcctgtg ttcaagcaat tctagtgcct 2400cagcctactt agtagctggg atgactggca tgtgcctcca cacccagcta atttttgtat 2460tttttgtaga gacagggttt tggcatgttg cccaggcttg tctcaaactc ctggcctcag 2520gtgatccatc tgccgtggcc tcccaaaatg ctgggattat aggcatgagc caccaccccc 2580tcctggaagg attgatatct tataacataa tttataatta cagaaaacat gtgagttcac 2640taggaataaa taaattttga agataataaa agattttcac ttatgttgtc atttcggcac 2700agtttggtat aggatgtgga gatgttaaca tttataccta gcttgctcgt aaactaagac 2760ctgaaagggt tgtgtctatc agctgcaccc ctgggtagcg acacaacctc gggaaggcct 2820cagccccctc ctcgtacagc actgcctgtt ggaaagcttg agggaggcta tggatgtgca 2880gcacttggca gagggtctgg tcatggaagt taccagcaaa tatgagctac ttttatgatt 2940ttattttatc caaaagaaag agaatgaaag aagaggggag gaaacaagac taatcaggaa 3000agatgaaggt ctaggggtga gggaaggagt aaggagacat aaaggcaatg tggagcagct 3060gaggggggaa atggctttca ccacttccca gcatctattg acattgcact ctcaaatatt 3120ttataagact ctatattcaa ggtaatgttt gaaccctgct gagccagtgg catgggtctc 3180tgagagaatc attaacttaa tttgactatc tggtttgtgg gtgcgtttac tctcatgtaa 3240gtcaacaatg tcctgggatt gggacacact ttctgggcac tgctggccag tcccaaaatg 3300gaacataagg aagtggttct tctacttctt ttatttctga aatcaggtaa gacatagttt 3360ttttaaatta taagaattat tttttctccc acaatgtagt aaaaatacat atgccatggc 3420tttatgtgca attcatttaa tttttgattc atgaaattcc cagttcaaaa tcttgtatat 3480gattgaaaaa ttcttaaaaa aataagttta atttccccgt gaagactgtc acggtgctgg 3540aatgaatggg cagaaaaaat aatggttgat ttttctaatc taaaagagtg tgcctacatg 3600atggccagtc tggctgaaaa ataaatagcc attgtagcta actatgcaaa ggatggctaa 3660gctcttcgct tggttctcag tttcattaat ttatatcatc tctgttcagg tgccatgctc 3720ccctcactag caagttgaaa caatgaaata actctttgaa tatgtttggt tccttgacct 3780gttcatggag tgggactcag catttctctc tttgttatgg cctgagtaag gctttccatc 3840ggtatacatt tgcttcttat ccctggagaa attatacaca tccatttgcc agatgatata 3900cgcatataat gattcaacaa atactcaggg tatttgttga gtgggttagg tccccacatt 3960tttatacata catacacaca tacacaccgt gtgtgattgt gaatgtaagt gtgtgtcctt 4020tacaaatact agcttattta gctcatggta taggtagggt agcatagtca tccccatttt 4080ataaacaaag aaatctagac ttaggaaaat catgttattt gtctcgtgac caaattccca 4140aatcaaggaa ataaagaaac ctggatttaa gccagatttc caagaaaaaa tctagggctc 4200ttctcacttt ttcatctttg ttccaacatt tgaaaaaata aatctaaaca cattccaatg 4260taactgaaga gcaggttaat tgtttgccac ttgcagaatc caattaagaa gagagaagtc 4320tggtataaag aaagtgattt gcttccaaag ctagcttagg ggaagaaatg cagcagtcct 4380gccgtactac ttcactttag gagcagaaag tggcactttt aaaaggcaac agaggaggcg 4440agcaaggatt caggggtcca tgctagcttg ggcaccttat ccaccaggta gttgagcagt 4500tgcctgctgg tgcctttgtg agcagggtgt tgtcccttga ggcaaatctc tggagggtga 4560gagttttgta gtgggcatgc tttggtttat aaatcacctg tgaactcagg agttccatct 4620tgaagcacat acatagttag atgaacttgc cctgcaggga gagtctgatg aaagggaggt 4680agatgcttgc aatttaatct ataaattacc agataaaatt ttacaagttg actttaaagt 4740caaacacatt tgaatttagt ggaagccatt caagaaaata tcaaagaaaa tacagagcag 4800gagaagatta agcaaagagt tttttgggga aattggtgtc tatgtctgtg tgtgtaggga 4860gtgcagggga tatgaatatt ctatttcagc ccatggaaac taggatgtag atcactgtga 4920acttattcag caggctacac ccaaaggcta gaacaaactt ctctgccaca ggattaacat 4980atgttttaat cgacctgggg ggcacattct ctgataagct cttttggaaa gccaggcttt 5040ctgtggacgt gttatctttc caatgtgtgc tggaatgccc ggggagagga aaaagtttct 5100tttacagcca tgctcagtga gaagcggaga aacatcttct attcacaaat tgctaagtct 5160tttacacatg caaatatgca tacacattca cacaccacag tgaggaagaa attctcacac 5220cattaataaa atacatttac ttcagtagca atatacatct acattttgcc tataatataa 5280aagtattttt cctattaaaa gatttgttta atgtttcttc accaacaaat aaaccctatt 5340aaatccccat tgccatatga gccctggagg tgaatcagag aaacaaaagg attgtggaaa 5400aatcatcagg ttaaaaaaag aaaaattgat tctgttttgg gatatttcct agcaacatga 5460gctggggagg ggatctcagc agtgatgctc tatgaagcat aataaaatga cacagttaca 5520ggtaacttag ttaaaggggg aaataaatgg aagtttcctc tttttgaata tcaattgtag 5580cctgctctgc tacatttcaa aaacactctt caaaatgttt aactgaactc actgtaggaa 5640gcaccttatt aatttattgt gtgttttgaa gtcacactgt gagctataga atttacccaa 5700gcacaactct tcctggaaaa gagagttcaa atgagaaaca gtgcggggtg aagacatgga 5760tatgggccta aaatatctat ttctcaatga tattttgata tatctatcaa gtgcttttta 5820gtggattagg ttcagaatgc atcagccaat gcctgttcaa taatccagtt ttccagcata 5880gagcatatta aattgaggaa ggacaaagtc acagaggtgg ggagcaggtg gactgtggcc 5940aaggactttg catgaaacag tgagcgtgca tcctcctcct tgccctgccc tcatggtctg 6000tgtactctca ggaggtcagg acaggccttt ctgagaatga gaatctgttc atctgccttt 6060ctactggata cttgtcatcg gcatacaaac acatgttctc tgcagtgtgt catctttcag 6120aacctcccct gaccctgtat tccctagaag tctcgctgct ttcagagcca ggcttctctc 6180ctgctgccac ccccactgct cttctagtca ctctttaacc cactccatct gcatgtggcc 6240cccaccacac ccctcaaagt ggtcaaggtt gtcctgttgc ttaattccat ggaagcttgg 6300ctatcttcat tttattagcc tcttttggcc tctcaccctg tgaaaatcac tacattttgt 6360gccagagatg gagctggcat ctccaggctt ggaagagggc tgctgaagct cagccaggtg 6420tcctaaggag cctcaggaca ggggatgctc agtagccttg caatgggaac acagctgagc 6480cccacttggc caccctttgc cacaaccagg cagaaagcag cttttgaaca gatttgttgc 6540ctcagatttg atctcaaaga aaaatcgtgg gcagtattgg tcccaggttc tgctttttta 6600caatttcctc tgaaatctgg atgcctatca acaccttgga aaaactgaat tctccccaac 6660taatagtggt gtgtcactgt agtaagccta gtacaaaaat ggccttcttt gtggaggagc 6720ttcatatcct ccattttttt tttgcttaat ttttgcccaa gatgagaaca taatttagtt 6780cactttttat ttattcccaa catcatccat gcaccaacat ttttgtaact aaaggaggga 6840ccattcagaa gatgcttatc aactgtcaaa gtgacagtgt tacaaccaat gcacatattg 6900taagaaatca aacaatggcc tccaaggttc atttctacac agggattagc agatcaacat 6960caatcttggc aacacagttg ccactgatgg tgtcttattt tttttatcat gacatggcaa 7020tcaagagcaa acatgattta ttcttattta agattttatg gttagactag gcagatagct 7080agatatgagc aggaggtgga agcccctgag agaatggagg tctggagaat ctgaaacccc 7140agagattacc caagtcctgc atgctagaca tgagtggagg agggggaata cctaggtaga 7200aaagaatgcc ccttaagatg cccagcagtc gctcactgtg cagttaactt ttcagaatgc 7260tgctagatac atgctgatag ggagggaaga gggcaaagga gaaattccta agagatacac 7320ggttgcagtt agtatacatc tgagtgctat acaaccttct ttgggtggtg gcaagaagca 7380atgcagccat tacgtagaat tcatatcaaa cacctgtatc acaggtgtta aagaaacaag 7440aaacattgta cttcttgtat tcttaataat gatttgcaat attgtcttta gtatcactgc 7500aaacctctat aaatatgatt tttaaaaagt atttctttag gttggaatta cttctacgca 7560ttgacttatc ttcctgggtt tcattagccg tacccgttgt actttcttcc ttaccactgt 7620ttatctcaaa ctcttgagat taaagtatgg gctcaggagg gagcgaggag cttcaggact 7680ctcacggacc tccagcacag tgtagctgcc ttatggaaaa gtggccacac tgttttctgc 7740actggtccct gcccctacta ttcctcactg ggcagagcac agccaccctg gccctgcctg 7800aacattttag tcagtgttgg ctctgtgctt ctctggggag gaaatccaag agacaaccca 7860cagcccctct gccatttcag ctgcagcagt accaccgtta atgcccttgg gcttgagaaa 7920gaagggacct ggccacttcc ctgacacctc cagcacacag cagggaaaga attccagttt 7980ctctttcttg tgagctttca cctgctactc ttcaccaggc aaggctcctg gcttgggccc 8040acagtgcagg cacctcgaac tcagttgaac atttccactg gctgcactct gtgtttttgt 8100ggggtgaagc tcccagaggt gactgaaagt ccttctgcca ctaacactgc agtcatactg 8160cccttgctgt acttggacta gggaaggaaa aaagatcctg agtgctttac tcacacccca 8220gtgtgcccca gccaccctat ggaaaagagg ccagtgtgtc atccctgcaa gcaccctgag 8280gcccctgccc ctgctgcccc caagctgtag agccagaata taaagctggc agaaaaatgt 8340aaaaaggcta gactggctta gcctcccagc ctacatcttt ctcctgtgct ggatccttcc 8400tgctcttgaa catcggactc caagttcttc agctgtggga cttggactgt cttccttgct 8460cctcagattg caggtggcct attatgggac cttgtaatct tgtgagttaa taccacttaa 8520taagctcccc tttgtgtgag tatatctata tctatagata gatataggta tactcactat 8580atatacacat atatacatat actctctctc tctctctctc atatatatat atatataatc 8640tcctattagt tctgtccctc tagagaaccc cgactaatac agattttcat accagaagtg 8700gttcttgagg aacagaatat taaggatgga attctttcat tggttttggg acttctggtg 8760ttggctgatt aatatgatta gaccaaaaaa tgctaaggac tctacttcta atagtatgga 8820gaacactgat agtacttggc ctgaattgtt tagagagtta tgcaaaataa atgcatttga 8880cactactgat tcatcactta tgagaggcaa ggagtttagt gactctatac ataatacctt 8940tgactatatg tggagaacca aggaacataa tgaagttggt tgattgctcc taagttctct

9000ggagaaagag atgaaagaaa atgatgatct caggggatct gtctcccacc ttcagaagca 9060gatactgagc cacaaatctg ctaagattgc cctgaatgag agttttaact cctgtagaga 9120aagagttgaa attgtgaaaa aacagagaca agctgttatc atgcgagtag ctgatctgca 9180acaagaggtg catgcacagc cttgccaggt gtttactgtt aaagtgaggg cattgactgg 9240aaaaaaatgg gaccctggaa cttggagtgg ggatgtgtgg gagaaccctg atgaagctga 9300ggacactgag tttgtgaact ctgatgaaac ttttttgcca gaagaaacag tttccccatc 9360cccagtagtg gtaacatccc ctccctgacc cgtgctgcca ttagcctttc cacctttgtc 9420tgaggatgta aaccctgcac tgcttgaggc aacagtgatg gccttccctg aggcagctgc 9480caggcaagat aatgttgatt ctcctcaaga ggcaccccta atgcccctga atgcttctag 9540acctataact aggctaaatt ccttgcgggc cccagaggtg aggttcagag tgtgacccat 9600gaggaggtgc attatactct aaaagaactg cttaagcttt ctaatttata ttggcagaaa 9660tctggagaac aggcatggga atggatatta agggtaaggg ataatggtgg aagggacata 9720gagttggatc aagctgaatt tattggtttg gccctactaa gtagggattc tgcatttaat 9780gttgcagctc ggggacttag aaaaggttct gatagggccg ggagcagtgg ctcacgcctg 9840taatcccagc accttgggag gcgggggcgg gcagatcacg agatcaggag attgagacaa 9900ttctggctaa aatggtgaaa ccccatctct gctaaaaata caaaaattag ctgggcatgg 9960tgatgcgtaa ctgtaatctc atctacttgg gaggctgagg caagagaact gcttgaacct 10020gtgaggcaga gattgcagtg agccaagatc gccccactgc attccagcct ggtaacagag 10080caagactcca tttccaaaaa aaaaaaaaaa aaagttataa tagtttattt gcttggttag 10140ctgaaatatg gattaaaaga tggtccaatg ttagtgagct ggaaatgcct tggtttaatg 10200tagaggaagt gatccaaagg cttagggaga ttaggatggt ggagtggatt agtcacttta 10260gacctactca tcccagctgg gagggtccag aagatacacc cttggccgaa gctttgtgaa 10320atagatttgt gagagcagca cctgtatttt tgaagagccc gtaattgctc ttctctgtat 10380gtcagatcta acagtaggaa ccacagtcac tcaactacaa aatttaaata caatgggaat 10440aattggatcc tgaggtggca ggggccaagt gttggcactg aaccatcaaa ggcaaggtgg 10500gcataactac cataatagac agcagaggca aagcagccat cagaatagtc tgactcatgt 10560agagctctgg cattggctaa ttaatcatgg tgttcctaga agtgaaattg atgggaaacc 10620tactgtattc ctacttgatt tatataaaca aaaaactgcc aggtagaatg gactaaagac 10680taatctgaat tataaaaaca gagaatcatg ggccctcaat caatttccag actcgaacct 10740gttacagttc cagaacccac tgaatgaagg ggaggctgga tccccttgag gaaggacacc 10800actaggctac tgacaactta tgctgttact ctttctccca tccttcccta aggagacctc 10860tggcctttta ccagggtaac tgtgtgtact ggagaaaggg aagtaatgag acatttcaga 10920aagtactgga cactggctct gagctgacgt tgattccagg gtacccaaaa cgttattgtg 10980gttccccagt taaagtaggg gcttatggag gttaggtaat taatggagtt ttagctcatt 11040tctgacttac agtggttcca gtgggtccct ggacttatcc tctggtcatt ttcccagtgc 11100caaaatgcat aatttgtata gacatactta ttagctggca gaaatgccac attggctccc 11160tgactggtag gatgagggct attatggtgg gaaaggccaa acagaagcca ttagagctgt 11220ctctacctag aaaaataaaa aaatcaaaaa caatatccca tccctggagg gactgaagtg 11280attagtgtca ccatcaagga cttgaaagac gcaggggtgg tgattcccac cacatccctg 11340ttcaactctc ccatttgacc tgtgcagagg acagatggat cttggaaaat gatggtggat 11400tattttaagc ttaaccaagt ggtgactcca attgcagctg ctctaccagt tgtggttttg 11460ttgcttgagc aaattaacac atctcctggt gcctggtatg cagccattgg cttggcaagt 11520ggctttttct ccattcctgt ccataagacc caccagaagc aatttgcctt cagctgacaa 11580ggccagcatt atacctttac caccctacct caggggtgta tcaactctcc agctttgtgt 11640cataatctta tttggagaga ccttgctcgc ttttcacttc cacgagatat aacactggtc 11700cattacattc atgacattat gatgattgga tacagtgagc aagaagtagc aaacacactg 11760aacttattgg tgagacattt gtatgccaga ggatgggaaa taaatccagc taaaatttag 11820ggactttcta cctcggtaaa atttctaggg ttccagtggc atgagaccta tggagatatt 11880ccttctaagg tgaagcataa cttgctgcgt ttggcccctc ttacaaccaa gaaagaggca 11940caatgcctgg tgggcctatt tggattttgg aggcaacaca ttcctcgttt gggtgtgtta 12000ctctggccca tttatcgagt gacctgaaag gctgccagat ttaagtgcag tctagaacaa 12060aagaaggctc tgaaacaggt ccaggctgct gtgaaagctg ctctgccatt tgggccacat 12120gaccccgcag atccaatggt gcttgaggtg tcagtggcag atagggatgc tgtttggagc 12180ctttggcagg cccccatagg tgaatcacag tggagacctc taggattttg gagcaaggcc 12240ctgccacttc tgcagataac tactctcctt ttgagagaca gctattggtc tgttattggg 12300ctttggtggt aactgaacgt ttgactgtgg gtcataaagt caccatgcta cctgaacctg 12360cctatcatga actggttgct ttctgaccca tctagccatg aagtgggtca gcacagcggc 12420atttcatcat caaattgaag tggtgtgtat gtgatcgggc ttgagcaggt cctgaaggca 12480caagtaagtt acataaggaa gtggctcaaa tgcccatgtt ctccactcat gccaccctgc 12540cttccctccc ccagcctgca ccaatggcct catggggagt tccctatgat cagttgacag 12600aggaagggaa gactaaggac tggttcatag atggttctgc acgatatgca ggcaccaccc 12660gaaagtggac agctgcagca ctatatccac tttctaaatg catgtgtaca cttgtgctaa 12720gaaaatatct ttattttatt tcctttattt ttcctttatc atgtgacctt agatttatgg 12780acttcacatc agcatttaag catttaagtg ttgttcatat cagcatttaa atattgttaa 12840ccttatgtaa taacttttgg tttggggatt ggtgcgtttc tggttgtatg aggatagttg 12900tattatatta ggcataatta tgaccttatt attgtcttta tttgaagatt atgtatgatt 12960tcaggatgtg tgtatgggtt caagttgaca aggagttgga cttgtgatgg ttaatactgt 13020caacttgatt ggattgaaag atgcaaagta ttaatctcgg ttatgtctgt gagggtgtgg 13080caaaaggaga ttaacatttg agtcagtggg ctgggaaggc agacccaccc ttaatctggg 13140tacacaccat ctaatcaagt tccagtgtgg ccagattgta aagcagggag aaaaatgtga 13200aaagactaga ctgaattagc ttcccagcct acatctttct cctgtgccaa atgcttcctg 13260ctcttgaaca tcggactcca agttcttcag cgttgggagt tggactggct ttcttgctcc 13320tcagcttgca gagggcctgt tgtggaacct tgtgatccgc tgagttaata ctacttaata 13380agatcccctt tatatacata taatatatta tattatatat aatatatata atatatatta 13440tatataatat atataatata ttatatatta tatataatat atattatata ttatatataa 13500tatatattat atataatata tattatatat tatatattat atataatata tattatatat 13560aatatatata aaatatatat atatcctatt agttctgtcc ctctagagaa ccctgactaa 13620tacaatttat gtcattaatc tcatttattg atttgtatac attgaaccaa ccttatatcc 13680caggaataaa acctacttga ttgtggtgga ttagcttttt gatgtactct tggattcaat 13740tgctggtatt ttattgagaa tttttgcatc tgtgttcatc aaggatattg gcttgaagtt 13800ttcttttttt gttgttccat atcagaatga tgacgacctc atagaatgag ttagtctgtc 13860ctcttttatc ttttggaatt gtttcaggag gcttgatatc agctcttctt tatatgactg 13920gtatactttg gctaggaatc tctctggtcc aggggttttt ctggtgtagg tttttaatta 13980ctgattcaac ttcagaactc attactcatt attgagttct aaaactcact ttcatgtact 14040cttcaaaaga ctgtcttctt ctgttgttga gcggggtgtt ctctcaaggt cgtttaggtg 14100aaggtggttg ctggtgttct tctgtatcct tactgcttgt ctttctcttt ttttattgac 14160tactgaggat taatggtgat gtgtccaact ttaactctag attagtctat ttctctttta 14220gattgtaact ctgttttata tattttgaag ctctgttgtt aggcatgtgt atttggattg 14280ttaggtcttc ttgatgatga cctttatcat tatgtaatgt ttcttcttat ctctggaagt 14340attcgttgtt ctgaagtcta tttgtgctga tatgaataca gccttcacag ctctattttc 14400actagtattt gtatatcttt ttctcagctt ttaaattgag atgttcagac catttgcatt 14460aaagtagttg ttaataggat taaatttaaa tctaccatta agttggttat ttctctttgt 14520cccatttaaa ctttgttcct tttttcatat ttttctgcct tcatttatat tgagtttatc 14580tccacgactt acttattaaa ttaattttta atggttttag tattttccac aatgtttata 14640atatatactt tgattttttc acattccacc ttcaaatgac agaattatac tggatatata 14700gaaatcttac atcattgcac ttctccttcc tccctctcaa aatgttgtgc tattgctctt 14760tgtaatagag gcttacttct attatgttat agctctcata atacattgac actattttta 14820ccctgaataa tcagttgttt tttaaagtga ttatgactac aaatattttg aataatttct 14880ttattttacc atttctggtg ctccttatct tttacagtag atcccaattt ccatctggag 14940tcacattctt tctgtgaaaa acaaccttta gcatttctta tagcacggga ctgctgttgc 15000tgttgtcttt cagcttttct ttgtctgaag aagtctttat tttgccttca gtttttaaaa 15060gtgattttgc tgagtataga tactgggttg agagtttcat tccttgtatc attttaacaa 15120tgatgttcca ttatattccg ttttgaatag tttctgacta gaaatctgat ctttgtttct 15180ttgtattcaa tagttccttt ttctctgact gcctttaaga tattctcatc tttgtttttc 15240aacagtttga ctataatttg tttattatta actttttgta tttattctgc ttgaggtttc 15300ctgagctcct tggatttgca gattgttgat ttttattgtt tttgtaaaat tcatagccat 15360tatctattct actgttttgt tttttttttc acttctctct ctctgtattc ttctttttgg 15420actgtaagta ttcaaatgtt agatcattca tattgcttca taaaccttat atgcttcttc 15480tgcttttttt tttttgtcag gaactctttt tttgtatctg tgttggtttg gataagttct 15540agtagactat gttcaagttt atggattatt ttgttagttg tgtctaattg actcctcagt 15600gcattcagag aattcttcat ctctgatatt ataaatctct tcctagcatt ttcatgttac 15660tcttttctat agtttccatc tctttgctga aattctcccc ctatccatgg atattgtcca 15720cctttaccac aagattcttt aacatattaa cataggtatc atacaaaccc aaactgatag 15780tttccagatg gtgtcttttc tgagtctgtc tgtcttgatt gctttattat ttaacagtga 15840cttatcttcc ctcttcagct tttggtgtgt cttgtaattg tttaatcaaa cactgggtat 15900cataaatgga ggaacagtag agattgcagt aaatattatt tatgctttga aatgggcacc 15960catcttctgt tgaaaatatg ttttgtggtc aattgagtca acctagtaac tggttgaact 16020gaatttggca tttgtgcttg ttgcttttat cttaaatgca ccacaggttt aaattcctcc 16080agtgatgggt tgctgctatc ttttgcttag agtggggcct ggggtgtgga agaattttct 16140cagtgttcct atctattatt agattttagc agtcactgca tgcctgcact acagagggga 16200tatcttcata cacataatct aaccccattg aaactgctgt ttcttcttaa tgaatgctca 16260atctttggtg gaaataaaca aatgctgtat ctcctggagc cacttcagtc ttagtcaggt 16320tctgcagggc tttgaaggga atgcattctc agtattcttg tgccttattt ggatggaact 16380tgaacctgtg gtgggtttgg agagaaagag tagcagacgt ctgctatgtt gcaatgcagg 16440atgctgggca caagaaaatt tccagtctct cctccaagga aataagattt gatcatctac 16500ctatccctga gaagtgaagg gctttgcctg cggtgctaga tgcaaaacca tttttctccc 16560cccattgccc agaaacttaa ggctttggct tttctgagca gtggtctagg gaattgtgca 16620aggttttcat atttgaccct gacagcccat caccacctac agcttgcagt gccaaatgta 16680tctccctctg atctctcctg tcctgtggtc ctcatgaaca ttaagaagag atttctaaaa 16740aagagcttgc acatgagcat agtttctggt gagaagaatt ctgatatgtt aacttcctct 16800aaacttttaa ataaaatatt tctaagaatt aaataaagtt ctagaatgat atgaatctat 16860tcctttggtt ttttgcacgt ctgtctgcct gctaatcaag agaagagaat ggtcgtaatt 16920ctcagagact ttttcctgtt tgtgtcataa atgacttcac atttttttct gttctaagaa 16980ctattcagct tgatttcttc tgttttaatt ttagcagcac ctgagcaaag ccatgtggtc 17040caggattgct accatggtga tggacagagt tatcgaggca cgtactccac cactgtcaca 17100ggaaggacct gccaagcttg gtcatctatg acaccacatc aacataatag gaccacagaa 17160aactacccaa atgcgtatgt cattaatctt acagtaagca aaacaaggtc caagtaaaat 17220ttgtcttaga aaaggtgtgc gtcaagctaa cttcttatga ttaaattttt ctcacacata 17280gaatgcatgg caaaatgtct gagaaacatt actttgagca aagagtatga tagaagagaa 17340atgttaagct ggctctcttt cctgagagtt tgataaaatc aggagaatat ctggcggtgg 17400tgaggccaca ataatggaaa atcagaatgt ttagacagag tcagcttcaa caacactcac 17460taaaggtcaa tgtgatcttt accccttgaa attctataat tctaatctcc aattcctgaa 17520gtgaaggttg tgttggcctt ttctgtcttg gctcacaagt aaatgatatg tgcatatcta 17580tggaaaggcg aatctatctt tttctatatc tatgtctatt ccaacgggta gaaacaccct 17640gggtcctgag caccagtggt ctgaaggaat acgggttgcc aggaagagag aagcaaaggc 17700aggaaggcag atgaaagtaa gaaatgagac agatgctaaa caataaaaag tgcgggaaga 17760tagacagaag ctggggtctg accacaccat ggccagtctt tcacacataa gtgactacca 17820aagacaagaa aaaatgattt ccgcttgttg gacaatagat ggtagaggac caagggaatt 17880gcgagagaga gaacaatgag atcaactcaa cagatgcact ggttttcttc ctggagaccc 17940ttcctgcact gaagggcagg agatggagcc caaaaaaaac tgtagccatc ttgctgaaca 18000gaggagggac attggagttt gggattattc aggtggctag gattttctag gcctgctaac 18060aatgagaaca gatttgtgga ggaaaggagt tctagaaata tgcatagaaa tctcctcgag 18120tcattggcta aacatgaagc tgcatgtaca cagaaaatag atccacaaga aagtagggca 18180aagaacatct acggaagagc agcaactaca atggaacagt gagctcaata aacatgacag 18240agctcaaata gcactaaggg atattggagt ttggaccaca cagaggagag agacttcact 18300gaacatcttg ggcattcagt agagacccag gaaaagccat actttaggag tagaattagt 18360atattcttag aataaaggca gctccacaca aacaatagca aaactgaaaa ggaagtctcc 18420aagcatcaga atgatgtcca agtcaatgaa ctgcctctga gaggaaaact caaccatctt 18480tagaggtaaa catcaaagtc aagtggctca gctatgcagt atccacagtg tgaggcctaa 18540atataaaact tgactacaca tagaaacctt ttagtgtgac ccacaagcag gaggaaaatc 18600agccaataca aacagaccca gaagagacag aaatgattag aatggcataa aaatttgaca 18660tatcactata taataattga gttctaggat ttaagaaaac atgaatatag aatgcaacag 18720acaccttatc cagagacagt aagagtataa agagccaaat cgaagaacta ctaagagata 18780tgtcttaaat gaaaaaatta ctagatggcc tccccatcta gttagacatt tcagaagaaa 18840ataccaaatg aaaaataatt gcatagaacc tacagaacca gatacacaca tacaaaacac 18900acgcatgcat acacacacac tcaaacatgt ataagcttac aaacacacac acacatccac 18960aaatgctgaa aaatgaaatc aaccgagcca cacagacata aaggaaaaca taaaaagatt 19020tcctacatgt gggaagcaag tcacagaaag ggggaaggag attggaacag aaatatatac 19080tgaaagcaag gatggctgaa aattttccaa atataaagaa gattaaaaaa tcacggactc 19140aagaagctca atggatcaga aaaataattt ctaaaatgac aattatagga tgccactggg 19200tacatagcag ttcaactgtc agagggcaaa gacataatac acagaaaaat ctcgtaagga 19260acgggaaaaa caaaaagctg tgtcttgcta gaggaacagt gatacaagtg actaatgtgt 19320tcccatcaga aacactgcaa cctggacaca aaagaataac attaaagtaa taaacgtaag 19380aaagaagagc tcaactgaga aggctacatc cagcaataaa atgccttgaa gttcatccat 19440gttggaggaa tgcacattgt gcactcccct aaacaaagaa accggaaact gtaagacttt 19500ggaatcagca ggcttatgta acaaaagagg tgaccctaag gaattaagga gaagaagaat 19560agaacaagaa gggaactttc tgcagcctat ataatgaaga acctagcaat tggcaaatgt 19620agatgaaaat gctacatgtt ttcttgatca aacgtttata tctttttaaa tgagagttga 19680cgagttgaag caaaatgata ccaatatatt taactttacc atatgtagaa gtaaaaattt 19740gaacatgtag cataaatcat gtagggatta attggaagtg taccactgta agtttcttac 19800ctcatgcacg atagtatgta atactaataa aaggttaatg tgtgggttca aagggatatt 19860gcaaatccta gagcaatcac aaagttttta actctgaggt ttgttgtata ataacaatat 19920tttatgtatt caaaagaggg aagccaagga agaaaaaaaa gtctttaaag agctctggct 19980cttagtacat ccagttgctc attgaatgag cttcctggaa tggagggtct gggactgaga 20040ctaggccaca tgtgtagagc cactagagac acaatgttgg atccccatgg cccataatac 20100atttcccatt ttctcaggca gccacaggtc atgaatgtga ggatactgag aggttggagc 20160aacgttcttg ggaggcataa ggaagagcga atgcttcaag atccccgcag cccaaactcc 20220tcagctgctt tgcctcctaa ttcattgttt tttgctcctc catagctgtc cgacctcttc 20280agatctctta gtcttcctgc catcttcctt tatgccatgg gacccactgt tctttcaact 20340catcccccag ttctggagtg gctgtggaca gcagaggata gactgagagc aggagagaag 20400gtcctgccca ggaacccatt ctagagatac tgcattctgc ctgggagcaa gttttccagg 20460gcagctttga gaagtcttgc agaaacaaac ctacttgacc gacatgatat gggaatgaca 20520gacagtaata ctatttgcac aatgcttttc catgggaaag gtagagcctt ttcactaggt 20580tttgagtaca tggagtgtga gagttgacct ggaaaggtta tcctccttga tgccatgttt 20640tctctgaaga actacatgtt cgttgcaact cccacattag aatatgaagt cctaccgaga 20700gagatacgga gactagacag atacagatgc atttgcatgt gaatacacaa tcccacaata 20760cagacgtcaa aacccatacc agttattcca gagagatgga ttgggcagaa ggcagaagga 20820gaatactctg atcgtttttc ggccacgtgt gtgtgttatc tcagtgtttc taagaagcgt 20880ttgctacttt agatttttta tttaaaaaaa atagtaataa tctattaagt atgagagatg 20940tgcagagagg attagtgatc gagagccatt tttgctggtg gcaatcatat ggtactttta 21000atgggaatat tagaaaggca ccggtaatga ccttgttgca gcacaaagga gagagtgtgg 21060ggtgcccctg catgttgtcc cacctcttgt gacgtgtatc gttttggaat ttccagtggc 21120ttgatcatga actactgcag gaatccagat gctgtggcag ctccttattg ttatacgagg 21180gatcccggtg tcaggtggga gtactgcaac ctgacgcaat gctcagacgc agaagggact 21240gccgtcgcgc ctccgactgt taccccggtt ccaagcctag aggctccttc cgaacaaggt 21300aaggagtctg tggccagaca tctacacgct tcgatgctgg gatgaaaagc catggaaatt 21360cccactgatg cagccgcctt caatggtaaa cggatgctcg agtgttgcct gagttctacc 21420atgtaggagg aagcctccgt gcactctctg ggggagccag cggagtgatt tctggtgcaa 21480cgtggttggg ctttgtcttt aggatgggca caaaccctcc agggggatcg acttcaaaat 21540tcaccttgtt gtaaaacggg ctacctcagt gtcccagcca aaatttttat tgtaacatgc 21600tgtcaggtgt gtcactcttt ccaagccagt aagcttttcc ggggatttct tcaagtagcc 21660agcattcaga gcaatcttca gcattgcaga ttctgagaaa tgtggctctg gagcctgtca 21720ccctcgagaa acctaagagg gctgcattga ttccatgtgg ccctgggtct atggagcagt 21780acatgagctc ccagtgctct aaggctcttc agccctaggc tttgaaggga gtgatttctc 21840agtattctta aacctctttc tgatgacact tgtacctgtg aggggtctag agagaaagag 21900tagtagactc ctactttact acaattcagg atgcagggca tgagaggatt ccctctctcc 21960tccaagggaa gaagcttttg gcgtgcacac atccctgaga agcaaagtgt ctttgtcttc 22020agtcagatac ataggaccgt tttctgcccc atggcccgga agccaaaggc cttggctttc 22080atgatcaacg gtctagggaa acatgcaaaa tttccatgtc tgtcccaaac tctgcccccg 22140acagccaatt accacctgca gcccgcattg ccaaatgcgg tgccgtttgc atgaagattc 22200agtagagttt cctagaaagg tgctacctcg tgagctcact ttccaatgag gaatctgatc 22260tgttgtgttt ctctaaggtg tcaggtgaaa tatttccaag aacttactac agttctagaa 22320tgggaggaat ctgttgcttt ggtgtttgtt tgttggtcgg ttttctcaca tccatctgcc 22380tatggataag gaaaagagaa cggtcgtaat tctcatagac tcctttctgg ttgtgtcaca 22440aatggcttca catgtttctc tatgctcaga gatactcagc ttgatttccc gtgttttcat 22500ttcagcaccg actgagcaaa ggcctggggt gcaggagtgc taccatggta atggacagag 22560ttatcgaggc acatactcca ccactgtcac aggaagaacc tgccaagctt ggtcatctat 22620gacaccacac tcgcatagtc ggaccccaga atactaccca aatgcgtatg tctttgttct 22680ttaccataag agaagaaagg gccaagtgaa gtttctgtta caagagatgt gtctcaagct 22740gagttctccg aactcaactt gtgacagatg cagatggcgt agcaaaatgt ctcaggatga 22800ttgccttgga gctaagggtc tgagagaagg gaaatgttaa gctccctctc cttcctccta 22860gttctattga gcagaaggga aatctggagg tgaggagatc acattatgaa gaaagtcaga 22920atgacaaagg accagacact tagattaccc ttccacaaca ccaactaaac gtcaatggag 22980actttccagt tggaattccg ttattctggc ttccacttcc tgaagggaag gttgcgtttg 23040ccttttctct ctgggttcaa gaggaaagaa taggtgctta tttatggaca ggtgaattga 23100tctgtttcta tatctacgta tattccgatt gtcagaaaaa cactcgttcc taagtaccag 23160tggcctgaag ggatacaggt tcccagcaag agaagatcca aggaaggaag gcagatgaga 23220gtcagcacag agagggatgc tgaaaagtaa aagggatggg tggatggaga gaagcccggg 23280tctgaccacc caatggccaa tattttggcc acaagcgact accagagaca tggaaaaatg 23340gtttctacat gtgggacaac agatggtaga ggacctagag aattgagaga ggggcaatga 23400tgggctccac tccgcagatg ccttggcttt cttcctggat acccttcctg cactgaatag 23460caaggagatg gagcccaagc agactgtagc catcttgctg aatggaggag agggattgga 23520gtttgggatg actgtggtag ctgaaatttt tctaggtctg ctagaaataa gaactggttt 23580gtgtggagga aaagagctct acaaatacgc atagaagtct cctccagtcg ttggcctgac 23640atgacgctgc ctgtgcacag gaaatggttc cacgagaaag tgtggcaaag aacatttact 23700gagaaacagc aagtacaaga gcacaggaag ctcaataaag aagagagaga tcacatagca 23760ctctgggata ctggagttct tcccagctag accagagagt cctcacggag cacattgcca 23820attcagtgga gaccccagaa cagccgtaat ttaaaggtac acttagtata ttactagaat 23880aaagtcagct gcagacaacc ccttgcacag ctggaaagca agtgtccaag catcaaatcg 23940gtttccaatc aatgaagtgc ctgtgagagg aaatctcaac tctctttaga agtaaacaac 24000aaagtcgatt gcctcagcta tgcggtatcc gcagagtgag tcctaaattt aaaatctgac

24060tacatgtaga aaagcgtttc gtgtgaccca tgaccaggaa ataaatcggg taatacaaac 24120aggctcagga atgagagaaa tgattagaat tgcgtgaaaa tttgacatat cagtatgata 24180actgatttca aatatttaaa aaaacaacat gcaagaaagc agatatcata tcaagagaaa 24240ttaacagtac agaatagcca aattaaatta aagaggtagt ataaaaaaag tatgtcttaa 24300ttgaaaaaaa ttactgtatg gccggctgat caatttagac gtttcagagg aaaacattac 24360ccaacacaca attctagaga acctacagaa tgagctacac acacacacac acacacacac 24420acacacactg aaaacacacc catactcaca cacacgcaga aactcacaag ttctaacaca 24480cacagacacg cgcacccctg aagaaacagt gaaatataaa attaagcgag cctcacagac 24540atgtaggaaa atatgaaaag atttcctgca tgtgggaagc aagtcacagt aaagagcaag 24600ggagtttata atagaaacaa ataccagaat caaggatggc tgataacttt tcaattacga 24660agaacattaa aaaaaatcac agaatcgtga aactcaaggg atcatatagg gaatttcgga 24720aaaaaaaccc aacctgtatg atgtactttt gtacatcaca gttcgaaggt aacaaggcaa 24780agatgtaata agaagaaacc tgtcacgaga aactggagga aaaagagctg tgtcttccta 24840caagtacact gatacaaatt gccaatgtgt tcacctcaga aacactggaa gccagatacc 24900agggaatatt gttaaaatga taatcaggaa caaaaagaga tcaaccggga atgctgaatc 24960cagcaataaa atgccttgaa ggtcatccat gtcggataaa tgcatattgt gcactgcccc 25020aaagaaagaa accggaaact gtaagaattg gaaatcagca ggcttatgta acaagagagg 25080tgacccgaag gaattaggta gaagaagaat tgaacaagaa aggaactttc tgcagcccac 25140gtaatgaaga atccagcaat tggcaaatgt agatagatgt aaatgcaaaa tattttcttg 25200atcaaatttc tatatctttg taaatgagag ttgactactt gaaacaaaat gatagcaaga 25260tatttaactt cagcatatgt agaggtaaga atttgaaatg gtagcataaa tcacgaaggg 25320attaattcga agtgtaccgt tgtaagtttc tttacctcat gcacgatggt gtgtcatatt 25380aataaaaggg tactgtgcgg gttcgaaggg atattgcaaa tcctagagca atcacaaagg 25440tttgaactct gaggtttttg gtataataag aatagtccat gcattcaaaa gagggaagcc 25500aaggaagaac tagaagtctt tcaagagctc aggctcttat acatccagtt gctcattgaa 25560ccagcttcct ggaatggagg gtctggggtt gagactaggc cacaagtcta gagtctctag 25620agagacagtg ttggaacccc atggcccata atacatttcc cattttctca ggcagccaga 25680ggtcatgaat gtgaggatac tgggaggttg gagcaacgtt cttgggaggc ataaggaaga 25740gcgaatgctt caagatcccc gcagcccaaa ctactcgcct gctttgcccc ctaatgcatt 25800tttctctgct gctccgtagc tgtccgacct cttcagatct cttagtccac cctgccgtct 25860tcctttatgc catgggtccc actgttcttt caactcatcc ccctttccct cagtcccgga 25920gtagctgcgg ccagcagagg gtagactgag agcaggagag aaggacctgc ctaggaaccc 25980cttctagaga tactgcatcc tgcctgggag caagttttcc agggcagctt tgagaagtct 26040tggagaaaca aacctactaa acctgacaga cagtaatact atttgcacaa tgcttttctg 26100tgggaaaggt agagcctttt cactacgtat tgagtacata gagtgtgagg gttgacctgg 26160aacggctatc ctcctggatg acgtgtgttt tctgaagaac tacatgttcg ttgcaactcc 26220cacattagaa tatgaagtcc taccgagaga gatacggaga ctagacagat acagatgcat 26280ttgcatgtga atacacaatc ccacaataca gacgtcaaaa cccataccag ttattccaga 26340gagatggatt gggcagaagg cagaaggaga atactctgat cgtttttcgg ccacgtgtgt 26400gtgttatctc agtgtttcta agaagcgttt gctactttag attttttatt taaaaaaata 26460gtaataatct attaagtatg agagatgtgc agagaggatt agtgatcgag agccattttt 26520gctggtggca atcatatggt acttttaatg ggaatattag aaaggcaccg gtaatgacct 26580tgttgcagca caaaggagag agtgtggggt gcccctgcat gttgtcccac ctcttgtgac 26640gtgtatcgtt ttggaatttc cagtggcttg atcatgaact actgcaggaa tccagatgct 26700gtggcagctc cttattgtta tacgagggat cccggtgtca ggtgggagta ctgcaacctg 26760acgcaatgct cagacgcaga agggactgcc gtcgcgcctc cgactgttac cccggttcca 26820agcctagagg ctccttccga acaaggtaag gagtctgtgg ccagacatct acacgcttcg 26880atgctgggat gaaaagccat ggaaattccc actgatgcag ccgccttcaa tggtaaacgg 26940atgctcgagt gttgcctgag ttctaccatg taggaggaag cctccgtgca ctctctgggg 27000gagccagcgg agtgatttct ggtgcaacgt ggttgggctt tgtctttagg atgggcacaa 27060accctccagg gggatcgact tcaaaattca ccttgttgta aaacgggcta cctcagtgtc 27120ccagccaaaa tttttattgt aacatgctgt caggtgtgtc actctttcca agccagtaag 27180cttttccggg gatttcttca agtagccagc attcagagca atcttcagca ttgcagattc 27240tgagaaatgt ggctctggag cctgtcaccc tcgagaaacc taagagggct gcattgattc 27300catgtggccc tgggtctatg gagcagtaca tgagctccca gtgctctaag gctcttcagc 27360cctaggcttt gaagggagtg atttctcagt attcttaaac ctctttctga tgacacttgt 27420acctgtgagg ggtctagaga gaaagagtag tagactccta ctttactaca attcaggatg 27480cagggcatga gaggattccc tctctcctcc aagggaagaa gcttttggcg tgcacacatc 27540cctgagaagc aaagtgtctt tgtcttcagt cagatacata ggaccgtttt ctgccccatg 27600gcccggaagc caaaggcctt ggctttcatg atcaacggtc tagggaaaca tgcaaaattt 27660ccatgtctgt cccaaactct gcccccgaca gccaattacc acctgcagcc cgcattgcca 27720aatgcggtgc cgtttgcatg aagattcagt agagtttcct agaaaggtgc tacctcgtga 27780gctcactttc caatgaggaa tctgatctgt tgtgtttctc taaggtgtca ggtgaaatat 27840ttccaagaac ttactacagt tctagaatgg gaggaatctg ttgctttggt gtttgtttgt 27900tggtcggttt tctcacatcc atctgcctat ggataaggaa aagagaacgg tcgtaattct 27960catagactcc tttctggttg tgtcacaaat ggcttcacat gtttctctat gctcagagat 28020actcagcttg atttcccgtg ttttcatttc agcaccgact gagcaaaggc ctggggtgca 28080ggagtgctac catggtaatg gacagagtta tcgaggcaca tactccacca ctgtcacagg 28140aagaacctgc caagcttggt catctatgac accacactcg catagtcgga ccccagaata 28200ctacccaaat gcgtatgtct ttgttcttta ccataagaga agaaagggcc aagtgaagtt 28260tctgttacaa gagatgtgtc tcaagctgag ttctccgaac tcaacttgtg acagatgcag 28320atggcgtagc aaaatgtctc aggatgattg ccttggagct aagggtctga gagaagggaa 28380atgttaagct ccctctcctt cctcctagtt ctattgagca gaagggaaat ctggaggtga 28440ggagatcaca ttatgaagaa agtcagaatg acaaaggacc agacacttag attacccttc 28500cacaacacca actaaacgtc aatggagact ttccagttgg aattccgtta ttctggcttc 28560cacttcctga agggaaggtt gcgtttgcct tttctctctg ggttcaagag gaaagaatag 28620gtgcttattt atggacaggt gaattgatct gtttctatat ctacgtatat tccgattgtc 28680agaaaaacac tcgttcctaa gtaccagtgg cctgaaggga tacaggttcc cagcaagaga 28740agatccaagg aaggaaggca gatgagagtc agcacagaga gggatgctga aaagtaaaag 28800ggatgggtgg atggagagaa gcccgggtct gaccacccaa tggccaatat tttggccaca 28860agcgactacc agagacatgg aaaaatggtt tctacatgtg ggacaacaga tggtagagga 28920cctagagaat tgagagaggg gcaatgatgg gctccactcc gcagatgcct tggctttctt 28980cctggatacc cttcctgcac tgaatagcaa ggagatggag cccaagcaga ctgtagccat 29040cttgctgaat ggaggagagg gattggagtt tgggatgact gtggtagctg aaatttttct 29100aggtctgcta gaaataagaa ctggtttgtg gaggaaaaga gctctacaaa tacgcataga 29160agtctcctcc agtcgttggc ctgacatgac gctgcctgtg cacaggaaat ggttccacga 29220gaaagtgtgg caaagaacat ttactgagaa acagcaagta caagagcaca ggaagctcaa 29280taaagaagag agagatcaca tagcactctg ggatactgga gttcttccca gctagaccag 29340agagtcctca cggagcacat tgccaattca gtggagaccc cagaacagcc gtaatttaaa 29400ggtacactta gtatattact agaataaagt cagctgcaga caaccccttg cacagctgga 29460aagcaagtgt ccaagcatca aatcggtttc caatcaatga agtgcctgtg agaggaaatc 29520tcaactctct ttagaagtaa acaacaaagt cgattgcctc agctatgcgg tatccgcaga 29580gtgagtccta aatttaaaat ctgactacat gtagaaaagc gtttcgtgtg acccatgacc 29640aggaaataaa tcgggtaata caaacaggct caggaatgag agaaatgatt agaattgcgt 29700gaaaatttga catatcagta tgataactga tttcaaatat ttaaaaaaac aacatgcaag 29760aaagcagata tcatatcaag agaaattaac agtacagaat agccaaatta aattaaagag 29820ctagtataaa aaaagtatgt cttaattgaa aaaaattact gtatggccgg ctgatcaatt 29880tagacgtttc agaggaaaac attacccaac acacaattct agagaaccta cagaatgagc 29940tacacacaca cacacacaca cacacacaaa ctgaaaacac acccatactc acacacacgc 30000agaaactcac aagttctaac acacacagac acgcgcaccc ctgaagaaac agtgaaatat 30060aaaattaagc gagcctcaca gacatgtagg aaaatatgaa aagatttcct gcatgtggga 30120agcaagtcac agtaaagagc aagggagttt ggaatagaaa caaataccgg aatcaaggat 30180ggctgataac ttttcaatta cgaagaacat taaaaaaaat cacagaatcg tgaaactcaa 30240gggatcacat agggaatttc ggaaaaaaaa cccaacctgt atgatgtact tttgtacatc 30300acagttcgaa ggtaacaagg caaagatata ataagaagaa acctgtcacg agaaactgga 30360ggaaaaagag ctgtgtcttc ctacaagtac actgatacaa attgccaatg tgttcacctc 30420agaaacactg gaagccagat accagggaat attgttaaaa tgataatcag gaacaaaaag 30480agatcaaccg ggaatgctga atccagcaat aaaatgcctt gaagatcatc catgtcggat 30540aaatgcatat tgtgcactgc cccaaagaaa gaaaccggaa actgtaagaa ttggaaatca 30600gcaggcttat gtaacaagag aggtgacccg aaggaattag gtagaagaag aattgaacaa 30660gaaaggaact ttctgcagcc cacgtaatga agaatccagc aattggcaaa tgtagataga 30720tgtaaatgca aaatattttc ttgatcaaat ttctatatct ttgtaaatga gagttgacta 30780cttgaaacaa aatgatagca agatatttaa cttcagcata tgtagaggta agaatttgaa 30840atggtagcat aaatcacgaa gggattaatt cgaagtgtac cgttgtaagt ttctttacct 30900catgcacgat ggtgtgtcat attaataaaa gggtactgtg cgggttcgaa gggatattgc 30960aaatcctaga gcaatcacaa aggtttgaac tctgaggttt ttggtataat aagaatagtc 31020catgcattca aaagagggaa gccaaggaag aactagaagt ctttcaagag ctcaggctct 31080tatacatcca gttgctcatt gaaccagctt cctggaatgg agggtctggg gttgagacta 31140ggccacaagt ctagagtctc tagagagaca gtgttggaac cccatggccc ataatacatt 31200tcccattttc tcaggcagcc agaggtcatg aatgtgagga tactgggagg ttggagcaac 31260gttcttggga ggcataagga agagcgaatg cttcaagatc cccgcagccc aaactactcg 31320cctgctttgc cccctaatgc atttttctct gctgctccgt agctgtccga cctcttcaga 31380tctcttagtc caccctgccg tcttccttta tgccatgggt cccactgttc tttcaactca 31440tccccctttc cctcagtccc ggagtagctg cggccagcag agggtagact gagagcagga 31500gagaaggacc tgcctaggaa ccccttctag agatactgca tcctgcctgg gagcaagttt 31560tccagggcag ctttgagaag tcttggagaa acaaacctac taaacctgac agacagtaat 31620actatttgca caatgctttt ctgtgggaaa ggtagagcct tttcactacg tattgagtac 31680atagagtgtg agggttgacc tggaacggct atcctcctgg atgacgtgtg ttttctgaag 31740aactacatgt tcgttgcaac tcccacatta gaatatgaag tcctaccgag agagatacgg 31800agactagaca gatacagatg catttgcatg tgaatacaca atcccacaat acagacgtca 31860aaacccatac cagttattcc agagagatgg attgggtagg aggcagaagg agaatactct 31920gatcgttttt cggccacgtg tgtgtgttat ctcagtgttt ctaagaagcg tttgctactt 31980tagatttttt atttaaaaaa aatagtaata atctattaag tatgagagat gtgcagagag 32040gattagtgat cgagagccat ttttgctggt ggcaatcata tggtactttt aatgggaata 32100ttagaaaggc accggtaatg accttgttgc agcacaaagg agagagtgtg gggtgcccct 32160gcatgttgtc ccacctcttg tgacgtgtat cgttttggaa tttccagtgg cttgatcatg 32220aactactgca ggaatccaga tgctgtggca gctccttatt gttatacgag ggatcccggt 32280gtcaggtggg agtactgcaa cctgacgcaa tgctcagacg cagaagggac tgccgtcgcg 32340cctccgactg ttaccccggt tccaagccta gaggctcctt ccgaacaagg taaggagtct 32400gtggccagac atctacacgc ttcgatgctg ggatgaaaag ccatggaaat tcccactgat 32460gcagccgcct tcaatggtaa acggatgctc gagtgttgcc ggagttctgc catgttgggg 32520gaagcctccg tgtactctct gggggagcca gcggagtgat ttctggtgca acttgggtgg 32580gctttgtctt tagaatgggc acaaaccttc cagggtgatg ggcttcacaa ctcacctcct 32640tctaaaatgg gctatctcag tgtcttagcc aaaattttta ttgtaacgtg ctgtcaggtg 32700tgtgattctt tctgtcgcag taagcttttc tggggatttc ttcaagtagc cagcagtcag 32760tgcaatcttc agcattgcag atttcaaaaa atgtggctct ggagcctgtc atcctcgaga 32820aacctaacag ggctgcatta attccatatg gtcctgggtc tatggagcag tatatgagct 32880cccaatgctc taaggctctt cagtcctagg ctttgaaggg agtgatttct cagtgttctt 32940aaacctcttt ctgatggcac ttgtacctgt gaggggtcta gagagaaagg ttagtagact 33000tctcctttac tgcaattcag gatgcagggc atgagaagat tccctccctc ctccaaggga 33060agaaggtttt ggcgtgcaca catccttgag aagcaaagtg tctttgcctt cagtcagata 33120tataggatcg ttttctgccc catggcctgg aagccagagg ccttggcttt catgatcaac 33180gatctaggga aacatgcaaa atttccatgt ctttcccctc ctctgccctc gacagccaat 33240taccacctgc atcctgcatt gccaaatgca gtgccctttg tatgaacatt cagtagagtt 33300tcatagaaag gtgctacttc gtgagcgcac tttgcagtga gaaggagtct gttctgttct 33360gtttttctaa ggatttcagg tgaaatattt cctagaactt actacagttc tagattggta 33420ggaatctgta ggtttgctgt atgttttttg gttggttttc tcccatccat ctgcctacag 33480gtaagggaaa gataacgttc gtaattctca tagactcctt tctggttgtg tcataaatgg 33540cttcacatat ttcgttattc tcagagatac tcagtttatt tcttgtgttt tcatttcagc 33600accgactgag cagaggcctg gggtgcagga gtgctaccac ggtaatggac agagttatcg 33660aggcacatac tccaccactg tcactggaag aacctgccaa gcttggtcat ctatgacacc 33720acactcgcat agtcggaccc cagaatacta cccaaatgcg tatgtctttg ttctttacca 33780taagagaaga aagggccaag tgaagtttct gttacaagag atgtgtctca agctgagttc 33840tccgaactca acttgtgaca gatgcagatg gcgtagcaaa atgtctcagg atgattgcct 33900tggagctaag ggtctgagag aagggaaatg ttaagctccc tctccttcct cctagttcta 33960ttgagcagaa gggaaatctg gaggtgagga gatcacatta tgaagaaagt cagaatgaca 34020aaggaccaga cacttagatt acccttccac aacaccaact aaacgtcaat ggagactttc 34080cagttggaat tccgttattc tggcttccac ttcctgaagg gaaggttgcg tttgcctttt 34140ctctctgggt tcaagaggaa agaataggtg cttatttatg gacaggtgaa ttgatctgtt 34200tctatatcta cgtatattcc gattgtcaga aaaacactcg ttcctaagta ccagtggcct 34260gaagggatac aggttcccag caagagaaga tccaaggaag gaaggcagat gagagccagc 34320acagagaggg atgctgaaaa gtaaaaggga tgggtggatg gagagaagcc cgggtctgac 34380cacccaatgg ccaatatttt ggccacaagc gactaccaga gacatggaaa aatggtttct 34440acatgtggga caacagatgg tagaggacct agagaattga gagaggggca atgatgggct 34500ccactccgca gatgccttgg ctttcttcct ggataccctt cctgcactga atagcaagga 34560gatggagccc aagcagactg tagccatctt gctgaatgga ggagagggat tggagtttgg 34620gatgactgtg gtagctgaaa tttttctagg tctgctagaa ataagaactg gtttgtggag 34680gaaaagagct ctacaaatac gcatagaagt ctcctccagt cgttggcctg acatgacgct 34740gcctgtgcac aggaaatggt tccacgagaa agtgtggcaa agaacattta ctgagaaaca 34800gcaagtacaa gagcacagga agctcaataa agaagagaga gatcacatag cactctggga 34860tactggagtt cttcccagct agaccagaga gtcctcacgg agcacattgc caattcagtg 34920gagaccccag aacagccgta atttaaaggt acacttagta tattactaga ataaagtcag 34980ctgcagacaa ccccttgcac agctggaaag caagtgtcca agcatcaaat cggtttccaa 35040tcaatgaagt gcctgtggga ggaaatctca actctcttta gaagtaaaca acaaagtcga 35100ttgcctcagc tatgcggtat ccgcagagtg agtcctaaat ttaaaatctg actacatgta 35160gaaaagcgtt tcgtgtgacc catgaccagg aaataaatcg ggtaatacaa acaggctcag 35220gaatgagaga aatgattaga attgcgtgaa aatttgacat atcagtatga taactgattt 35280caaatattta aaaaaacaac atgcaagaaa gcagatatca tatcaagaga aattaacagt 35340acagaatagc caaattaaat taaagagcta gtataaaaaa agtatgtctt aattgaaaaa 35400aattactgta tggccggctg atcaaattag acgtttcaga ggaaaacatt acccaacaca 35460caattctaga gaacctacag aatgagctac acacacacac acacacacac acacacacac 35520tgaaaacaca cccatactca cacacacgca gaaactcaca agttctaaca cacacagaca 35580cgcgcacccc tgaagaaaca gtgaaatata aaattaagcg agcctcacag acatgtagga 35640aaatatgaaa agatttcctg catgtgggaa gcaagtcaca gtaaagagca agggagtttg 35700gaatagaaac aaataccgga atcaaggatg gctgataact tttcaattac gaagaacatt 35760aaaaaaaatc acagaatcgt gaaactcaag ggatcatata gggaatttcg gaaaaaaaac 35820ccaacctgta tgatgtactt ttgtacatca cagttcgaag gtaacaaggc aaagatataa 35880taagaagaaa cctgtcacga gaaactggag gaaaaagagc tgtgtcttcc tacaagtaca 35940ctgatacaaa ttgccaatgt gttcacctca gaaacactgg aagccagata ccagggaata 36000ttgttaaaat gataatcagg aacaaaaaga gatcaaccgg gaatgctgaa tccagcaata 36060aaatgccttg aagatcatcc atgtcggata aatgcatatt gtgcactgcc ccaaagaaag 36120aaaccggaaa ctgtcagaat tggaaatcag caggcttatg taacaagaga ggtgacccga 36180aggaattagg tagaagaaga attgaacaag aaaggaactt tctgcagccc acgtaatgaa 36240gaatccagca attggcaaat gtagatagat gtaaatgcaa aatattttct tgatcaaatt 36300tctatatctt tgtaaatgag agttgactac ttgaaacaaa atgatagcaa gatatttaac 36360ttcagcatat gtagaggtaa gaatttgaaa tggtagcata aatcacgaag ggattaattc 36420gaagtgtacc gttgtaagtt tctttacctc atgcacgatg gtgtgtcata ttaataaaag 36480ggtactgtgc gggttcgaag ggatattgca aatcctagag caatcacaaa ggtttgaact 36540ctgaggtttt tggtataata agaatagtcc atgcattcaa aagagggaag ccaaggaaga 36600actagaagtc tttcaagagc tcaggctctt atacatccag ttgctcattg aaccagcttc 36660ctggaatgga gggtctgggg ttgagactag gccacaagtc tagagtctct agagagacag 36720tgttggaacc ccatggccca taatacattt cccattttct caggcagcca gaggtcatga 36780atgtgaggat actgggaggt tggagcaacg ttcttgggag gcataaggaa gagcgaatgc 36840ttcaagatcc ccgcagccca aactactcgc ctgctttgcc ccctaatgca tttttctctg 36900ctgctccgta gctgtccgac ctcttcagat ctcttagtcc accctgccgt cttcctttat 36960gccatgggtc ccattgttct ttcaactcat ccccctttcc ctcagtcccg gagtagctgc 37020ggccagcaga gggtagactg agagcaggag agaaggacct gcctaggaac cccttctaga 37080gatactgcat cctgcctggg agcaagtttt ccagggcagc tttgagaagt cttggagaaa 37140caaacctact aaacctgaca gacagtaata ctatttgcac aatgcttttc tgtgggaaag 37200gtagagcctt ttcactacgt attgagtaca tagagtgtga gggttgacct ggaacggcta 37260tcctcctgga tgacgtgcgt tttctgaaga actacatgtt cgttgcaact cccacattag 37320aatatgaagt cctaccgaga gagatacgga gactagacag atacagatgc atttgcatgt 37380gaatacacaa tcccacaata cagacgtcaa aacccatacc agttattcca gagagatgga 37440ttgggcagaa ggcagaagga gaatactctg atcgtttttc ggccacgtgt gtgtgttatc 37500tcagtgtttc taagaagcgt ttgctacttt agatttttta tttaaaaaaa atagtaataa 37560tctattaagt atgagagatg tgcagagagg attagtgatc gagagccatt tttgctggtg 37620gcaatcatat ggtactttta atgggaatat tagaaaggca ccggtaatga ccttgttgca 37680gcacaaagga gagagtgtgg ggtgcccctg catgttgtcc cacctcttgt gacgtgtatc 37740gttttggaat ttccagtggc ttgatcatga actactgcag gaatccagat gctgtggcag 37800ctccttattg ttatacgagg gatcccggtg tcaggtggga gtactgcaac ctgacgcaat 37860gctcagacgc agaagggact gccgtcgcgc ctccgactgt taccccggtt ccaagcctag 37920aggctccttc cgaacaaggt aaggagtctg tggccagaca tctacacgct tcgatgctgg 37980gatgaaaagc catggaaatt cccactgatg cagccgcctt caatggtaaa cggatgctcg 38040agtgttgcct gagttctacc atgtaggagg aagcctccgt gcactctctg ggggagccag 38100cggagtgatt tctggtgcaa cgtggttggg ctttgtcttt aggatgggca caaaccctcc 38160agggggatcg acttcaaaat tcaccttgtt gtaaaacggg ctacctcagt gtcccagcca 38220aaatttttat tgtaacatgc tgtcaggtgt gtcactcttt ccaagccagt aagcttttcc 38280ggggatttct tcaagtagcc agcattcaga gcaatcttca gcattgcaga ttctgagaaa 38340tgtggctctg gagcctgtca ccctcgagaa acctaagagg gctgcattga ttccatgtgg 38400ccctgggtct atggagcagt acatgagctc ccagtgctct aaggctcttc agccctaggc 38460tttgaaggga gtgatttctc agtattctta aacctctttc tgatgacact tgtacctgtg 38520aggggtctag agagaaagag tagtagactc ctactttact acaattcagg atgcagggca 38580tgagaggatt ccctctctcc tccaagggaa gaagcttttg gcgtgcacac atccctgaga 38640agcaaagtgt ctttgtcttc agtcagatac ataggaccgt tttctgcccc atggcccgga 38700agccaaaggc cttggctttc atgatcaacg gtctagggaa acatgcaaaa tttccatgtc 38760tgtcccaaac tctgcccccg acagccaatt accacctgca gcccgcattg ccaaatgcgg 38820tgccgtttgc atgaagattc agtagagttt cctagaaagg tgctacctcg tgagctcact 38880ttccaatgag gaatctgatc tgttgtgttt ctctaaggtg tcaggtgaaa tatttccaag 38940aacttactac agttctagaa tgggaggaat ctgttgcttt ggtgtttgtt tgttggtcgg 39000ttttctcaca tccatctgcc tatggataag gaaaagagaa cggtcgtaat tctcatagac 39060tcctttctgg ttgtgtcaca aatggcttca catgtttctc tatgctcaga gatactcagc

39120ttgatttccc gtgttttcat ttcagcaccg actgagcaaa ggcctggggt gcaggagtgc 39180taccatggta atggacagag ttatcgaggc acatactcca ccactgtcac aggaagaacc 39240tgccaagctt ggtcatctat gacaccacac tcgcatagtc ggaccccaga atactaccca 39300aatgcgtatg tctttgttct ttaccataag agaagaaagg gccaagtgaa gtttctgtta 39360caagagatgt gtctcaagct gagttctccg aactcaactt gtgacagatg cagatggcgt 39420agcaaaatgt ctcaggatga ttgccttgga gctaagggtc tgagagaagg gaaatgttaa 39480gctccctctc cttcctccta gttctattga gcagaaggga aatctggagg tgaggagatc 39540acattatgaa gaaagtcaga atgacaaagg accagacact tagattaccc ttccacaaca 39600ccaactaaac gtcaatggag actttccagt tggaattccg ttattctggc ttccacttcc 39660tgaagggaag gttgcgtttg ccttttctct ctgggttcaa gaggaaagaa taggtgctta 39720tttatggaca ggtgaattga tctgtttcta tatctacgta tattccgatt gtcagaaaaa 39780cactcgttcc taagtaccag tggcctgaag ggatacaggt tcccagcaag agaagatcca 39840aggaaggaag gcagatgaga gtcagcacag agagggatgc tgaaaagtaa aagggatggg 39900tggatggaga gaagcccggg tctgaccacc caatggccaa tattttggcc acaagcgact 39960accagagaca tggaaaaatg gtttctacat gtgggacaac agatggtaga ggacctagag 40020aattgagaga ggggcaatga tgggctccac tccgcagatg ccttggcttt cttcctggat 40080acccttcctg cactgaatag caaggagatg gagcccaagc agactgtagc catcttgctg 40140aatggaggag agggattgga gtttgggatg actgtggtag ctgaaatttt tctaggtctg 40200ctagaaataa gaactggttt gtggaggaaa agagctctac aaatacgcat agaagtctcc 40260tccagtcgtt ggcctgacat gacgctgcct gtgcacagga aatggttcca cgagaaagtg 40320tggcaaagaa catttactga gaaacagcaa gtacaagagc acaggaagct caataaagaa 40380gagagagatc acatagcact ctgggatact ggagttcttc ccagctagac cagagagtcc 40440tcacggagca cattgccaat tcagtggaga ccccagaaca gccgtaattt aaaggtacac 40500ttagtatatt actagaataa agtcagctgc agacaacccc ttgcacagct ggaaagcaag 40560tgtccaagca tcaaatcggt ttccaatcaa tgaagtgcct gtgagaggaa atctcaactc 40620tctttagaag taaacaacaa agtcgattgc ctcagctatg cggtatccgc agagtgagtc 40680ctaaatttaa aatctgacta catgtagaaa agcgtttcgt gtgacccatg accaggaaat 40740aaatcgggta atacaaacag gctcaggaat gagagaaatg attagaattg cgtgaaaatt 40800tgaaatatca gtatgataac tgatttcaaa tatttaaaaa aacaacatgc aagaaagcag 40860atatcatatc aagagaaatt aacagtacag aatagccaaa ttaaattaaa gagctagtat 40920aaaaaaagta tgtcttaatt gaaaaaaatt actgtatggc cggctgatca atttagacgt 40980ttcagaggaa aacattaccc aacacacaat tctagagaac ctacagaatg agctacacac 41040acacacacac acacacacac aaactgaaaa cacacccata ctcacacaca cgcagaaact 41100cacaagttct aacacacaca gacacgcgca cccctgaaga aacagtgaaa tataaaatta 41160agcgagcctc acagacatgt aggaaaatat gaaaagattt cctgcatgtg ggaagcaagt 41220cacagtaaag agcaagggag tttggaatag aaacaaatac cagaatcaag gatggctgat 41280aacttttcaa ttacgaagaa cattaaaaaa aatcacagaa tcgtgaaact caagggatca 41340catagggaat ttcggaaaaa aaacccaacc tgtatgatgt acttttgtac atcacagttc 41400gaaggtaaca aggcaaagat ataataagaa gaaacctgtc acgagaaact ggaggaaaaa 41460gagctgtgtc ttcctacaag tacactgata caaattgcca atgtgttcac ctcagaaaca 41520ctggaagcca gataccaggg aatattgtta aaatgataat caggaacaaa aagagatcaa 41580ccgggaatgc tgaatccagc aataaaatgc cttgaagatc atccatgtcg gataaatgca 41640tattgtgcac tgccccaaag aaagaaaccg gaaactgtaa gaattggaaa tcagcaggct 41700tatgtaacaa gagaggtgac ccgaaggaat taggtagaag aagaattgaa caagaaagga 41760actttctgca gcccacgtaa tgaagaatcc agcaattggc aaatgtagat agatgtaaat 41820gcaaaatatt ttcttgatca aatttctata tctttgtaaa tgagagttga ctacttgaaa 41880caaaatgata gcaagatatt taacttcagc atatgtagag gtaagaattt gaaatggtag 41940cataaatcac gaagggatta attcgaagtg taccgttgta agtttcttta cctcatgcac 42000gatggtgtgt catattaata aaagggtact gtgcgggttc gaagggatat tgcaaatcct 42060agagcaatca caaaggtttg aactctgagg tttttggtat aataagaata gtccatgcat 42120tcaaaagagg gaagccaagg aagaactaga agtctttcaa gagctcaggc tcttatacat 42180ccagttgctc attgaaccag cttcctggaa tggagggtct ggggttgaga ctaggccaca 42240agtctagagt ctctagagag acagtgttgg aaccccatgg cccataatac atttcccatt 42300ttctcaggca gccagaggtc atgaatgtga ggatactggg aggttggagc aacgttcttg 42360ggaggcataa ggaagagcga atgcttcaag atccccgcag cccaaactac tcgcctgctt 42420tgccccctaa tgcatttttc tctgctgctc cgtagctgtc cgacctcttc agatctctta 42480gtccaccctg ccgtcttcct ttatgccatg ggtcccactg ttctttcaac tcatccccct 42540ttccctcagt cccggagtag ctgcggccag cagagggtag actgagagca ggagagaagg 42600acctgcctag gaaccccttc tagagatact gcatcctgcc tgggagcaag ttttccaggg 42660cagctttgag aagtcttgga gaaacaaacc tactaaacct gacagacagt aatactattt 42720gcacaatgct tttctgtggg aaaggtagag ccttttcact acgtattgag tacatagagt 42780gtgagggttg acctggaacg gctatcctcc tggatgacgt gtgttttctg aagaactaca 42840tgttcgttgc aactcccaca ttagaatatg aagtcctacc gagagagata cggagactag 42900acagatacag atgcatttgc atgtgaatac acaatcccac aatacagacg tcaaaaccca 42960taccagttat tccagagaga tggattgggc agaaggcaga aggagaatac tctgatcgtt 43020tttcggccac gtgtgtgtgt tatctcagtg tttctaagaa gcgtttgcta ctttagattt 43080tttatttaaa aaaaatagta ataatctatt aagtatgaga gatgtgcaga gaggattagt 43140gatcgagagc catttttgct ggtggcaatc atatggtact tttaatggga atattagaaa 43200ggcaccggta atgaccttgt tgcagcacaa aggagagagt gtggggtgcc cctgcatgtt 43260gtcccacctc ttgtgacgtg tatcgttttg gaatttccag tggcttgatc atgaactact 43320gcaggaatcc agatgctgtg gcagctcctt attgttatac gagggatccc ggtgtcaggt 43380gggagtactg caacctgacg caatgctcag acgcagaagg gactgccgtc gcgcctccga 43440ctgttacccc ggttccaagc ctagaggctc cttccgaaca aggtaaggag tctgtggcca 43500gacatctaca cgcttcgatg ctgggatgaa aagccatgga aattcccact gatgcagccg 43560ccttcaatgg taaacggatg ctcgagtgtt gcctgagttc taccatgtag gaggaagcct 43620ccgtgcactc tctgggggag ccagcggagt gatttctggt gcaacgtggt tgggctttgt 43680ctttaggatg ggcacaaacc ctccaggggg atcgacttca aaattcacct tgttgtaaaa 43740cgggctacct cagtgtccca gccaaaattt ttattgtaac atgctgtcag gtgtgtcact 43800ctttccaagc cagtaagctt ttccggggat ttcttcaagt agccagcatt cagagcaatc 43860ttcagcattg cagattctga gaaatgtggc tctggagcct gtcaccctcg agaaacctaa 43920gagggctgca ttgattccat gtggccctgg gtctatggag cagtacatga gctcccagtg 43980ctctaaggct cttcagccct aggctttgaa gggagtgatt tctcagtatt cttaaacctc 44040tttctgatga cacttgtacc tgtgaggggt ctagagagaa agagtagtag actcctactt 44100tactacaatt caggatgcag ggcatgagag gattccctct ctcctccaag ggaagaagct 44160tttggcgtgc acacatccct gagaagcaaa gtgtctttgt cttcagtcag atacatagga 44220ccgttttctg ccccatggcc cggaagccaa aggccttggc tttcatgatc aacggtctag 44280ggaaacatgc aaaatttcca tgtctgtccc aaactcttcc cccgacagcc aattaccacc 44340tgcagcccgc attgccaaat gcggtgccgt ttgcatgaag attcagtaga gtttcctaga 44400aaggtgctac ctcgtgagct cactttccaa tgaggaatct gatctgttgt gtttctctaa 44460ggtgtcaggt gaaatatttc caagaactta ctacagttct agaatgggag gaatctgttg 44520ctttggtgtt tgtttgttgg tcggttttct cacatccatc tgcctatgga taaggaaaag 44580agaacggtcg taattctcat agactccttt ctggttgtgt cacaaatggc ttcacatgtt 44640tctctatgct cagagatact cagcttgatt tcccgtgttt tcatttcagc accgactgag 44700caaaggcctg gggtgcagga gtgctaccat ggtaatggac agagttatcg aggcacatac 44760tccaccactg tcacaggaag aacctgccaa gcttggtcat ctatgacacc acactcgcat 44820agtcggaccc cagaatacta cccaaatgcg tatgtctttg ttctttacca taagagaaga 44880aagggccaag tgaagtttct gttacaagag atgtgtctca agctgagttc tccgaactca 44940acttgtgaca gatgcagatg gcgtagcaaa atgtctcagg atgattgcct tggagctaag 45000ggtctgagag aagggaaatg ttaagctccc tctccttcct cctagttcta ttgagcagaa 45060gggaaatctg gaggtgagaa gatcacatta tgaagaaagt cagaatgaca aaggaccaga 45120cacttagatt acccttccac aacaccaact aaacgtcaat ggagactttc cagttggaat 45180tccgttattc tggcttccac ttcctgaagg gaaggttgcg tttgcctttt ctctctgggt 45240tcaagaggaa agaataggtg cttatttatg gacaggtgaa ttgatctgtt tctatatcta 45300cgtatattcc gattgtcaga aaaacactcg ttcctaagta ccagtggcct gaagggatac 45360aggttcccag caagagaaga tccaaggaag gaaggcagat gagagtcagc acagagaggg 45420atgctgaaaa gtaaaaggga tgggtggatg gagagaagcc cgggtctgac cacccaatgg 45480ccaatatttt ggccacaagc gactaccaga gacatggaaa aatggtttct acatgtggga 45540caacagatgg tagaggacct agagaattga gagaggggca atgatgggct ccactccgca 45600gatgccttgg ctttcttcct ggataccctt cctgcactga atagcaagga gatggagccc 45660aagcagactg tagccatctt gctgaatgga ggagagggat tggagtttgg gatgactgtg 45720gtagctgaaa tttttctagg tctgctagaa ataagaactg gtttgtgtgg aggaaaagag 45780ctctacaaat acgcatagaa gtctcctcca gtcgttggcc tgacatgacg ctgcctgtgc 45840acaggaaatg gttccacgag aaagtgtggc aaagaacatt tactgagaaa cagcaagtac 45900aagagcacag gaagctcaat aaagaagaga gagatcacat agcactctgg gatactggag 45960ttcttcccag ctagaccaga gagtcctcac ggagcacatt gccaattcag tggagacccc 46020agaacagccg taatttaaag gtacacttag tatattacta gaataaagtc agctgcagac 46080aaccccttgc acagctggaa agcaagtgtc caagcatcaa atcggtttcc aatcaatgaa 46140gtgcctgtga gaggaaatct caactctctt tagaagtaaa caacaaagtc gattgcctca 46200gctatgcggt atccgcagag tgagtcctaa atttaaaatc tgactacatg tagaaaagcg 46260tttcgtgtga cccatgacca ggaaataaat cgggtaatac aaacaggctc aggaatgaga 46320gaaatgatta gaattgcgtg aaaatttgac atatcagtat gataactgat ttcaaatatt 46380taaaaaaaca acatgcaaga aagcagatat catatcaaga gaaattaaca gtacagaata 46440gccaaattaa attaaagagg tagtataaaa aaagtatgtc ttaattgaaa aaaattactg 46500tatggccggc tgatcaattt agacgtttca gaggaaaaca ttacccaaca cacaattcta 46560gagaacctac agaatgagct acacacacac acacacacac acacacaaac tgaaaacaca 46620cccatactca cacacacgca gaaactcaca agttctaaca cacacagaca cgcgcacccc 46680tgaagaaaca gtgaaatata aaattaagcg agcctcacag acatgtagga aaatatgaaa 46740agatttcctg catgtgggaa gcaagtcaca gtaaagagca agggagtttg gaatagaaac 46800aaataccgga atcaaggatg gctgataact tttcaattac gaagaacatt aaaaaaaatc 46860acagaatcgt gaaactcaag ggatcacata gggaatttcg gaaaaaaaac ccaacctgta 46920tgatgtactt ttgtacatca cagttcgaag gtaacaaggc aaagatataa taagaagaaa 46980cctgtcacga gaaactggag gaaaaagagc tgtgtcttcc tacaagtaca ctgatacaaa 47040ttgccaatgt gttcacctca gaaacactgg aagccagata ccagggaata ttgttaaaat 47100gataatcagg aacaaaaaga gatcaaccgg gaatgctgaa tccagcaata aaatgccttg 47160aaggtcatcc atgtcggata aatgcatatt gtgcactgcc ccaaagaaag aaaccggaaa 47220ctgtaagaat tggaaatcag caggcttatg taacaagaga ggtgacccga aggaattagg 47280tagaagaaga attgaacaag aaaggaactt tctgcagccc acgtaatgaa gaatccagca 47340attggcaaat gtagatagat gtaaatgcaa aatattttct tgatcaaatt tctatatctt 47400tgtaaatgag agttgactac ttgaaacaaa atgatagcaa gatatttaac ttcagcatat 47460gtagaggtaa gaatttgaaa tggtagcata aatcacgaag ggattaattc gaagtgtacc 47520gttgtaagtt tctttacctc atgcacgatg gtgtgtcata ttaataaaag ggtactgtgc 47580gggttcgaag ggatattgca aatcctagag caatcacaaa ggtttgaact ctgaggtttt 47640tggtataata agaatagtcc atgcattcaa aagagggaag ccaaggaaga actagaagtc 47700tttcaagagc tcaggctctt atacatccag ttgctcattg aaccagcttc ctggaatgga 47760gggtctgggg ttgagactag gccacaagtc tagagtctct agagagacag tgttggaacc 47820ccatggccca taatacattt cccattttct caggcagcca gaggtcatga atgtgaggat 47880actgggaggt tggagcaacg ttcttgggag gcataaggaa gagcgaatgc ttcaagatcc 47940ccgcagccca aactactcgc ctgctttgcc ccctaatgca tttttctctg ctgctccgta 48000gctgtccgac ctcttcagat ctcttagtcc accctgccgt cttcctttat gccatgggtc 48060ccactgttct ttcaactcat ccccctttcc ctcagtcccg gagtagctgc ggccagcaga 48120gggtagactg agagcaggag agaaggacct gcctaggaac cccttctaga gatactgcat 48180cctgcctggg agcaagtttt ccagggcagc tttgagaagt cttggagaaa caaacctact 48240aaacctgaca gacagtaata ctatttgcac aatgcttttc tgtgggaaag gtagagcctt 48300ttcactacgt attgagtaca tagagtgtga gggttgacct ggaacggcta tcctcctgga 48360tgacgtgcgt tttctgaaga actacatgtt cgttgcaact cccacattag aatatgaagt 48420cctaccgaga gagatacgga gactagacag atacagatgc atttgcatgt gaatacacaa 48480tcccacaata cagacgtcaa aacccatacc agttattcca gagagatgga ttgggcagaa 48540ggcagaagga gaatactctg atcgtttttc ggccacgtgt gtgtgttatc tcagtgtttc 48600taagaagcgt ttgctacttt agatttttta tttaaaaaaa atagtaataa tctattaagt 48660atgagagatg tgcagagagg attagtgatc gagagccatt tttgctggtg gcaatcatat 48720ggtactttta atgggaatat tagaaaggca ccggtaatga ccttgttgca gcacaaagga 48780gagagtgtgg ggtgcccctg catgttgtcc cacctcttgt gacgtgtatc gttttggaat 48840ttccagtggc ttgatcatga actactgcag gaatccagat gctgtggcag ctccttattg 48900ttatacgagg gatcccggtg tcaggtggga gtactgcaac ctgacgcaat gctcagacgc 48960agaagggact gccgtcgcgc ctccgactgt taccccggtt ccaagcctag aggctccttc 49020cgaacaaggt aaggagtctg tggccagaca tctacacgct tcgatgctgg gatgaaaagc 49080catggaaatt cccactgatg cagccgcctt caatggtaaa cggatgctcg agtgttgcct 49140gagttctacc atgtaggagg aagcctccgt gcactctctg ggggagccag cggagtgatt 49200tctggtgcaa cgtggttggg ctttgtcttt aggatgggca caaaccctcc agggggatcg 49260acttcaaaat tcaccttgtt gtaaaacggg ctacctcagt gtcccagcca aaatttttat 49320tgtaacatgc tgtcaggtgt gtcactcttt ccaagccagt aagcttttcc ggggatttct 49380tcaagtagcc agcattcaga gcaatcttca gcattgcaga ttctgagaaa tgtggctctg 49440gagcctgtca ccctcgagaa acctaagagg gctgcattga ttccatgtgg ccctgggtct 49500atggagcagt acatgagctc ccagtgctct aaggctcttc agccctaggc tttgaaggga 49560gtgatttctc agtattctta aacctctttc tgatgacact tgtacctgtg aggggtctag 49620agagaaagag tagtagactc ctactttact acaattcagg atgcagggca tgagaggatt 49680ccctctctcc tccaagggaa gaagcttttg gcgtgcacac atccctgaga agcaaagtgt 49740ctttgtcttc agtcagatac ataggaccgt tttctgcccc atggcccgga agccaaaggc 49800cttggctttc atgatcaacg gtctagggaa acatgcaaaa tttccatgtc tgtcccaaac 49860tctgcccccg acagccaatt accacctgca gcccgcattg ccaaatgcgg tgccgtttgc 49920atgaagattc agtagagttt cctagaaagg tgctacctcg tgagctcact ttccaatgag 49980gaatctgatc tgttgtgttt ctctaaggtg tcaggtgaaa tatttccaag aacttactac 50040agttctagaa tgggaggaat ctgttgcttt ggtgtttgtt tgttggtcgg ttttctcaca 50100tccatctgcc tatggataag gaaaagagaa cggtcgtaat tctcatagac tcctttctgg 50160ttgtgtcaca aatggcttca catgtttctc tatgctcaga gatactcagc ttgatttccc 50220gtgttttcat ttcagcaccg actgagcaaa ggcctggggt gcaggagtgc taccatggta 50280atggacagag ttatcgaggc acatactcca ccactgtcac aggaagaacc tgccaagctt 50340ggtcatctat gacaccacac tcgcatagtc ggaccccaga atactaccca aatgcgtatg 50400tctttgttct ttaccataag agaagaaagg gccaagtgaa gtttctgtta caagagatgt 50460gtctcaagct gagttctccg aactcaactt gtgacagatg cagatggcgt agcaaaatgt 50520ctcaggatga ttgccttgga gctaagggtc tgagagaagg gaaatgttaa gctccctctc 50580cttcctccta gttctattga gcagaaggga aatctggagg tgaggagatc acattatgaa 50640gaaagtcaga atgacaaagg accagacact tagattaccc ttccacaaca ccaactaaac 50700gtcaatggag actttccagt tggaattccg ttattctggc ttccacttcc tgaagggaag 50760gttgcgtttg ccttttctct ctgggttcaa gaggaaagaa taggtgctta tttatggaca 50820ggtgaattga tctgtttcta tatctacgta tattccgatt gtcagaaaaa cactcgttcc 50880taagtaccag tggcctgaag ggatacaggt tcccagcaag agaagatcca aggaaggaag 50940gcagatgaga gtcagcacag agagggatgc tgaaaagtaa aagggatggg tggatggaga 51000gaagcccggg tctgaccacc caatggccaa tattttggcc acaagcgact accagagaca 51060tggaaaaatg gtttctacat gtgggacaac agatggtaga ggacctagag aattgagaga 51120ggggcaatga tgggctccac tccgcagatg ccttggcttt cttcctggat acccttcctg 51180cactgaatag caaggagatg gagcccaagc agactgtagc catcttgctg aatggaggag 51240agggattgga gtttgggatg actgtggtag ctgaaatttt tctaggtctg ctagaaataa 51300gaactggttt gtgtggagga aaagagctct acaaatacgc atagaagtct cctccagtcg 51360ttggcctgac atgacgctgc ctgtgcacag gaaatggttc cacgagaaag tgtggcaaag 51420aacatttact gagaaacagc aagtacaaga gcacaggaag ctcaataaag aagagagaga 51480tcacatagca ctctgggata ctggagttct tcccagctag accagagagt cctcacggag 51540cacattgcca attcagtgga gaccccagaa cagccgtaat ttaaaggtac acttagaata 51600ttactagaat aaagtcagct gcagacaacc ccttgcacag ctggaaagca agtgtccaag 51660catcaaatcg gtttccaatc aatgaagtgc ctgtgagagg aaatctcaac tctctttaga 51720agtaaacaac aaagtcgatt gcctcagcta tgcggtatcc gcagagtgag tcctaaattt 51780aaaatctgac tacatgtaga aaagcgtttc gtgtgaccca tgaccaggaa ataaatcggg 51840taatacaaac aggctcagga atgagagaaa tgattagaat tgcgtgaaaa tttgacatat 51900cagtatgata actgatttca aatatttaaa aaaacaacat gcaagaaagc agatatcata 51960tcaagagaaa ttaacagtac agaatagcca aattaaatta aagagctagt ataaaaaaag 52020tatgtcttaa ttgaaaaaaa ttactgtatg gccggctgat caaattagac gtttcagagg 52080aaaacattac ccaacacaca attttagaga acctacagaa tgagctacac acacacacac 52140acacacacac acacacacaa actgaaaaca cacccatact cacacacacg cagaaactca 52200caagttctaa cacacacaga cacgcgcacc cctgaagaaa cagtgaaata taaaattaag 52260cgagcctcac agacatgtag gaaaatatga aaagatttcc tgcatgtggg aagcaagtca 52320cagtaaagag caagggagtt tataatagaa acaaatacca gaatcaagga tggctgataa 52380cttttcaatt acgaagaaca ttaaaaaaaa tcacagaatc gtgaaactca agggatcata 52440tagggaattt cggaaaaaaa acccaacctg tatgatgtac ttttgtacat cacagttcga 52500aggtaacaag gcaaagatgt aataagaaga aacctgtcac gagaaactgg aggaaaaaga 52560gctgtgtctt cctacaagta cactgataca aattgccaat gtgttcacct cagaaacact 52620ggaagccaga taccagggaa tattgttaaa atgataatca ggaacaaaaa gagatcaacc 52680gggaatgctg aatccagcaa taaaatgcct tgaaggtcat ccatgtcgga taaatgcata 52740ttgtgcactg ccccaaagaa agaaaccgga aactgtaaga attggaaatc agcaggctta 52800tgtaacaaga gaggtgaccc gaaggaatta ggtagaagaa gaattgaaca agaaaggaac 52860tttctgcagc ccacgtaatg aagaatccag caattggcaa atgtagatag atgtaaatgc 52920aaaatatttt cttgatcaaa tttctatatc tttgtaaatg agagttgact acttgaaaca 52980aaatgatagc aagatattta acttcagcat atgtagaggt aagaatttga aatggtagca 53040taaatcacga agggattaat tcgaagtgta ccgttgtaag tttctttacc tcatgcacga 53100tggtgtgtca tattaataaa agggtactgt gcgggttcga agggatattg caaatcctag 53160agcaatcaca aaggtttgaa ctctgaggtt tttggtataa taagaatagt ccatgcattc 53220aaaagaggga agccaaggaa gaactagaag tctttcaaga gctcaggctc ttatacatcc 53280agttgctcat tgaaccagct tcctggaatg gagggtctgg ggttgagact aggccacaag 53340tctagagtct ctagagagac agtgttggaa ccccatggcc cataatacat ttcccatttt 53400ctcaggcagc cagaggtcat gaatgtgagg atactgggag gttggagcaa cgttcttggg 53460aggcataagg aagagcgaat gcttcaagat ccccgcagcc caaactactc gcctgctttg 53520ccccctaatg catttttctc tgctgctccg tagctgtccg acctcttcag atctcttagt 53580ccaccctgcc gtcttccttt atgccatggg tcccactgtt ctttcaactc atcccccttt 53640ccctcagtcc cggagtagct gcggccagca gagggtagac tgagagcagg agagaaggac 53700ctgcctagga accccttcta gagatactgc atcctgcctg ggagcaagtt ttccagggca 53760gctttgagaa gtcttggaga aacaaaccta ctaaacctga cagacagtaa tactatttgc 53820acaatgcttt tctgtgggaa aggtagagcc ttttcactac gtattgagta catagagtgt 53880gagggttgac ctggaacggc tatcctcctg gatgacgtgc gttttctgaa gaactacatg 53940ttcgttgcaa ctcccacatt agaatatgaa gtcctaccga gagagatacg gagactagac 54000agatacagat gcatttgcat gtgaatacac aatcccacaa tacagacgtc aaaacccata 54060ccagttattc cagagagatg gattgggcag aaggcagaag gagaatactc tgatcgtttt 54120tcggccacgt gtgtgtgtta tctcagtgtt tctaagaagc gtttgctact ttagattttt

54180tatttaaaaa aaatagtaat aatctattaa gtatgagaga tgtgcagaga cgattagtga 54240tcgagagcca tttttgctgg tggcaatcat atggtacttt taatgggaat attagaaagg 54300caccggtaat gaccttgttg cagcacaaag gagagagtgt ggggtgcccc tgcatgttgt 54360cccacctctt gtgacgtgta tcgttttgga atttccagtg gcttgatcat gaactactgc 54420aggaatccag atgctgtggc agctccttat tgttatacga gggatcccgg tgtcaggtgg 54480gagtactgca acctgacgca atgctcagac gcagaaggga ctgccgtcgc gcctccgact 54540gttaccccgg ttccaagcct agaggctcct tccgaacaag gtaaggagtc tgtggccaga 54600catctacacg cttcgatgct gggatgaaaa gccatggaaa ttcccactga tgcagccgcc 54660ttcaatggta aacggatgct cgagtgttgc ctgagttcta ccatgtagga ggaagcctcc 54720gtgcactctc tgggggagcc agcggagtga tttctggtgc aacgtggttg ggctttgtct 54780ttaggatggg cacaaaccct ccagggggat cgacttcaaa attcaccttg ttgtaaaacg 54840ggctacctca gtgtcccagc caaaattttt attgtaacat gctgtcaggt gtgtcactct 54900ttccaagcca gtaagctttt ccggggattt cttcaagtag ccagcattca gagcaatctt 54960cagcattgca gattctgaga aatgtggctc tggagcctgt catcctcgag aaacctaaca 55020gggctgcatt aattccatat ggtcctgggt ctatggagca gtatatgagc tcccaatgct 55080ctaaggctct tcagtcctag gctttgaagg gagtgatttc tcagtgttct taaacctctt 55140tctgatggca cttgtacctg tgaggggtct agagagaaag gttagtagac ttctccttta 55200ctgcaattca ggatgcaggg catgagaaga ttccctccct cctccaaggg aagaaggttt 55260tggcgtgcac acatccttga gaagcaaagt gtctttgcct tcagtcagat atataggatc 55320gttttctgcc ccatggcctg gaagccagag gccttggctt tcatgatcaa cgatctaggg 55380aaacatgcaa aatttccatg tctttcccct cctctgccct cgacagccaa ttaccacctg 55440catcctgcat tgccaaatgc agtgcccttt gtatgaacat tcagtagagt ttcatagaaa 55500ggtgctactt cgtgagcgca ctttgcagtg agaaggagtc tgttctgttc tgtttttcta 55560aggatttcag gtgaaatatt tcctagaact tactacagtt ctagattggt aggaatctgt 55620aggtttgctg tatgtttttt ggttggtttt ctcccatcca tctgcctaca ggtaagggaa 55680agataacgtt cataattctc atagactcct ttctggttgt gtcataaatg gcttcacata 55740tttcgttatt ctcagagata ctcagtttat ttcttgtgtt ttcatttcag caccgactga 55800gcagaggcct ggggtgcagg agtgctacca cggtaatgga cagagttatc gaggcacata 55860ctccaccact gtcactggaa gaacctgcca agcttggtca tctatgacac cacactcgca 55920tagtcggacc ccagaatact acccaaatgc gtatgtcttt gttctttacc ataagagaat 55980aaagggccaa ctgaagtttc tgtgacaaga gacatgcttc aagctgagtt ctccgaactc 56040aacttgtgtc agattcagat ggtgtagcaa aatgtctcag gatgatttcc ttggagctaa 56100gggtctgaga gaagagaaat gttaagctgc ctcaccttcc tcctagtttt gtggagcaga 56160agggaaatga ggaggcgagg agatcacctt atgaagaaag tcagaatgac gaaccaccaa 56220acacttagat tacccttgcc caacacccac taagcgtcaa tgaagacttt ccagttggaa 56280ttccgttatt ctgacttcca attcctgaag ggaagattgt gtttgccttt tctgtctggg 56340ctcatgagga aagtttatgt gcttacttat ggacaggtga attgatctgt ttctatttct 56400acctgtattc caatagggag aaaatctctt ggtcctaagt accagtggcc tgaaaggata 56460gaggttccca gcaagagaag atccaaggaa ggaaggcaga tgagagtcag cacagagagg 56520gatgctgaaa agtaaaaggg atgggtagat ggatagaagc cctggtctga ccaccccatg 56580gccaatcatt tggccataat caacaaccaa agacatggaa aaatggtttc tacatgtggg 56640acaacagatg gtagaggacc tagagaattg agagagggcc aatgatgagc tcaactccat 56700agatgccttg gctttcttcc tggataccct tcctgcactg aatagcaagg agatggagct 56760caagcagcct gtagccatct agctgagcag aggagaggga ttggagtttg ggatgactct 56820ggtattttct aggtccgcta caaataagaa ctggtttgtg gaggaaagga gctctacaaa 56880tacgcataga agtctcctcc agtagttggc ctcacatgac actgcatgtg cacagaaaat 56940ggttctacag aaagtgtggc aaagaacatt tactgagaaa cagcaactac aagagaacag 57000caagctcaat taagaagata gagatcacat agcactctgt gttattggag ttcttaccag 57060ctagatgaga gagtgctcac ggaacacatt gccaattcag tggagacccc agaacagcca 57120taatttcaaa gtacaattag tatattacta gaataaaggc agctgcagac aaccccttgc 57180acagctgaaa agcaagtgtc caagcatcaa atgggtttcc aatcaatgaa gtgcctgtga 57240gaggaaatct caactctctt cagaagtaaa caacaaagtc aattgcctca gctatgcggt 57300atccccagag tgagtcctaa attaaaaatt tgactacgtg tagaaaagaa tttcgtgtga 57360tccatgacca gaaaataaat caggcaatac aaacaggctc agaaatgaca tcgataatta 57420gaattgcatg aaaatttgac atatcagtat gataactgat ttcagatatt taaaaaaagt 57480gcaacaaagc aggtatcata tcaagacaaa ttaatagtat agaatagcca aatcaaatta 57540aagaactatt atacaaaaag tatgtcttaa atgaagaaat tactgtatgt ccgcctgaaa 57600aatttagatg tttcagaaga aaaaattaac caaaaacaat tctgcagaac ctacagaatg 57660agccacacac acacacattc aaaacacacc catacacaca cacatgcaaa aactcacaag 57720ttctaacaca cacacaaaca cacacacaca tgcacatccc taaagaaata gggaaatata 57780aaattaaccg accctcagag acatgcagga aaatataaga agatttcctg catgtgggaa 57840gcaagtcaca gtaaagagca agggagtttg gagtagatac aaataccgga atcacggatg 57900gctgataact tttcaattat gaagaacgtt agaaaaatca cagattcatg aaactaaagg 57960gatcaaatag gaaatttcga gaaaaaaaac tacatgatgc acttctctac atcacagttc 58020aaaggtaaca aggcaaggat ataagaagaa gaaacatctc acgagaaact ggagaaaaaa 58080gagctgtgtc ttcctagagt acagtgatac aaattgctaa tgcgttcacc tcagaaacac 58140tggaagccag ataccaggga atattattaa aatgataatg aggaacaaga agagatcaac 58200cgagaatgct gaatccagca ataaaatgcc ttgaagatca tccatgttgg ataaatgcat 58260attgtgcact gcccaaaaca aagaaactgg aaagtgtaag actttggaat cagcaggctt 58320atgtagcaac agaggtgacc cgaaagaatt aggtataaga agaatagaag aattgcatga 58380aaatttgaca tatgactaag ataactattt caaatattta aaaaaagatg aatatgtaat 58440aaaacagata aaatatcaaa agaaagtaac agtattgact agccaaatca aattaaagac 58500ttagtgtaaa aagctatgtc ttaaaagaaa aaattactgg atggctgcct gatcaattta 58560gacatttctg aataggaaac taaccaaaaa tcaattctac agaaccaact acacacatat 58620atacacatac aacacaccca tacacaccca cgcaaaaact cacaagttca cacacacaca 58680cacacacaca caaccctcaa gaaatagtga aatagaaaac caaccgaacc tcacagacat 58740gttgcaaaat aggaaaagat ttcctgcata tgggaagcaa gtcacagaaa agagaacggg 58800agattggaaa cagaaacaaa taccggaatc aaggatggcc gaaaactttt cattgatcaa 58860gaatattaac aaaatcgcaa aaacacgaaa ttcaatgcat caaataggcg tttcgaaaaa 58920aagaaaaaat ctggtatgat gcacttttgt acttcacatt ttcacggtaa gaagacaaag 58980atataataac aagaaacttc ttatgagaaa ctggggaaaa acaagctgtt tcttgctaga 59040agaacagtga tacaaattgc taatgcattc tcgtcaaaaa cactggaagc cagataccgg 59100gaatgttatt aatgtggtaa acaggaacaa gaagagatca accaagaatg ctaaatccag 59160caataaaatg ccttgaagat catccatgct gcataaatgt atgttgtgca ctgccccaaa 59220caaagaaacc ggaaactgta agaatttgga atcagcaggc tgatgtaaca agagaggtga 59280cccaaaggaa ttaggtagaa gaagaatagt acaagaaggg aactttctgc agcccatgta 59340atgaagaacc cagcaattgg caaatgtaga tgtaaatgca aaatattttc ttgaccaaat 59400ttctatatat ttttaaatga gcgttgacta ctggaaacaa aatgatagca atatatttaa 59460ttttagcata tgtagaggta agaatttgaa caagtagcgt aaatcatgta gggaataatt 59520agaagtgtac cattgtaagt ttcttacctc atgcacaatg gtatgtaata ttaataaaat 59580gttactgtgt gggttcaagg agatattgca aatcctagag caatcacaaa gttttgaact 59640ctgaggtata ttgtataata agaatattcc atgtattcaa aagagagaag ccaaggaaga 59700aagaaatttg tcacgagttt gggctcttag tacatcctgt agctcattga accagcttcc 59760tggaatggag ggtctgggat tgacactagg ccacatgtat agagtctcta gagagacagt 59820gtttcatccc catggcccgt aatacatttc ccattttctc aggcagccac aggtcatgaa 59880tgtgaggata gagagaggtt ggagcaacgt tcttgggagg cataaggaag agcaaatgct 59940tcaagatccc cgcagcccaa actcctacct gctttgcccc ctaatgcagt gttcctccgt 60000agctgtccga cctcttcaga tctcttagtc taccctgcca tcttccttta tgccatgggt 60060cccactgttc tttcaactca tccccctttc cctcagtgca gagtagctgc ggccagcaga 60120gggtagactg agagcaggag agaaggtcct gcccaggaac ccattctaga gatgctgcat 60180tctgcctggg agcaagtttt ccagggcagc tttgagaagt cttgcagaaa caaacctatt 60240tgacccacat gatatgggaa tgacagaaag taatacaatt tgcacagtgc ttttccatgg 60300gaaaagtaga gccttttcgc gaggttttga gtacatagag agtgaaggtt gacctggaaa 60360ggttatcctc ctggatccca tgttttttct gaagaactac ctgttagttg caacttgcac 60420attagaatat gaagtcctac cgagagagat acggagaact agataaatac agatactttt 60480gtatgtgaat aaacgattcc acaatacaca catcaaaatc cataccagtt attccagaga 60540gatggattgg gcagaaggca gaaggagaat actctgatcg ttttttgccc acgtgtatgt 60600attatctcag tgtttctaag aagcgtttgc tactttagat ttttttttat aataataatc 60660ttttaagtat gagaaatgtg cagacaggat tagtgattga gagccatttg tgcttgtggc 60720aatcatatgg tacttttatg ggaatattag aaaggcactg gtaatgacct tgttgcagca 60780caaaggagag ggtgtggggt gcccctgcat attgtcccac ctcttgtgac gtgtatcgtt 60840ttggaatttc cagtggcttg atcatgaact actgcaggaa tccagatcct gtggcagccc 60900cttattgtta tacgagggat cccagtgtca ggtgggagta ctgcaacctg acacaatgct 60960cagacgcaga agggactgcc gtcgcgcctc caactattac cccgattcca agcctagagg 61020ctccttctga acaaggtaag gagcctgtgg ccagaaacct acacgtttcg atgctgggat 61080gaaaagccat ggaaattccc actgatgcag cagcctccaa tggtaaacgg atgctcgagt 61140gttgactgag ttctgtcatg taggaggaag cctccgtgca ctctctgggg gagccagcgg 61200attgatttct ggtacaacgt tgggtgggct gtgtctttag aattggcaca aaccctccag 61260ggtgatcgac ttcacaactc acctcgttga aaaatgggct atctcagtgt cttagccaaa 61320atttttattg taacatgctg tcagatgtgt gactctttcc aagccagtaa gcttttcctg 61380ggacttcttc aattagccag cattcagtgc aatcttcagc attgcagatt cagagaaatg 61440tggctctgga gcctgtcacc cttgagaaac agggctaaca gggttgcatt aattccaaat 61500caccctggtt ctatggagca gtacatgaac tcccaatgat ctatgtttca ggacttcctc 61560agtcataggt gggctctgca gccctaggtt tttaagtgag tgactgcccc gtgttctggt 61620ggcagttgta cctgtgagcg gtctggatag aaagagtcgg agacttctgt attattgcaa 61680ctcaggatgt gggtcatgag aggatttcat ctctcctgca ggggagtaag ctgttcgcct 61740ccacccatcc ctgataactg aagtgtcttt gtctgcagtc ctagacgaag gactgttgtc 61800tctcccatgg cccagaagct gaagaccttg ccttttgtta tgaaacgttc attgttttca 61860tgtctgtccg tttctctgcc cctaacaccc aatcaccatg tatggcctgt acccccaaat 61920gcatcgtgct ttgctgtttg ctgccccata gtcctcatga acattcagta gaaattccca 61980taaatgtgct tgcacgtgag cacagtttcc attgagaagc cctctcattt gtcctttttt 62040tctaagcttt tatgtgaaat atttctaaga acttactaca gttctaaagt gttaggaatt 62100tgtttctttg gtgtttttgt ttgttggttg gttgttgctt ttctcaagtc catctgccta 62160caaataaaga aacaagaatg ttacttgtca tattctcctg aggtcataat tctcagagac 62220ttttttctgg tttgtgccat aagtggcttc acatgtttgt ctcttcttgg aaacactcag 62280tttgatttct tttcttttca tttcagcacc aactgagcaa aggcctgggg tgcaggagtg 62340ctaccacgga aatggacaga gttatcaagg cacatacttc attactgtca caggaagaac 62400ctgccaagct tggtcatcta tgacaccaca ctcgcatagt cggaccccag catactaccc 62460aaatgcgtat gtctattttc tttaccataa gtgaaggaag ggtcagtgga aatttctgtt 62520agtagagtca tgcttcaagc tgagtgttca ggactcaagt tgtctcagat gaacagtgca 62580tagcaaaatg tctcaggaac attgtctttg agcaaagagt ctaagagaag acaaatgtta 62640atctggctct ccttcctcct agtttaatgg agcagaaagg tatctggagg caaggatatc 62700acattaagaa acaagtcaag atgacaaatg atgaaactct tagagtaccc ttccacaaca 62760cccactaagg ttcaatgcag ccttttctcc ttggaattct attaaactaa actccaattc 62820ctgaagtgaa ggttctgttg gggttttctg ttttggctta caaggaaagt atatatgtat 62880atctatggag aggcaaatct atctctttct atatctacgt ctattccaat atgtagaaac 62940acagtcggtt ctgaccacca gtggtctgaa gggatactgg ttgttagaga ataaaaatgg 63000caggaaggca gatgagagtc agcaaagaga gagatcctgt aaagtaaaag ggtggataga 63060tggacagaag cccaggtctg accagcccat ggccaggctt taggccataa gtgacaccaa 63120agacatggaa aaatggtttc tacatgttgg acaacagaca gtagtggacc aaaagaatag 63180tgacaggggg aacaatgaga tcaactccat agataccttg gctttcttcc tggaggccct 63240tcttgcactg aagagcaagg tgatggagcc cagatggact gtagccatct tcctgaatgc 63300aggagagaga ttggaatttg ggactactgt ggtagctagg attttatagg cctgctgaga 63360atgagaatgg atttgtggat gaaaggagct ccaggggcac gcatagtagt ctcctcgaat 63420ctttggctaa acatgacgtt gcatgtgccc agaaaaaggt tccacaagaa agtagagaaa 63480agaatatatc ctgaggaata gcaactgcga ttgaacagtg agctcaataa agaggacaga 63540gccctcatag cattctggga tactggagtt ctgaccagct ggaggagaga cctcactgaa 63600cctcttggga atacagtaga gactccagaa aagtcatact ttaggagtag aattagtaaa 63660tttctagaaa aaaaggcagc tctagacaaa ccctggcaaa actgaaaagc aagtctccaa 63720gcattaaaat catttccaag tcaattaact gcctgggaga ggaaaaccct ctttagaggt 63780aaacaacaaa gtcaagtggc tcagctatgt ggtgttcaca gtgtgagttc taaatttaaa 63840acttgactac acatagagaa gcttttagta tgaaccatga ccaggtgaaa aatcagtcaa 63900tacaaataga cctagaaatg acagaaatga ttagaatggc aaaaaatttg acatatcaat 63960atgtcaactg agttttaggt tttaagaaaa catgaatacg gaatgaagca gataccatat 64020caagagacag taacagtata gaagagccaa attaaattaa agaactagta taagaaggta 64080tgtcttaaat gaaaaaatta ctggatgtat tcccaatgga gtgagatgtt tcagaagtaa 64140aaactaactg aaaaacaatt ttataccacc tacagaacca gctacacata cacaaatgac 64200acacacatat acacacatac tcacacatgc acaggcttag aaacatgcac gcacacacac 64260acacacacac acacacacct ccacaaatac taaaaaatga aatccactga tcctcacaga 64320caggcgggaa aatataaaaa gatttcctgc atgtgggtag gaagtcacag aaggagagga 64380aggagagatt gctacaggaa caaatactgg aagcaaggat agctaaaaac ttttcaaata 64440agaagaatat taaaaaccac agattcaaga agctgaatga atcagacagg gaatttccaa 64500aaaaaaaaaa aaaaaaactg tatgattcac ttttgtacat caccgttcaa cagtcagaag 64560gcaaagatat aataacaaga aacatctcat gagaaactgg aggaaaaaga gctgtgtctt 64620gctagaagaa cagtgataca aattgctaat gcattctcat cagaaacact ggaacccagt 64680taacagggga tatcattaaa atgataaact agaaaaaaaa gagatcaaat gagaatgcta 64740catccagcaa taaaatgcct tgaagatcat ccatgttgga taaatgcata ttgtgcactg 64800ccccaaataa ataaaccaaa aactaataat ttggaatcag caggcttgtg taacaagaga 64860tgttgcccaa agaaaattag ctagaagaag aatagttcaa gaggagaact ttctgcagcc 64920cacgtaatga agaacccagc aaatggcaaa tgtagatgta aatgcaaaat attttcttga 64980tcaaatttct atatcttttt aaatgagagt tgactacttg aagcaaaatg atagcaatat 65040atttaacttt agcatatgta gaggtaaaaa tttgaacata tagactaaat catgtgggga 65100ataattggaa gtgtaccatt gtaagtttct taccttatcc acgatggtat gtaatattaa 65160tgaaaggttg aatttgtggg tccaaaggga tattgtaaat cctaaagcaa tcataaaatt 65220ttgaattctg agggatatta tataataaga attttccatg tatccaaaag agggaagcca 65280aggaagaaaa agaagtcttt caagtactca agctctgagc acatccagtt gctcattgaa 65340ccagcttcct ggaatggagg gtctgggctt gagactaggt cacatgtgta gagtctctag 65400agagacagtg ttggatcccc atggcccata atacatttcc cgttttccca ggcagccaca 65460ggtcacgaat gggaggattc tgagaggttg gagcaatgtt cttaggaggc ataaggagga 65520gtgaatgctc tgagatttcc ccagcctgag gtcctccata gctgcccgac ctcttcagac 65580ctcatagtct gcccagctgt ctccctttat gccatgagtg ccactgttct ttcaactcat 65640cccccattcc ctcagtcccg gaattgctgt ggccagcaga ggatggactg agagcaggag 65700aggaagtcct gaccaggaac ccatcctaga gatactgcat cctgcctgaa agctaggttt 65760ccagggcagc tttgagaagt cttgcagaaa gaaacccact tgacccacct gatacggtat 65820cgacagacag gaatactttt tgtgcaatgg ttttacatgc tgaacataga gccttttggc 65880tacattttga gtacattgaa tgagactgct ggcctgggaa ggatatcatg ctggatgcca 65940tttttttctc tggagaacta tgtgttagtt ccaactcgca cattactata tgaagtccta 66000cacagagaga tacggagagc tagacagata gagatacttt tgtatgtgca taaccaattc 66060cacaatacac acgtcaaaat ccataccagt tattccagag agatggattg ggcagaaggc 66120agaaggagga tattctgatc cctttttggc cacatgtatg tataatctca gtgtttctag 66180gaagtgtgtg ctgcattaga ttttttttct ttaaaaaaag tgataatata ttaagtatga 66240gaaatgtgca gagaggatta gagattgaga gccatttgtc attgtggcaa ttgtatggta 66300tctcttttgg gaatatttca aaggcaccag taatgacctt gttgtagcaa aatatacagt 66360gttcctgcat atgtacccat tttttgtgat gtgtattctt ttggaatttc cagtggcttg 66420atcaagaact actgccgaaa tccagatcct gtggcagccc cttggtgtta tacaacagat 66480cccagtgtca ggtgggagta ctgcaacctg acacgatgct cagatgcaga atggactgcc 66540ttcgtccctc cgaatgttat tctggctcca agcctagagg ctttttttga acaaggtaag 66600aagttgtgcc agacatttac ctgcttggat gctgggatga aaagccatgg atacccccac 66660tgacgcacaa cccttcagtg ctacactggt tctcgtgtgt tggttctggg tctgccatgt 66720gggaggaagc cttagcgcac tctctggggg agccagaggt gtgatttttg gtgcaacctg 66780tgcgagctgt gtctttagga tgggcggaaa ccattctggg tgctcgactt caccactccc 66840ctcattgtaa aaggggctat ctcattgtcc tagacaaaat tcttattgta atatgctgtc 66900agatgtgtgt gtctttccaa gccagtaaac ttttccaggg atttcttcaa gtagacagca 66960ttcagtgcaa tcttcagcat tgcagattcc gagaaatgtg gctctagatc ctgttatcct 67020tgagaaacct aactgggttg cattaattcc atatctccct gggtctgtgg agtagtacat 67080gagctcccga agctctatct ctcaggtctt tttcagtccg aggcaggttg tgcagttctt 67140agctttgaag ggagtgattt tttcgtgtgc ttttgcctct ttctgatgga acttgtacct 67200gcggggggtc tggagaaaaa gagtagtaga cttttgcttt attgcaatgc attatgctgg 67260gcacgagagg attccctatc ttattgtagg tgataagctt ttggcctcca ctcatccctg 67320agaagtgaag tgttgttgcc tacagtttta gctgcaggac tgttgtctgc cccatcacca 67380ggagtttaat gctttctttt ttgagcaatc atctagggac acatgcaagg tttttatatg 67440tccttgcctc ctccccaaaa aaccatttta atgcttggag acttgctttt cagctttgcc 67500aaatgcatca ccctttcttc tatgctgttc catgtcgtca tgaacactct gtagagattc 67560ctagaaatga gcttccatgt tagtggagtt tccgatgaga agcaatctga tatttctttt 67620ccactaagtt ttacatgaaa tatttctaag aacttactac agttctagaa tggtaggcat 67680ctcttacttt cgtgtttgtt tgtgtgtttt ctcatgtcca tttgcctatt aataaagaat 67740agagaatggt tgtaaatctc agtgactctt ttttggttta tgtcataaat ggcttcctgt 67800atttttctgt tctaggaaat aataagcttg atgtcttctg ttttaatttc agcactgact 67860gaggaaaccc ccggggtaca ggactgctac taccattatg gacagagtta ccgaggcaca 67920tactccacca ctgtcacagg aagaacttgc caagcttggt catctatgac accacaccag 67980catagtcgga ccccagaaaa ctacccaaat gcgtacgtct ttgttcttta ccataagcga 68040aggaagggcc aatggaagtt tctgttagaa gagtcatgct tcaaggtgac tgctcaggac 68100tcaacttggc tcagatgcag aggaacattt cctgtgagca aaagttctta gagaagactt 68160tgtttttttg agacagagtc ttgctttgtt gcccaggctg gagtgcagtg gcatgatctc 68220ggctcactgc aagctccgcc tcccgggttc acaccattct cctgcttcag cctctctagc 68280agctgggact acaggcaccc accaccacac ccggctaatt ttttgtattt ttagtagaga 68340cagggtttca ctgttctagc caggatggtc ttggtctcct gacctcgtga tccgcctgcc 68400tcagcctccc aaagtgctgg gattacaggc gtgagccacc gtgcctggct gagaagacat 68460tttttaagct ggctctcctt cctcctagtt ttatggaagc agaaggatat atggagttga 68520gaagatctta ttaataaaac agccgggatg acaaatgacc aaagagttag agtatccttc 68580tacaacatcg gctgagggtt aatacaacct tttcaccttg gaattctatc attctaagct 68640ctagtccctg aagtgaatgt tgtgttggcc ttttgcatct tgggtcacag ggaattgata 68700cttgcacatc tatggagagg caaatctttt tctatctact tctttttcaa tgggtacaaa 68760cacacttggt cctgagcacc agtggtctga agagatacgg tctgcccaga ggagaagaac 68820aaaggcagga aagcagatga gagtcagcaa aggggcgatg ctgaaaagta aaaggggcgg 68880gtagatggac agaagccatg atctggccat tctatggcca gtctttcggc cataagtgac 68940taccaaagac acggcaaaac ggtttccaca tgttgaacaa cagatgctag aggaccaaga 69000gtattgcaag agggagaaaa tgagatcaac ccatcaatgc cttggctttc ttcaaggaga 69060cccttcctgc actgaagagc aaggagatgg agcccaagct gactgtagcc atgttgctga 69120acagaggaga gtgattggac tttgggatta ctcaggtagt taggattttc tagccatgct 69180aagagtaaga atggacttgt ggaggatagg agctccaggc atagaagtct cctcaagtgt

69240tagtctaaac ataaagcagc acttgcatag aagattttcc acaagaaaat atggcaaaaa 69300aacaccatat attgaggaac aacaactaca agggaacagt gagcttaata aaggtgacag 69360agctcacata gtgctctgga atattggagt tttgaccagc tagagagaag agacctcatt 69420gaaaatcttg ggcattcagt agagacctca gaaaagtcag actttatgag tagactttgt 69480atattcctag aataaaggca gctccagaaa aaacctagca aagctgaaaa gcaaatctcc 69540aagcattaaa atggtgtcct agtcaattaa ctgccttcta gaagaaaact caacactctt 69600tacaggtgaa caacaaagtt aagttgctga gctatgcaat atccacagtg tgagtcctaa 69660atttataact ttactacaca taaaaaagca tttagtgtga accataacca ggaaaataat 69720cagtcaataa aaatagaacc aggaatgata gaaatgattt aaatggcatg agaatttgac 69780atattagtat cataactgca ttgctggatt taagaaaaca taaacatgga acgtaacaga 69840tatcatatca agggaaagta aaaggataaa agagtcaaat caaattaaag gactattaaa 69900aggtatatct taaatgaaaa attcactgga tggtctccca atcaggttag ttgtttccag 69960ggaaaaaatt aactgaaaaa taattcaata gaatctacag aaatagctgc acatatatac 70020acacaatggc acacgtgcac acacccacac ccacacaggt gtgaatccta gagccacacg 70080agcattgaaa catagagaag taaaaattgt tcattgagga atatgtagca atgctcaatg 70140tgttttaccc taataagagc ttttgtgatg tatgattgaa aaactgacac aactgaagag 70200agaaatagat aagcccacac tctgagttag agatttcctt gattctctca ctatggttat 70260aaatctttcc caaacacaac aggctagaac aaatatgcag aaaattagac atagtatctt 70320tgttctcaat aaaaacgtcg acctatttaa cattataccg aactaccgag tacacattaa 70380agtgtgcatg gagcattcac tgaggtgtac tctacacatg accttccagc aagtctccat 70440agatttaaaa gaattaaagt catacagagt gtgtcacttt attctcccag aataaagtga 70500gatatgaata atgagaagtt tgccagcttc tcaaatattt gggagtcata cggtgcattt 70560caaaatactc tttgggacaa agaaaacatc actaaggaat ttagaaaagt tttgaactga 70620gtaagaatat aacacaattt atccaaactt aggagatgca gtgaatgtct ttaggctttt 70680acataatttt agatgctctt agggaaaaac agaagcatgt aataatcaag atttcaaact 70740gcaattctca aagtgtagtc tagagaaacc tgaggacctt tgagtacctt cagagacagt 70800ccatgaggtt aaaggacttt gctacgtgaa aagtaagatg ctattggccc tttttacttt 70860cattttccaa caagagaaga ggggagtttt ccagcagtta cataatatgt aatggcatca 70920tgtctctgat ggctaagaaa atgggcaatt gttgactttg tgtgttaaaa aaattctcag 70980tgttggtttc ttatactata aatattcatc ttgtgttttg aaaaagaaaa gctctttgga 71040atcccctatg aacaaagact ttgacagttg ttgatctaag accacagctt aaatatctac 71100acaagaaaaa aaaaaaaagc aaataagagc caaggaaagc agatggaagg aagtagtcca 71160aaccagtgac attcagtgaa caagaaaaga gaccaacaag ggagtaaact cttgaaacag 71220aaagttgatt ctttgaaaag atccatatga ttgaacacag tctggctaaa caaatgacag 71280accaatgagg gtgcacaacc atcaccatct ggagtaacag aggagaggtg ccattactat 71340agcatcttcc agttctgaaa gctgaaaaga agattttgag aacaattgta tgtgaataaa 71400ttcaggaatg ttaatcatgt gggccaattc ctgaggaaga caacaaatca gcaaaccaga 71460tgctgaatag ttagtgtagt cctgtagaga gacatacaga gaggctgaca gagaaatatt 71520tgtatgtgca taaaacaatc tacaagacac acttcaaaat caatctcagt taatctggag 71580gaacatattt cacagaaggt ggaaggaggg tattctgatc ctcttgtaca ttgtacaaca 71640ttgtacaatg tacagagtat aattgtacaa gtacaattga agttgtacaa gtacaagtgc 71700aacttgcaca atgtacagag taaacattga tgtttactct caattttctt atggagcaca 71760gatgactttg gatgtgttac aatatgaatg ataatttgtc tttgagatgt tcgcagttgt 71820ttagaagttg aggaccattt gtgcatatta tgggaccttt agtgaaaata tttcaaagtc 71880tctttttaca ctttgttaca gcaaaatgta gagggcgcta agtgcccttg aatcttctcc 71940catctctggt gacctgtgtt gttttgaaat ttgcagtggc ctgaccagga actactgcag 72000gaatccagat gctgagattc gcccttggtg ttacaccatg gatcccagtg tcaggtggga 72060gtactgcaac ctgacacaat gcctggtgac agaatcaagt gtccttgcaa ctctcacggt 72120ggtcccagat ccaagcacag aggcttcttc tgaagaaggt aggaagtcta tggccagaca 72180accacaccct aggacgttgg gatgaaaaga gttgcaaaat cttagtgata tagaagcctt 72240ccatgctcac acaattccaa gtagaatgtg gactcagggt cagccactgg gaaggaacac 72300tcagcgcctt ctctgggaga accagagctg tgatgtttgg taccctgtga aagggtggta 72360tctataggaa gggtgcagac cctctagggc actggactta ccactcccct ggttattcaa 72420aggatcattt tagtgtctta gccagaagaa tattctaaca ttttgccaaa tttgtgaaga 72480tttaccaagc tcatgataag cctttcatgg tatttcttca agtagtcagt gttcattgca 72540tctttggctt tgcggtttcg gaggaatgcg gtttttgagt ctgtcatcct tgagaaacct 72600aatatgactt ttcttagttc catatacttc tgggtccagg tagcagtaca tagccaacaa 72660atgctccatc gttctggcct atctccatct taagccagtc ctgcacaact aggctttgat 72720gggagggatc tctcagtgtt cttgcccctc cttctcatgg aacatatatc tgtgttggtc 72780tctgagaaga agagtagtgg atatctactt tgttgcaatg cagaatcctg ggccaaagat 72840accagccatc cctccaaggg aataaaattt tggccagtag ccctctctga gagacaattt 72900gtctttgcct acgagtccta gatgcaggac cgcttcctgc cccatcttca agaagctgaa 72960ggctttggct ttggaggatc agcagtctag ggaaatgtgt gacggtttca tgtctgtccc 73020cactgacagt caatcaccac ctacaacctg cacagcctga tgcatagcag tctagtttcc 73080tgccttattc tcaggaacac ccagaagatg tctatattaa agagcatgca catgagtgca 73140attttgactg ataggcactc tgatctttcc tttggtgcct gtgttttaaa ggaaatcttt 73200ctaagaactc gttaaagttc tagaatgcta tgaatctttg ggttttatta ttggtatgtc 73260catctgcctg ctagtacaga acagagcatg gtagtctttc tcagagacaa tgatcctgtt 73320tcagtcacag atttcttctg atgcttctgt gttctagaaa ttactcagct tgatttctcc 73380tctttgaatt tcagcaccaa cggagcaaag ccccggggtc caggattgct accatggtga 73440tggacagagt tatcgaggct cattctctac cactgtcaca ggaaggacat gtcagtcttg 73500gtcctctatg acaccacact ggcatcagag gacaacagaa tattatccaa atgggtacaa 73560ccttgagttt tcttcaaaga cagacagcag cccccttaca tttctcttgg aagggccatg 73620cttccaacta acttcttatg acaaatttat ctcagatctg gaatgttggg tagaatgtct 73680caggcttctt tcttcaggca cagtgtctga aaggagagaa atgtcaggcc agctctcttt 73740tctcatagtt gacagaagca ggaggatatt tgaaggtggt gagttctcat gaatagaaag 73800ctcaggacac atggccacgt gcttagaaat agcaccattc cacaatgccc actaaagacc 73860aatgcaatag ttcaaccagg gatttctgtc attctaatct ccaagtcctg aagtgaaggt 73920tgtattagcc atgttcatct tgggcaacaa ataaaggata tctatgttga catccagatc 73980ttccaatcac tttctcctct aacctgtacc tgggttctga gaacaaggta tctgaagagc 74040tatgtgttgc cagcacatga ggggcaaaag taggaaggca gctgagagtc aggaagtata 74100aagattctga agagttacac atgcaggaag atggacagaa acccagttca gaccacgtca 74160gcgtttctgc catgaaggac tatcaaatac ataggaaaag tgttttcata ggttggacaa 74220cagacatgac aggcctgaga aaattcagaa agggaatcaa aggagatcaa ccttatcatg 74280tccctggcat ccttccttga gacccttgaa gggcaagcag atggagccca gctgaccaca 74340gcagtcttgc ttaactgagg agagagactg gagtttgtga tgcctcaggc atctgacgta 74400ttctaggctg gctaagaatg agaggggatt tgtggaggaa aggagctcca agaatacaca 74460ccgaagtctt ctcaaggctt tggctaaata caaagctgcg tatgcacaag gagagttttc 74520acaaagaaag aacaataaag aaaagctact ggggaaagaa caactgcaag ggaacagtga 74580gctcaatgga gatgctagag ctcacatagc actgggggat atttgagttc tgaccactca 74640gaggagagac acctcactga acatcttggg cattcagtag aggtcaaaga aagccataat 74700ttgggagtag gatcttcgga ttcctagaaa taaggtgact ccagaaacac tccagcaacc 74760cttcttccaa gccagtctaa aaggatccaa atgatttcca agtaaattaa ctgccttcca 74820gaaaaaagta aactcaaccc tccttagagg taaggaacga atacaagttt ctcagttata 74880tgacatcccc agagtgcaac ttgcatttaa aaatttacta gacacaaaag aagttttcac 74940tgtgatccat aactgggaga aaaatcactc aacacaaata ggcccagaaa taatagaaat 75000tatggcattg gcaagaacat ttaaaatgca cctctgagaa ctgtgtttca ggaaaatgtc 75060agcaaaagct gaccatgaga gaaatgaatg cataatatca gaaaagaaaa gaattgaaga 75120gccaaatgga aatttaaaaa ctgagaaaag ttatatctgt aatgaggaat tcactggatg 75180gccttataac cagtttagat attatggtag gaaaaggtga acgagaaaat gattcaatta 75240aagctagaca aaccacaaga cagacagaca gacacaaata cacatacaca caatgactga 75300accaattaat caacagagcc tcaaggacat ctaggaaaac atccacacat ttaatatatg 75360tgttaggcaa gtcacagaaa gagaggaaaa agataatgtg acagaagtta tacttgaagc 75420catgacggct gacaaatttc caaacataca gaaaatgaga aattcatagt catgaagctc 75480aatgactcag gtatagattt ttaaagagca aaactctgat ttactggggt acatcatagt 75540taaattgtct gatttcaaag ctaagaagaa aaaaaggggg ttcctatgaa caaacatttt 75600gacagttgat ctaagaccac agcttaaata tctaggcaag gaaaagcaaa taagacacaa 75660ggaaagggga tggatggaaa tagtccaaac caatgacatt cagtgaacaa gaaaatagac 75720caacaaagga gtaaatccat gaaacagaaa gttggttctt tgaaaagatt catgtgattg 75780accacagtct ggctgaacag atgacagacc aaggagggag tacaaccatc accatttgaa 75840gtaacagggg agaggagcca ttgctatacc atactccagg tctgaaagct gacaagaaga 75900tatcaagaaa aactgtatgt gaataaattc atgaatgtag atcatgtgga tcaattcctt 75960aggtaaacaa caaatcagca aaccagatac tgaatagatt gggtactcct atagaaagac 76020atacagatag ccagacagag aaacatttgt acgtgcataa aacaatctac aagactcact 76080tcaaaatctc tcagttaatc caaagtaaca tatttggcag aaggtggaag gagggtattc 76140tgatcctttc ttgtacacat tgatgttttc tctcggtttt cttatggagt atagacgagt 76200ttggatgtgt tacaataaga atgataatct gtctttgaaa tgttcacagt tgtttagaag 76260ttgaggacga tttgtgattg ttacaggacc tttagtgaga atatttcaaa gtcacttttt 76320accactttgt tacaacaaaa tgtagaggat gtctggtgcc cttgtatctt ctcccatctc 76380tggtgaactg tattgttttg taatttgcag tggcctgacc aggaactact gcaggaatcc 76440agatgctgag attagtcctt ggtgttatac catggatccc aatgtcagat gggagtactg 76500caacctgaca caatgtccag tgacagaatc aagtgtcctt gcgacgtcca cggctgtttc 76560tgaacaaggt aagaagtctc tggccagaca accacaccct tggacgttgg gataaaaaga 76620gttgcaaaat cttagtgata cagaagcctt ccatgctgca cgggaatctg aatgtggact 76680cagggtcagc caatgggaag gaagcctcag cgccttctct gggggaacca gggctgagat 76740ttttggcacc ccgtgacagg gtggtgtctt taggaagcgt gcagaccttc tagggcactg 76800gatttaccac tcccctggtt attcaataga ttatttcagt gtcctagtga aaatggatat 76860tctaacatcc tgccaaattt gtgatgattt accaagctca tcatgagcct ttcctggtat 76920ttcttcaagt agacagtact cattgcaaac ttcagcttta cagtttcaga ggaatgtggt 76980ttttgagtct gtcatccttg agaaacctga tatgacttta cttagttcca tatcctcctg 77040ggtctaggta acagtacata gccagcaaat gctctatctc cctgtctacc ttaatcttag 77100gcaggtgctg cacacctagg ctttgatgga agggatttct tagtgttctt gcccctcctt 77160ctcatggaac acgtatctgt gttgctgttt gtgaagaaga gtagtggatg tctactttgt 77220tgcaatgcag gatcctgggc ccaagatttc ccgccgtccc tccaagggaa taaaattttg 77280gccagtaccc ctctctgaga gacaatgtgt ctttgcctgg aagtcctaga tggaggacca 77340cttcctgccc catcttccag aaacttaagg ctttggcttt ggaggatcag tgctctggag 77400aaatgtgtga cggtttcatg tctgccccca ctgacaacca ccacctacag cctgcaccgc 77460ctgatgcatg gcactctggt ctcctgcctt gttctcagga acacccaaaa gagatctttg 77520ccaaagaaca ggcacatgag tgcaattttg actgataggc actctgatct gtcctttggt 77580gcccaggttt taaagaaaat ctttctaaaa actcattgaa gttccagaat gctatgaatc 77640tttgagcttt gttattggca tgtccatctg cctactaatg tagaacagag catggtcgtc 77700attttcagag atgatgtcct gtttctatca tggatttttt ttctcatgct tctgtgttct 77760ggaaattact cagtttgttt tctcctcttt gaatttcagc accaacggag caaagcccca 77820cagtccagga ctgctaccat ggtgatggac agagttatcg aggctcattc tccaccactg 77880ttacaggaag gacatgtcag tcttggtcct ctatgacacc acactggcat cagagaacca 77940cagaatacta cccaaatggg tatgtctttg agttttctcc caagagaaac agccacccac 78000ttaaatttct cctggaagag ccatgcttcc agctaacttc ttatgaccca atttctctca 78060gacccagaat gttggacaga atgtctcagg cttcttgctt tgggcacagg gtctgagagg 78120agagaaatgt caggccagct ctcttttctc atagttgata gaagtaggag gatacttgga 78180ggtggtgagg tctcatgaat agaaagctca gaagaacata tgaccatgtg cttagaaata 78240gcaccattcc acaatgccca ctaaagacca gtgaaatagt tcaaccaggg aattctgtca 78300ttctaatctc caagccctgg agtgaaggtt gtgtttgcca tgtttgtctt gggtaacaag 78360tgaaggatat ctatattgac ttcgagatct tccgatcact ttctcctcta acctgtataa 78420acacattggg ttctgagaac aaggtgtctg aaaagctatg tgttgccagc ccatgagggg 78480caaaaggagg aaggcagctg agagtcagga agtatagaga tgctgaagag ttacacattc 78540aggaagatgg acagaaaccc atgtctggct atgccagcct ttctgccatg aaggactatc 78600aaatacatga gaaaacagtt ttcacaggtt ggacaacaga tatggtaggc ttgagagaac 78660tgagaaaggg aatcaaagga gatcaacttc atcattaacc tgtcttcctt cctggacaca 78720gtgttggatt gaaggacaag cagatggagc ccagctgacc acagcagtct tgcttaactg 78780aggagagaga ctggagtctg cgatgcctca ggcagctgat gtgttctagg ctggctaaga 78840atgagaaggg atttgtggaa gaaaggagct ccaggaatac acacagaagt ctcctcaagg 78900ctttggctaa atacaaagct gcgtatgcac agggagagtt ttcataaaga aagaacaaca 78960aagaaaagct acttgggaaa gaacaactgc aggggaacag taagctcaat ggagatgcca 79020gagctcacat agcactgggg gatatttgaa ttctgaccac tcagaggaga aacacctcac 79080tacattttgg gcattcagta gagaccaaag aaagctgtat tttgggattg ggatcatctt 79140attcctagaa tcaaggtgac tccagaaaaa ctccaacaac ccttcttcca agccagtcta 79200aaaggatcca aatgatctcc aagtaaatta actgcattcc acaagaaaaa aaaaactcaa 79260ccccccttag aggcaaggga caaatacaag ttgctcagtt atatggcatt cctattgcgt 79320tacttctatt taaaaattta atagagacac aagaagcttt cactgtgata cataactggg 79380agaaaaaatc actcaacaca aacaggccca gaaattatag aattgatgac attggtgaga 79440acatttaaaa tgcacctctg agaactgtgt ttcaggaaaa tgtcagcaaa agctgaccat 79500gagagaaaca aaagcagaat agcaagagaa aagaaaagaa ccggagagcc aaatgaaaat 79560taaagaactg agaaaaggta catctctaat gaagaactca ctggatggcc ttatcatcac 79620tttagacatt acggtaggaa aggtgaccta gaaaataatt caataggagc tacacaaatc 79680acaggacaga cagacagacc aacagacaga aacacacaca cacacacaca cacacacaca 79740cacacacaca cacacacaca aagactgaac ctattaatca acagagcctc aagggcatct 79800aggaaaaatc cacacattta atatatgtgt taggcaagtc acagaaggag aagaaaaaga 79860tatcatgaca gacattatac ttgaagcgat gatggctcgc aacacgccaa atatacagaa 79920aacaagaaac tcatagtcaa gaagctaaat gactcaggta tagaatttta aagagcaaaa 79980ctctatgatt tactgggata tatcatagtt aagttgcctc aattcaaagc taaaaagaaa 80040aaaagggggt tcctatgaac aacagctttg acagctgttg atctaagacc acagcttaaa 80100tatctaggca aggaaaagca aataaggcac aaggaaagag gatggaagga aatagtccaa 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81840ccccacaccc cagaatctga aggcttttgc tttggaggag cagtggtcta gtgtgcaagg 81900gtttcatgta taccccccac taacagccaa tcaccaccta tagcctgaac agcttgatgc 81960atggcaccct ggtctcctgc cttgttctca tgaacaccca gaagaggtgt aagcaaaaga 82020ccattcacat gagtgtaatt ttgaagtata ggcactctga tctgtttttt gtttgtttct 82080ttgtttgttt gttttccagg gttgaattaa aatatttatg actacttatt aaatttctag 82140aatcctataa gtctatttgt atttttattc tacatttcaa tttgcatgct aatatagaag 82200agtgtaaatt gttaatcctc agattattcc actttgtgtg tcataatttt tttcacattt 82260cccttttcta ggcaatactg agcttgattt tctcttttaa tttcagcacc aactgaaaac 82320agcactgggg tccaggactg ctaccgaggt gatggacaga gttatcgagg cacactctcc 82380accactatca caggaagaac atgtcagtct tggtcgtcta tgacaccaca ttggcatcgg 82440aggatcccat tatactatcc aaatgcgtat gtctatcatg ttagccataa aaggaacaat 82500agtcaactaa aatttctctt agctggccca tgctacaagc tcacttccta ggtccaaatt 82560tctcatagac tcagagtttg tagcaaaatg tctcaggaaa cttacttttg agcaaaaggt 82620ctgaatgaag agaagtttta ggattgctat ctttcataac aatttgatgg aagcagcagg 82680atatatggag gtggtgaagt ctcattaatg taaagctaag gagatcaaat gaccaaatgc 82740tgagacaaag tatcattcca caatgcccac taaaggtcca tgcagtcttt caaccatgca 82800attctatcat tctatcctcc attccctgaa gtgaaatttg tgtttgccat ttttgacacg 82860aatcagaagt aacaaattca ggctgggtgc agtggctcag gcctgtgatc ccaacacttt 82920gggaggacaa gacgggcaga tcaccagagg tcaggagttc aagaccagcc tggctaacat 82980ggcaaaaccc catctctacg aaaaattaaa aaattagccg gtcatggtgg tgggtacctg 83040taattccaac tacttgggag gctgaggcag gagaaacact tgagcctggg attcagagtt 83100tgctgtgagc cgagaacatg ccactgcact ccagcctggg tgacagagca agactcaatc 83160tcaaaaaaaa aaaaaaagaa gaagaagaag aaaagaagaa gaggaagaag aagaagagga 83220agaagaagaa gaagaagaag aggaagagga agaggaggag gaggaggagg aggaagaaga 83280agaagaagaa gaagaagaag aagaagaaga agaagaagaa gaagaagaag aagaagaaga 83340aaatagaaat gagtgcatat atttatatat gagtactagc ctgtatgaac acactgggtt 83400ctaagcacca gttttctgaa gggatatggg ttgtcaggca gagtaaaagc aggaatgcag 83460atgagagtca ggaagtaaac agatgtggtg attaaaatgg gcaggtacat ggacaaaaaa 83520atgcatgtct gacaaaaact ggcctcttgc cataagtgag tatgaataat atggaaaaac 83580tgtttgcaca tgttgaacag cagacagtac aacctgagat agtttagaaa gggaaacaaa 83640taagatcaac cccataatta cccttcctag acttaagggc aaagagtttt aaccaaagca 83700ttccacagca gtcttgctaa actggggaga gagactggag ttttgtttac taataaaacc 83760gagattttct aggttaggta ataatgagaa agtatttgtg gagaaaagga gctccaggaa 83820tacacacaga agtctcttca agtctctggc tgaacagaaa gctgtgtatg cacagaaaga 83880gtttccagag agaaaggaga acaaagaaca gctactgggg aaagaacaac tgctggggaa 83940cagtgagctc aatgaagatg ccagagctca catagcactg ggaggtattt gagctctgac 84000cagcctgagg agagacactt cattgaacat cttgggcatt cagcaaagac cccaaaaaac 84060catacttcag gagtagaatt aatgcattcc tagaataaag tctactccag aaacacccta 84120gaaaagctta gaaaccaagt ctaaaaagat ccaaatgatc tccaagtaaa ttaattgcct 84180gtcagaagaa aacaacctct tcagaggtaa acaacaaaat taaattgctc aattatatag 84240tatgcacaat gtgtggcata catttaaaaa tttgctaaac atacaaaaag catttagtgt

84300gacccataac caggagaaaa atcagtcaat acaaatagac ccaaaaatga taaaaataac 84360agaattggca aggagattta aaatgtatgt atcataattg tgttcaagga tttaaagaaa 84420gcgtggacaa gaaataaata aatggataat atcaacagaa agaaaaattg taaaaggacc 84480aaatggagag tcaagaactg aaaaaaaaga catctcttta atgagaaaat cactacatgg 84540ccttataatc atattagata gtacagatga taaagctaac tagaaaatat tagggtggtg 84600caaaccatag cacgcttata caaagcctga gaagataaac agagcctcaa ggacatctat 84660gaaaatatca aaatatttaa tatttgttta aagcaagtca cagaggaagg gaaagagata 84720ttggaacaga aaaaatactt gaagcagtga tggctgatga ctttctaaat atggaaaaaa 84780tgataaactc acatagtcaa gaagctcaat ggatcagata taggatttta aaaagtaaag 84840ctgtatgatt tatttggaca catcataatt aaattgtcca taatcaaaga tagaaagtaa 84900aatcttattt gaagcccaag ggaaaaaaca tacctttaca tagagtaaca gtgacacaaa 84960tgactgatgc cttctcatca gaaacaacac aaatcagaaa caatagaata acacctttag 85020agtggtaaga agaaaaaaag atcaaatcag aaacaacaaa ataacacgtt tagagtggta 85080aggaggaaaa caagatcaaa tcagaaacaa tggaataaca cctttagagt gtaagaaaga 85140aaaaaagatc aaatcaggaa caacagaata acgccttcag agtggtaaga aggaaaacaa 85200gataaaatca gaaacaatga aataacacct ttagagtagt aagaagaaga aaagatcagg 85260tcagaaaaaa tggaataata tgctaagaag aaaaaaaaag atcaagtcag aaacaatgga 85320ataacacctt tagagtgaaa agaaggaaaa aaacccagca agcttaaacg ctatgcacag 85380caaacaattc cactgaaaat gaatgttacg taagtacata ttctgtcctc ctaaaaacaa 85440agaacaaata aaagaatgtt tcatcagcag gattatgtaa taaaagatgt gaaagaatgc 85500tatgtaagta gaagaaaaat aataccatat gggaattggc atcaaaacca caaaatacta 85560tcaaaacaaa aaaactttat tgataaattt aacacaatat gcaaaagaac tataccatgt 85620atactacata acattggtga gaagaaaatt agaagatcta aataaagaca catcatgctt 85680atagattaaa aaatccaatg tcacttttca caaaactgat ctttagtttc aacccacacc 85740caagcagaat tcctgcagtc ttttcttgaa aacctaacag aatgtatatg ctagaatcac 85800caagacaatc tttaaaaaga ataaaaaact tggaataaaa tcacaagttt gtgggataga 85860tgcatatggt aatatggaaa ttctcataaa gacacagtaa tcaagacatg tggtattggc 85920tgggacgctt ggctgtaatc ctaacacttt gggaggccaa gatgagagga ttgcctgaga 85980tgaggagttg cagacaagcc tgggcaacat agcaagaccc tcatctctac aaatatttaa 86040aaaaattagc caggtttggt gccatgtgcc tgtagtccca gctattcagg aagctgaggt 86100gggaggatca ctggagccca tgaggtggag gctgaaatga gccatgattg tgctactgaa 86160ctttagcctg ggagacagat taaaaccttc cctctctctc tcaaacaaac aaacaaaaaa 86220tacatagtat tgggcaaaac atatgcaaac aaaaacagaa aagggtcagc ataaatttac 86280atatatggtc aatttatttt caatacaggt agcaaagcaa tttaatgagg aaattttttt 86340ccaaaattgg tctgaaacaa ctggatagcc atagaaaaaa actataacaa atgtgacgct 86400tgaatcctac tgtatgactc aaattaaatt aatttgagat agctcttaga cctcaatgta 86460acagctaatt ctgaggctga aatataagac tgctatgaaa aagtatagta tcttataacc 86520ttggagaagg aaaaattttt tgagggaaga accagaaaac actaactgta aaagaaaaca 86580aatgataatg tggacattca ttgaataaaa acttatgctc accaaatatg actgttaaga 86640aaataaataa gtaagtaaca cactggaaga aaaacactct catccatata tctgacaaat 86700ggcctgtatc cagagtatag aaacatttct cccactcact aatcagagga caaacaacct 86760aatcaaaatg ggcaacaggc ttgaatagtc atttcttagg agaagatgca cacagagcca 86820acaatcacct gaaaaagtgc acaacatctt agccatcaaa aatcaagagt tataaccctc 86880ataagatgac actgaacatc cagtgtacat ggatatcatt aagaagacac aataataagt 86940ggtgtcaccg atttggagct agaatgtgcc actctctcat atgctggtgg aagttcaaaa 87000tcatacaaca aattaaaaaa tcagtctgat gctttcttat aaagttcgat aaatatgcat 87060ctatcctaca aacctgtaat tctattcttg aatatttacc ccccaaaatg aaaacataag 87120tccacaaaaa tctatataaa tattcatagc agctttatgt tttataaact caaaataaaa 87180actatttcaa tgttttcatc aaaagaaaat gaaaactatt taaatggttt catcaaaaga 87240aaatgaaaaa agaatttcca gtatatttat acaaaggaat actattcatc aacaaggaac 87300aagttactga tagtctcaga agcatgaaca aacctcaaaa atatattaag gaaagaagcc 87360agacgtcaaa gtgtatagtc tgtatgagtc cattcatgtg agtttataga aaacacaatt 87420tatggtgaaa gaaaccaata gcatttgaca ctggccgtgg gaagagggta gcagagattg 87480attgagcagc cacacaaggg agtttctggg gtggtgaaaa tgttctgcat tgtgagggca 87540gtgtgggcta cacaagtata tgtatttatc aaatctcatc cagctacatt taagatctgt 87600gcatctcact ctatgtgaaa atatactcaa ctgaaaaaca gagcaggtat ctgtttcagg 87660tgctacatca cttgatacgt ccagttgtgt taaaaaccac tgcctaacat cctcaaatgg 87720gggatctggg cttgagacta ggtcacatgt gtagagtctc tacagagacc gtgttggatt 87780cccatgctcc ataatacgtt ccaagttttc tcagacagcc acaggtcatg aatgtgagga 87840ttctgagagg ttggagcaac gttcttggga ggcataatgg ggaaggcatt ctccaagatt 87900cctccagcct ggggtcttca cctgctgtgc ctcttactgc attgttttct gactcatcca 87960tagccacttg accccttcag atcccatagt ctacctagcc gtctcccttt atgccttggg 88020tcccgctgtt ctttcaactc atcacccatt ccttcagtcc cagagtggct gcagccagca 88080gaggatggac tgagagcagg agaggaggtc gtgcccatga acccatccta gagaagcagc 88140atcctgcctg ggagctagtt ttccagggaa gcttttataa gtcctgtaga cccaaaccca 88200cttgctctac cagatacagt atttatagta atactatttt catgattatt ttatattgca 88260aatgtagagc atttatgcta cactatgagt aaatagagta agggggctgg catgggaatt 88320atataatctt ggatgccact tcttccttgg ggaaatgtat ttgagttcca acttacatat 88380tactatatag tcttatagag agagagacaa agagctagac agacagagat atctttgtat 88440gtgcattaaa aaatctaaga tacatatttc aaaatctgtg tcatttattc tggaggaaag 88500tatttggcag aaggtgaaag gaagatattc tgatcctttc ttgtacagac atgtattatc 88560tcagttttca tagagagcat atactacttt tgatgtttta aaacaaaaat tataatctgt 88620gatgtgtcca cagttgttta aaagttgaag ctgaagacca tttgtgcttg tggcaatatt 88680attgtggtat aatgggaata tttcaaaggc acttgttaac actttgttac agcaaaatgt 88740agagggcgct aagtgccctt gaatattctc ccatctctgg tgacctgtgt tgttttgaaa 88800tttgcagtgg cctgaccagg aactactgca ggaatccaga tgctgagatt cgcccttggt 88860gttacaccat ggatcccagt gtcaggtggg agtactgcaa cctgacacga tgtccagtga 88920cagaatcgag tgtcctcaca actcccacag tggccccggt tccaagcaca gaggctcctt 88980ctgaacaagg taagaaattt gtggttagac atctatatac tgggatgaaa aaccatggaa 89040aatcttactg atgcagaagc cttcagtggt acactggagg gttggttgag ggtctgcaat 89100gtggaggaaa gcctcagcgc cctctctggg ggatccagaa ctgtgatttt tggcacgctg 89160tgaggaggca gtgtctttag gaagggcacg gtgtctttag gaagggcaca gacccgccag 89220ggcactggac ttaccactcc cctggttatt aaatgggtca tttcagtgtc ctagccaaaa 89280tggatattct aacagcctgc caaatatgtg aagatttcca agccaataag cctttccagt 89340gatttaaagt agactttttt cattgcaatc tacagtttgc agtttcttaa gaacatggcc 89400tttgagtatg atatcctaga gaaacctaag gagactgcat tatttttcta ttgtcctggg 89460gctgcatagc aggaggtaac caacgaatgc tgtctctccc tggcctatct cagtctttca 89520caggctctgt tcacctcagc tttgaagtta gaaatttcta ggtgttcttg cctcttcttc 89580tcatgaaacc tgcattggca gtgagtctac agaagaagag gaagagaatt ctgctttgtt 89640acaattcagg actctgggca ctagaagatt ccctatctct cctccaaggg aataagttgt 89700ttgtctctaa ccctccttga gaaacaatga gtctttgcct gcactcctaa atgtaggatg 89760atttcctgcc caaattttca aaagattaag ccttttgcct tggtatgagc aatggtctag 89820ggaaatgcgc aagggtcttg tgtcggcccc tgactgacca ccagtcacct cctacagcct 89880gcaccaagga atgcattgca ttctggtctt ctgccctgtg gttctcatga aaaccagcag 89940agattcatat gatggagctg cacatgaatg taatttccaa tgtccagcat tctcctctgt 90000tctttatctt tagatttaaa aataatgttt ctatgaactt attaaaattc tagaatacta 90060tgaatctact gggtcttttc acatcctttt gctactagta gaaaaaagaa tagtaataat 90120tttcagaggc tactgtccag tatgtgacat aaattgtctc ccatgtttct ctgctcatgc 90180aattactgag tatgatttat tttattttaa tttcagcacc acctgagaaa agccctgtgg 90240tccaggattg ctaccatggt gatggacgga gttatcgagg catatcctcc accactgtca 90300caggaaggac ctgtcaatct tggtcatcta tgataccaca ctggcatcag aggaccccag 90360aaaactaccc aaatgcgtat gtatttgatt aaaaccataa gaggagcaac agccaactca 90420aatattggtt agaagaccca tgctttaagc tcacttccta gggacaaatt tctcttagac 90480tcacattttg gcaaaatgtc tcaggacctt tgcttttgag caaagagtct aagagaagag 90540aaattttagg cctgctattt ttcctaatag ttttatggaa ggagtagaat atacggaagt 90600ggcgaagtca tattaatgta aagctcagaa gataaatgac caaagcttaa acacagcacc 90660attccacaat gcccactaaa aatcaatgtc atctttcact cgtgcaattc tgtcattcta 90720aatttcaatt cccgaaggtt tgtttgccat ttttgtcatg ggtaataagt aaaaaaaaaa 90780aaattaagat gtgtatatat atatatatat atatatatat acacacacac acacacacac 90840aaacatctga atatttatat atatgtctga atatttatat acttgtgtat aaaacttata 90900tttaaatttt tgcataaatt tatatatttt taatatttca ttaaaaatta tattgtttca 90960ctatgtatgt ctgagtattt ttatatattt taatataaca ttttaaatat ttatatataa 91020atattcaggt atgtaactga atattcattt acacacacaa atatatgtgt gcatgtgtgt 91080atatatatat atacccatat atatatatat atatatatat acatatatat atatatatat 91140atatgtatat atatatatat atatatatat acacacacac acacacacac atacatacag 91200gtataaacac actgggcctg aagcaccagt ggtctgaaag gacatgtgtt gccaggactt 91260gaagagcaaa agcaggaagg cggatgagag tcaggaggta cacaaacgct gaaaagtaaa 91320atggacaagt acatggacaa aaagcaggta taagcataac agccttttgg aagtaaatga 91380ctataaaata tatgaaaata ctgttttcac aagttgcaca acagatagta gtgtattgag 91440ataatttaga acagaaaaca aatgtgatca accccataag tgtgctgtat ttcatcatgg 91500attgaaggaa aaagagatgg agcccaagaa gaccacagca gtcttgatga actgagagac 91560accagagttt gggattacaa aggcagctgg gattttctac acttggtaat aatgagaaag 91620aatttgtgga gataaagagc tacagtcatg tacctagaag tcacctcagt gtaatataaa 91680tctgcatatg cacagggagt gattccacaa tgaaagtagg acaaagaaca gctactgggg 91740aaagaataac tacaagggaa caatgagttc aatggagatg gcagagctca caaagcactg 91800ggggatattt gagttcttac cagctagaaa agagacctca ttgcaaatct tgggcattca 91860gtagagaccc cagaaaagcc actctttgga aacagagttg atgtatttta agagcaaaat 91920ctactccaca aaaatcctag caaaattgaa aagcaagtca gaaagaccaa aatcctctca 91980acataaatta gttgcccatc agaagaaagc ttaacctctt cataggtaaa caataaaatc 92040aaattgctca gttatctggc atccacaata tgtgacataa atttaaaaat ttactagaca 92100tacaagaagc atttagtgtg atccataacc aggagaaaaa tcattcaata caaatagacc 92160cagaaatgac agaaatgata gaattagcaa aaacatttaa aatatacata tgatcatttg 92220atcttgtgat cagatatcac aagagaagaa agagatactt gaacagaaaa aatgcctgaa 92280gcaatgatgg ctgaaaactt tccaaatatg aagaaaaaaa agctcacaga ttcaagaaaa 92340ctaatcaatc agaaatatga ttttgaaaag taaaaatgta tgatttactt tggcaaatct 92400tcttggttaa attgtctaaa atcaaagaaa gctaggaaaa ttttataagc cagaggaaaa 92460aagattgttt atataaagga acagttacac aaatgactga tgccttctca tcagaaacaa 92520tgaaagtcag aaacaataaa gtaacatctt taaagtaata gaagaaaaac ccaagaggtg 92580agggatcgtg gcagacagga ggcaggacta gattgcagct ctggacagag cagcatgcag 92640aggctcatat tgtgaatttt agccccatat tgactgcaag aacagaccag caatcctgag 92700aggacccaca gaccgtgtga aggaagcaga ctgctcctgc aggataaggg agacacccca 92760aatactgtga gttccccaac tgcagaagtg gaaaagggag gccttactcc ctcaaacaca 92820ccccacaact ggagaagctg aaagtctgtt tgcaggagaa gttcccaact ttacctgggc 92880ctcagtaaat ttagagagct gagccaagca aaatataggg gtagaggaag cagcagagaa 92940gacctcagag cttgctggat ccccaagcag ctcattcctg cctggcacca cagagatcca 93000tcagaagtgt ggccaaagga acagagggta aaactccaca tggaggactg ctctacctga 93060actttctaac aatttgaaca gggggagaag cctcctggcc agaacttggg ggagggcatg 93120aatctggttt gcagacttca caggtggggg aaggactaaa gcccttttct ttcacagctg 93180ggaggtggaa agcctcaggc aagttttcaa gcctgacttt ccccccacct ggaaacagac 93240ttggagctgt tgcggggttg ggggcatggt gggagtaaga ccagcccttc agtttgcatg 93300ggtgctgggt gaggcctgtg actgacagct tccctccact tccccgacaa ctcagatgac 93360tcagcagagg cagccataat cctcctaggt acacaactcc agtgacctgg gaacttcacc 93420cccacaccat acagaagctt cagtaagacg tgcccaagga aagtctgagc tcagacacgc 93480ctagtcccac ccccaactga tggtccttcc ctacccaccc tggtagcaga agacaaagag 93540catataatct ttggagttct agggcccacc cacctctagt ccctctccac actagtatag 93600ctgatgcagg aggccaacca gcacaaaaat agagcattaa accaccaaag ctaggaaccc 93660ctatggagtc cattgcaccc tcctccacct ccaccagaac aggcactggt atccacagct 93720gagagaccca tagatggttc acatcacagg actctgtaca gacagtcccc agtaccagcc 93780cagagctggg tagacttgct aggtggcaag acccagaaga caggcaataa tcactgcagt 93840tcagctcaca ggaagccaca tccataggaa aagagggaga gtactacatc aagggaacac 93900cccatgggat aaaaacatct gaacaacagc cttcagccct accttccctc tgacacagtc 93960tacccaaatg agaaggaacc agaaaaccaa ccctggtaat atgacaaaac aaggctcatc 94020acactcccag ttcaccagca atggatccaa accaagaaga aatccctgat ttacctgaaa 94080gagaattcag gaggttagtt attaagctaa tcagggaggg accagagaaa ggcaaagccc 94140aatgcaagga aatccaaaaa aaaaaaggta taagaagtaa aaggtgaaat attcaacaaa 94200atagatagct taataaaaaa acaataaaaa attcagtaga ctttggacac acctttggaa 94260atgtgacatg ctctggaaag tctcagcaat agaactgaac aagtagaaaa aataaattca 94320gagctcaaag acaaggactt caaattaacc caatccaaca aagacaaaga ataaaggata 94380agaaaatatg aacaaagcct tcaagatgtc tgggattatg ttaaatgacc aaatataaga 94440ataatcgtgg ctcctgagga aaaagacaat actaaaagct tggaaaacat atttggggga 94500ataactgggg aaaacttacc tggccttgct ggacacctag acatgcaaat acaagaaaca 94560caaagaacat gtaaatacaa gcagcacaaa gaacacctgg gaaattcatc acaaaaagat 94620cttagcctag gcacattctc atcaggttat gcaaagttaa gacgaaggca agaatcttaa 94680gagctgtgag acagaagcac caggtaatgt ataaaggaaa ccctatcaga ttaacagcca 94740gtttttcagc aggaactgta caagctataa aggattggag ccctatcata gcctcctcaa 94800acaaaacaat tatcagtcaa gaattttgta tccagcgaaa gtaagcatca tatatgaagg 94860aaagatacag tcgtttttgg acaaacaaat gctaagagaa ttcaccatta ccaagtcacc 94920actagaagaa ctgctaaaag gagctctaaa tcttgaaaca aatcctagaa acacatgaaa 94980acagaatctc tttaaagcat aaatcacaca ggacctataa aacaaaagta caagttaaaa 95040aacaaaaaca aaaaacaaaa ccaaagtacg gaggcaataa agaatatgat gaatgcagtg 95100gcacctcaca tttcaatgct aaaattgaat ctaaatggcc taaatgctcc acttaaagga 95160tacaaaaaga gttggtggct ggcaagatgg ctgaatagga acagctccag tctgccgctc 95220cccgtgagat caacacatag ggtgggtcat ttctgcattt ccaaccaagg tacccggctc 95280atctcattgg gactggttag acagtgggtg cagcccacag agggtgacct gaagcagggt 95340ggggtgtcac ctcacctggg aagtggaagg ggtcagggaa ctccctcccc tagccaaagg 95400aagccgtgag ggactgtgcc gtgaagacca gtgcattctg gcacaaatac tatgcttttc 95460ccacggtctt tgcaacctga agaccaggag attcccttgg gtgcctacac caccagggcc 95520ctggatttca agcccaaaac tgggctggca tttgggcaga cactaagcta gctgcaggag 95580ttttttttca taccccagtg gtccctggaa tgccagcaag acagaaccat tcacccccgt 95640gaagaaaggg ctgaagccag ggagctaagt ggtctttctc agtggatccc acccccatgg 95700agcccagcaa gctaagctcc actggcttga aattcttgct gccagcacag cagtctgaag 95760ttgacctggg acgctcaagc ttggtgggag gaggggtatc cacaaatact ggggcttgag 95820taggaggttt tcccctcaca gtgtaagcaa aaccgctagg aagtttgaac tgggcagggt 95880gcactgcagc ttggcaaagc cattgtagca agagtgcctc tctagattcc tcctctctgg 95940gcagggcatc tctgaaagaa aggcagcagc cccagtcaga agcttataga taaaactccc 96000atctccctgg gacagagcaa ctggaggaag gggtggctgt gagtgcagct ccagcagact 96060tagtttcctg cctgccagct ctgaaaagag caccagatcc cccaacacag cactagagct 96120ctgataaggg acagactgcc tcctcaagtg ggtcctggtt tcagaagata ataagaaact 96180cctctgagct aaaggagcat gttctaacac aatgcaagga agctaagaac cttgaaaaag 96240gtcagaggaa ttgctaacta cagtaagcag tttagagaag aacataaatg accttaggga 96300gctgaaaaac acagcacgag aacttcatga cacatacaca agtatcaata gcaaaatcga 96360tcaagtggaa gaaaggatat cagagattga aaatcaactt aatgaagtaa agcgtgaaaa 96420caagattaag gaataaagaa tgaaaaggaa tgaacaaatc ctccaagtat gggactatgt 96480gaaaagattg aacctacgtt tgattggtgt acctgaaagt gatgggagaa tggaaccaag 96540ttggaaaaca ctcttcagga tattatccag gagaacttcc ccaacctagc aagacaggcc 96600aacattcaaa ttaaggaaat acagagaata ccacattcaa attcaggaaa tacagagaac 96660accacaaaga tactcctcaa gaagagcaac ctgaagacac ataatcgtca gattcaccaa 96720ggttgaaatg aaggaaaaaa atgttgaggg cagccagaga gaaagtttgg gttacccaca 96780aagggaaccc catcagacta acagtggatc ttcctgcaga aactctacaa gccagaagag 96840agtgggaggc caatattcaa cattcttttt tactattatt atactttaag ttctagggta 96900catgtgcaca aggtgcaggt ttgttacata tgtatacatg tgccatgttg gtgtgctgca 96960cccattaact cttcatttac attaggtata tctcctaata ctatccctcc ccactccccc 97020catcccatga caggccccgg tgtgtgatgt tccccactct gtgtccatgt actctcattg 97080ttcaattccc acctatgagt gagaacattc ggtgtttgga tttctgtcct tgtgatagtt 97140tgctgagaat gatggtttcc agcttcatcc acatccctac aaaggacatg aagtcatcct 97200tctttatggc tgcatagtat tccatggtgt atatgtgcca cattttctta atccagtcta 97260ccattgatgg acgtttgtgt tggttccaag tctttgctat tgtgaatagt gccgcaataa 97320acatatgtgt gcatgtgtct ttatagcagc atgatttata atcctttaga tatatatcca 97380gtaattgtat ggctgtgtca aatggtattt ctagttctaa atccttgagg aatcaccgca 97440ctgtcttcca caatggttga actagtttac agtcccacca ccagtgtaaa aatgttccta 97500tttctccaca tcctctctag catctgttgt ttcctgactt tttaatgatc accattctaa 97560ctggtatgag atggtatctc attgtggttt tgatttgcat ttctctgatg gccagtgatg 97620gtgagcactt tttcatgtgt ctcttgactg cataaaagtt ttcttttgag aattgtctgt 97680taatatcctt tgccaacttt ttgatggggt tgtttgattt tttttcttgt aaatttgttt 97740atgttctttg tagattctgg atattagccc tttgtcagat gggtagattg taaaaatttt 97800ctcccattct gtagcttgcc tgttcattct gagggtagtt tcttttgctg tgcagaagct 97860ctttagttta attagatccc attggtcaat tttggctttt gttgctattg cttttggtga 97920tttagtcatg aagtccttgc ccatgcctat gtcctgaatg gtattgctta ggttttcttc 97980tagggtttat atggttttag gtctaacatt taagtcttta atccatcttg aattaatttt 98040tatataaggt gtaaggaagg gatccagttt cagctttcta catatggcta ggcagttttc 98100ccagcaccat gtattaaata gggaaacctt tccctatttc ttgtttttgt caggtttgtc 98160atagatcaga tggttgtaga tgtgtggtat tatttctgag ggctctgttc tgttccattg 98220gtctatatct ctgttttggt accagtacca tgctgttttg gttactgtag ccttgtaatg 98280tagtttgaag tcaggcagag tgatgcctcc agctttgctt ttttggctta ggattgtctt 98340ggcaatgcat gctctttttt gttccatatg aactttaaag tagttttttc caattctgtg 98400aagaaagtca ttggtagctt gatggggatg gcattgaatc tataaattac cttaggcagt 98460atggccattt tcacaatatt gattcttcct atccatgagc atggaatgtt cttccatttg 98520tttgtgtcct cttttatttc attaagcagt ggtttgtagt tctccttgaa gaggtccttc 98580ccatcccttg taagttggat tcctaggtat tttattctct ttgaagcaat tgtgaatggg 98640agttcatcca tgtccctaca aaggacatga agtcatgtat gggaatgctt gtgatttttg 98700cacattgatt ttgtatcttg agactttgct gaagttgctt atcagcttaa ggagattttg 98760gtctgagaag atggggtttt ctaaatatac aatcatgtca tctgcaaaca gggacaattt 98820aacttcctct tttcctaact gaataccctt tatttccttc tcctgcctaa ttgccctggc 98880cagaacttcc aacactatgt tgaataggag tggtgagaga gggcatccct gtcttgtgcc 98940agttttcaaa gggaatgctt ccagtttttg cccattcagt atgatattgg ctatgggttt 99000gtcataaata gctcttatta ttttgagata tgtcccatca atacatagtt tattgagagt 99060tcagcatgga gagctgttga attttgtcaa aggccttttc tgcatctatt gagataatca 99120tgtggttttt gtctttggtt ctgtttatat gatggattac atttattgat ttgcatatgt 99180tgaaccagcc ttgcatccca gggataaagc caacttgatc atggtggata agctttttga 99240tgtgctgctg gattcggttt gccagtattt tattgaggat ttttgcatca atgttcatca 99300tggatgttgg tctaaaattc tcatttttgt tgtgtctctg ccaggatttg gtatcaggat

99360gatgctggcc tcataaaatg agttagggag gattccctct ttttctatga ttggaatagt 99420ttcagaagaa ttggtaccag ctcctctttg tatctgtggt agaattcggc tatgaatctc 99480tcctggactt tttttggttg gtaggctctt aattattgcc tcaatttcag agcctgttat 99540tggtctattc aaggattcaa tttctttctg gtttagtctt ggtagggtgt atgtgtccag 99600gaatttttcc atttcttcta gattttctag tttatttgca cagaggtgtt tataatattc 99660tctgatggta gtttgtattt ctgtgggatt ggtagtgata tcccctttat cattttttat 99720tgcatctatt tgattcttct ctcttttctt ctttattagt cttgctagtg gtctatcaat 99780tttgttgatc ttttcaaaaa accagctcct ggattcattg atgttttgaa ggtttttttg 99840tgtctctatc tccttcagtt ctgctctggt cttagttatt tcttgccttc tgctagcttt 99900ttaatgtgtt tgctcttgct tctctagttc ttttaatggt gatgttaggg tgtcaatttt 99960agatctttcc tgctttctct tgtgggcatt tagtgctgta aatctccccc tacacactgc 100020tttaaatgtg tcccagagat tctggtatgt tgtgtctttg ttgtcattgg tttcaaagaa 100080tatctttatt tctgccttca tttcgttaca tacccagtag tcactcaggt gcaggttgtt 100140cagtttccat atagttgagc agtttttaat gagtttctta atcctgagtc ctagtttgat 100200tgcactgtgg tctgagagac agtttgttat aatttctgtt cttttacatt tgctgaggaa 100260tgcctcactt ccaactatct ggtcaatttc agaataagtg cgatgtggtg ctgagaagaa 100320tgtatattct gttgatttgg ggtggagagt tctgtagatg tctattaggt ctgcttggtg 100380cagagctgag ttcaattcct ggatatccat gttaactttc tgtctcattg atctgtctaa 100440tgttgacagt ggggtgttaa agtctcccat tattattgtg tgggagtcta agtctctttg 100500taggtctcta aggacttgct ttatgaatct aggtgctcct gtattgggtg catatatatt 100560taggatagtt agctcttctt gttaaattgg tccctttacc attatgtaat ggccttcttt 100620gtctcttttg atctttgtta gtttaaagtc tgttttatca gagactagga ttgcaacccc 100680tgcttttttt gttgttttcc atttgcttgg tagatcttcc tccatccctt tattttgagc 100740ctatgtgtgt ctctgcacgt gagatgtgtc ttcagaatac agcacactga tggatcttga 100800ctctttatcc aattttccag tctgtgtctt ttaattggag catttagccc atttacattt 100860aaggttaata tttttatgtg tgaatttgat cctgtcatca tgatgttcgc tggttatttt 100920gctcattagt tgatgcagtt tcttcctagc atcgatggtt tttacaattt ggcatgtttg 100980tgcagtggct gataccgatt gtttctttcc atgtttagtg cttccttcag gagctcttgt 101040aaggcaggcc tggtggtgac aaaatctctc agcatttgct tgtctgtaaa ggattttatt 101100tctccttcac ttatgaagct tagtttggct ggatatgata ttctcagttg aaaattcttt 101160tctttaagaa tgttgaatat tggctgccac tctcttctgg cttgtagagt ttctgctgag 101220agatctgctg ttagtctgat gggcttccct ttgtgggtaa cccgaccttt ctggtgaatc 101280tgacaattat gtgtcttgga gttactcttc tcgaggagta tttttgtggc attctctgta 101340tttcctgaat ttgaatgttg gcctgccttt gtaggttggg gaagttctcc tggataatat 101400cctgaagagt gttttccaac ttggttccat tctcctcgtc actttcaggt acaccaagca 101460gatgtagatt tggtcttttc acatagtccc atatttattg gaggctttgt tcatttcttt 101520ttactccttt ttttctctaa acttctcttc tcgcttcatt tcattcattt gatctttaat 101580cactgatacc ctttcttcca cttgattgaa tcaactactg aaacttgttc atgtgtcacg 101640tagttctcgt gccatggttt tcagctccat tagatcattt aaggtcttct ctatgctgtt 101700tattttagtc tgccattcat ctaaactttt tcaaggtttt tagcttcttt gcaatgggtt 101760cgaacatcct tctttagctc ggagaaattt gttattacag atcgtctgaa gccttcttct 101820ctcaactcat caaagtcatt ctctgtccag ctttgttctg ttgctcgtga ggagctgcgt 101880tccttcggag gagaagaggc accctgattt ttagaatttt cagctgttct gctctggttt 101940ctccccatct ttgtggttta tctacctttg gttcttgatg atggtgatgt acagatgggg 102000ttttggtgtg gatgtctttt ctgtttgtta gttttccttc taacagtcag gaccctcagc 102060tgcaggtctg ttggagtttg ctggaggtcc actccagtcc ctgtttgcct gggtattacc 102120agtggaggct gcagaacagc aaatattaca gaacagcaaa tgttgctgcc tgattcttcc 102180tctggaagct tcatctcaga ggggcaccca gctgtatgag gtgtcagttg gcccctactg 102240ggaggtgtcc cccagttagg ctactcgggg gtcacggacc cacttgagga ggcagtctgt 102300ccattctcag atctcaaact ctctgctggg agaaccacta ctctcttcaa agctgtcaga 102360cagggatgtt taagtctgca gaagtttctg ctgccttttg ttcagctatg ccctgccccc 102420agaggtggag tctacagagg caggcaggtc tccttgagct gtggtgggct ccacccagtt 102480tgagcttcct ggtcgctttg tttacctact caagtctcag caatggcaga cgcccctccc 102540ccagctttgc tgccgccttg cagttcggtc tcagactact gtgctagcag ttcaatctca 102600gactgctgta ctagcagtga gcaaggctct gtgggcatgg gaccctctga gccatgtgca 102660ggatataatc tcctggtgtg ccgtttgcta agaccattgg aaaagtgcaa tattagggtg 102720ggagtgtccc gattttccgg gtacatctgt catggcttcc cttggctagg aaagggaatt 102780ccctgacccc ttacacttcc cgggtgaggc aatatcccgc cttgcttcgg ctcactctcc 102840gtgggctgca cccactgtct gacaagcccc ggtgagatga acccagtacc tcagctggaa 102900atgcagaaac cacccatctt ctgctttgct catgctggga actgtggact ggagctgttc 102960ctattcggcc atcttgaaac ctcccctctc tcacgatcac aaggtcccac aataggccgt 103020ctgcaggctg aggagcaaga aaagccagtc tgaattccaa aactgaagaa attggagtct 103080gatgttcaag ggcaggaaac atccagtgcc aaagaaagat gtagaatatt caacattctt 103140aaagaaaata attttcaacc tagaatttca tatccagcca aactaagctt tataacaaag 103200gagaagtaaa atcctttaca aacaagcaaa tgctgaggaa ttttgtcaac accaggcctg 103260ccttacaaga ggtcctgaag aaaacactaa atatggaaag gaaaaaccag taacagctac 103320tgcaaaaaca taccaaattg taaacaccat caacactata aagaaactgc atcaactaat 103380gggcaaaata gccagctagc atcataatga caggatcaaa ttcacacata acaatattaa 103440ccttaaatgt aaatgggcta aatgccccaa ttaaaagaca cagactggga aattgaataa 103500agagtcaaga cccattggtt tgctgtgttc agaagaccca tctcagggtg aaaagacata 103560catgggctca aaataaagaa atgaaggaat atttaccaag caaatggaaa gaaaaaaaaa 103620gcagcggttg caatcttagt ctttgatgaa acagacttta aaccatcaaa gatcaaaaga 103680gacaaaggag ggcattacct aatggtaaaa gtatcaatgc aacaagaaga tctgactgtc 103740ctacttatat atgcacccaa tacaggagca cccagattaa taaagcaagt tcttagagac 103800ctacaaagag acttagactt ccacacaaaa atagtgggag actttaacac cccacagcca 103860atattagatc gacgtgacag aaaattaaca aggatattca ggacgtgaat tcagctctgg 103920accaagctga cctaatagac atctacagaa ctcgacacca caaatcaaca gaatatacat 103980tcttctcagc accacattgc acttattcta aaattgacca cataattgga agtaaaacac 104040ttctcagcaa atgccgtaga atggaaatca taacaaacag tctctcagac caaagtgcaa 104100tcaaactaga actcaggatt aataaactca ctcaaaacca cacaactata tggaaactga 104160acaacctgct cctgaattac tactgggtaa ataacaaaat taaggcagaa gtagataagt 104220tcttagaaac caaagagaac aaagacacaa tgtgccagaa tctctggtac acagctaaag 104280ccatgtttag agggaaattt atagcactaa atgcccacag gagaaagcgg gaaagatcta 104340aaatcaacac cctaacatca caattcaaag aaccagagaa gcaagagcaa acaaatacaa 104400aagctagcag aagacaagaa ataactaaga tcagagcaga actgaagggg ataaagacac 104460gaaaaccctt taaaaaatta ataaatccaa gagctggttt tttgaaaaga ttaacaaaat 104520acatagaagc ctagccagac taataaagaa gaaaatagag aagaatcaaa tagacacaat 104580aaagaataat aaaggggata tcaccaatga tgccacagaa atacaaacta ccatcagaga 104640atactttaaa cacctctatg caaataaaat agaaaatcta aaagaaatgg ataaattcct 104700ggacacatac accctcccaa gactaaacca ggaagaagtc aaatccctga atagaccaat 104760aacaagttct gaaatcgagg cagtaattaa tagcttacca accaaaaaaa gcccagacca 104820gagggattaa cagtcaaatc ctaacagagg tacaaagaag agctagtact attccttctg 104880aaactattcc acacaataga aaaagaggga ctcctgccta actcatttta tgaggccagc 104940atcattctga taccaaaacc tggcagagac acaacaagaa aagaaaattt caggccaaca 105000tccctgatga acatcaatgt gaaaatcctc aataaaatac tggcaaactg aatccagcag 105060cacatcaaaa agcttatcca ccatgatcaa gttggcttca tccctgggat gcaaggctgg 105120ttcaacatat tcaaatcaat aaacataatc catcacataa acagaaccaa tgacaaaaac 105180cgtatgatta tcgcaataga cgcagaaaag gcctttgata aaattcaata cccaatcatg 105240ctaaaaactc ttaataaact aggtattgat ggagcatgtc tcaaaataat aagagctact 105300tatgacaaat gcatagccaa tatcatactg aatgagcaga agctggaagc attccctttg 105360aaaaccagca caagacaagg atgccctctc tcaccactcc tattcaacat agtattggaa 105420attctgtcca gggcaatcag gcaagagaaa gaaataaagg tattcaagtg ggaagagagg 105480gagtcaaatt atttctcttt gcagatgaca tgattgtata tttagaaaac tctatcatct 105540cagcccaaaa tctccttaag ctgataagca acttcagcaa agtctcagga tacaaaatca 105600atgtgcaaaa atcacaagca ttcctataca ccaataagag acacagagcc aaatcctgag 105660tgaattccca ttcacaattg ctacaaagag aataaaatat acctaggaat ccaacttaca 105720agggatgtga aggacctctt caaggagaac tacaaaccac tgctcaagga aataagatag 105780gacacaaaca aatggaaaaa cattccatgc taatggattg gaagaatcaa tattgtgaaa 105840attgccatac tgcccaaagt gatttataga ttcaatgtta tccccatcaa gctaccattg 105900atttcttcac ataattagaa aaaactactt tcaatttcat atggaataga aaaagggcct 105960gtatatccaa gacaacctaa gcaaaaagaa caaagctgga ggcatcatgc tatctgactt 106020caaaatatac tacaaggcta cagtaacaaa aacagcatgg tatggtactg gtaccaaaac 106080agatatatag accaatagaa cagaacagag gcctcagaaa taacaccaca catctacaac 106140tattggatct ttgacaaact ggacaaaaat aagcaatggg gaaaggattc cctatttaat 106200aaatggtgtt gggaaaactg gctagccata tgcagaaaac tgaaactgga tcccttcctt 106260acaccttata cacaaattaa ctcaagatag attaaagaat taaatgtaag acctaaaacc 106320ataaaaaccc tagaagacac tttgggaggc cgaggtggat ggatcacgag gtcaggagat 106380cgagaccatc ttggctaaca cagtgaaagc ccatctctac taaaaataca aaaaattagc 106440tgggtgtggt cgtgggcacc tgtagtccca gctacttggg aggctgaggc aggagaatgg 106500catgagctga ggaggttgag cttgcagcaa gccaagattg tgccactgca ctccagcctg 106560ggcaacagag tgagactcca tcaaaaaaac aaaaacaaaa acaaaaaatc aaaccctaga 106620agaaaacata ggcaatacca ttcaggacat aggcatggga gaagacttca tgactaaaac 106680agcaaaacca atggcaacaa aagccaaaat ttacaaatca gatctaatta aaataaagag 106740cttctgcaca gcaaaaaact ctcatcagag tgaaaaagca acctatggag aaaaattctg 106800tggtctagcc atctgacaaa gggctaatgt ttagaatgta caagcaactt aaacaaatgt 106860acaagaaaaa aaaaacaacc ccatcaaaaa gtgggcaaag gatatgaaca gacacttctg 106920acaggaagac ctttatgtgg ctgacaaaca tgaaaaaagc tcatcatcac tgttaattag 106980agaaatgcaa atcgaaacca caatgagata ccatctcatg cccgttagaa tggcgatcat 107040taaaaagtca ggaaacaaca gatgctgaag aggatgtgtg gagaaagagg aacacattta 107100cactgttggt gggagtgtaa attagttcaa ccattgtgga agacagtgcg gtgattcctc 107160aaggatctag aaccagaagt accatttgac ccagcaatcc cattactggg tatataccca 107220aaggattata aatcattcta caataaagac acatgcacac gtatgtttat tgtagcacta 107280ttcacaatag caaagacttg gaaccaactg aaatgcccat caatgataga ctggataaag 107340aaaatgtggc acatatacac tgtggaatac tatgcagcca taaaacagga tgagttcatg 107400tcttttgcag ggacatggat gaagctggaa accatcattc tcagcaaact aacacaagaa 107460cagaaaacca aacaccatat gttctcactc ataagtgtga gttgaacaat gagaacacat 107520ggacacagga aggggaacat cacacacagg ggcctgttgg ggagttgagg ctaggggagg 107580gattggatta ggagaaatac ctaatgtaga tgatgggttg ctgggtgcag caaaccacca 107640tgacacgtgt atacctatgt aacaaaccca cacattctac acatgtatct cagaacttaa 107700agtataataa taataagata cagaactgca gaatgaataa gaactcacca accatctgct 107760gccttcagga gactcattta agacataagg actcacataa acttaaagta aatgggtgga 107820aataataata agtggtgtca ctgatgtgga ggtagattat aaaactctta tcatatgctg 107880gtggaagatc aaaatgataa aacgaattaa aaaatcagtc agatggtttc ttaaaaagtt 107940ccatcaatat gcctctatct tacaaacctg caattctatt cctgaatctt tatcccaagg 108000aaatgaaaaa gtaagtccac aaagagttct atatgaatat ttataggagc tttatttatt 108060ataattcaaa ctgtaaaaat aatttcaatg ttcatcaata acaaaatgaa aaaataattt 108120gcaacctact ggtacacttg aatactattc agcactgagt atcttaaata gcatggatgg 108180agctcaaaaa tatactcagg aaagaagcca tgtatattct gtatgagttc atttacatga 108240gatcatttac atttcctcca aaagaggaaa aactaatttc tgttgaaaga aaccaatgta 108300tttgcctctg gcagtggtaa gggggtagca cagattaatt gggtagggac tcaagagagt 108360ttctggggtc acagaaatgt tccgtgtggt gatgggagtt tgggctccac aggtataggt 108420gttgatccaa aatcatcaaa aaaacaacat tgcagatctg tgcatctcac tctgtgggaa 108480agtatatctc aactgtaaaa agggcagaaa ttgcttttaa acgctcagcc ttttagcaca 108540tccagttgct tggagaacca gcttactcaa atgggggtct aggctggaga ctaggtcaca 108600ggcatagagt ctctaaactt tcccatggca cataatacgt ttcaggtttt ctcagagagc 108660tgcaggttag taatctgagg attctgacaa gttgggtcaa cgttcctagg aggcatgaat 108720gggagtgcat tctctaagat ccctccaccc cagggtcctt gctttctgtg cctcttactc 108780cattgttttc tgactcctct gtagccactc gacctcttca gatcccattg tctacccagc 108840catcgccctt tatgacttgg gtcccactgt tctttcatct catcctccat tccctcagtt 108900tcggagtggc tgccgctagc agaggatgga ctgagagcag gagaggtggt cctgcccagg 108960aacccatcct agagaaatgg catcctgtct gggagctagt tttttagggc aggttttata 109020agtcttgtaa agccagacac acttgatcta cctggtatgt tatttacagt aatactattt 109080tcataattgc ttttcactct aaaagtagag ccttttagct acactgtgag taaataaagg 109140ggctggcctg ggaatggtat catgttggat gttgtttctt ccctgaagta atatatatca 109200gttacaattt acatgttact gcagagtcct agagagagac acagagaatg agacagatac 109260caatacattt ttatgtgcat taaaaaaatc taaggccagg cgcagtggct cacacctgta 109320atcccagcac tttgggaggc cgaggtgggt ggatcacgag gtcaggagat tgagaccatc 109380ctggctaaca cggtgaaacc ctgtctctac taaaaataca aaaaattagc caggcgtggt 109440ggcgggcgcc tgtagtccca gctactcagg agactgaggc aggagaatgg cttgaaccca 109500ggaggcagac cttgcagtga gccgagattg cgccactgca ctccagtctg ggcgacagag 109560cgagactccg tcacaaaaaa aaaaaaaaat ctaaaatgca ctcttcaaaa tctatgtcat 109620ttattctgga ggaatgcagt tggcagaagg aggaagatat tccgaatttt tcttgtatac 109680atttatgtat gatctcagtt tttttatgga tcatagacca attttgatat tttaaaataa 109740aaattataat ctatcttgga aatttacatg gttctttaga acttgaggac cgtttttgct 109800tttcggaata ttattgtacc taaaatggga atattacaac gtcacttttt aacactttgt 109860tataacaaag tttagacagc gctgggtgcc cctgaatttt ttcccgcctc ttgtgacctg 109920tgttgttttg gaatttgcag tggcctgacc gagaactact gcaggaatcc agattctggg 109980aaacaaccct ggtgttacac aaccgatccg tgtgtgaggt gggagtactg caatctgaca 110040caatgctcag aaacagaatc aggtgtccta gagactccca ctgttgttcc agttccaagc 110100atggaggctc attctgaagc aggtaagaag tctgtggcca gatatctaca catttgaaca 110160ttgggatgaa aagagatgga aaatctgact gatgcagaag ccttccatgc tacacagaaa 110220cttgagggta tggcaggtgg aaagaagcct cagcactctc tctggtggag caatttttgg 110280cgcaacgtgc gtgggcggtg acttcaggaa tggtgcaaac ccacctgggc acttgactta 110340ccactcactt tgttatgaaa ggggttatct cggtgttcca gacaaaattc caattctaac 110400atcaggccaa atttgtgcca aatttcacac tagtgagtgt ttccaggcat ttattaaaat 110460ggacagtgtt cattgcaatc ttcagcattg cagttgctga ggtatgtggc cgctgagttt 110520gtcatcctgg ggaaacctaa tatgatgata tttattccat ctaatcctgg ggctatttgg 110580cagtaaatac cacagaatac actatttctc tggcttattt cagtcttagg taggctctgc 110640acacctatgc ttggaaggca ggaatttctt ggtgttcttg tgccttcttc tcatggaacg 110700tgcatctttg gtgtgtgttg agaggaaggg tagtagactt ctgctttgtt gcaatgcagg 110760atgctggaac aagaggattc cctgtctcta ctgtaaggga ataagatttt agcctccatc 110820cttctctaag aagcaatgtg tctttgcctc caagtactag atgcaggacc atgaactgcc 110880ccgtccacca gaagcttaag gctttggctt ttcaggagca atcatctagg gaactgtgca 110940gggttttcat gtctgtcccc tactgacagc caatcaccat acagcctgca taacctaatc 111000catcatcgtc tggtttcctg cctcattgtt ttcatgaaca accagtagag agccatacga 111060aagagcttgc acatgagtct ttgttccaat tgtaagagca ctgataggtc cttttcccac 111120caggttttga atataaaatt tctaagaact tattaaaata ttagaatgtt attaatctat 111180tgtttttgct tcagcatgtc cttctgcttg tgagtatact aaagagaaca gtcataattc 111240tgaaactact gtcctgtttg tgtcataaat tgcttcacat gtttctgcat actagtagtt 111300actcagcttg attttgtcta ttttcagcac caactgagca aacccctgtg gtccggcagt 111360gctaccatgg taatggccag agttatcgag gcacattctc caccactgtc acaggaagga 111420catgtcaatc ttggtcatcc atgacaccac accggcatca gaggacccca gaaaactacc 111480caaatgagta tgtctttgat gttacttgta agaggagcaa cagccaactt aagttcctcc 111540tagaagagcc ttgcttcaag ctaacttgtt aggacaaatt tcccttagac ccagaaggtg 111600tgtcaaaatg tccagacaac tttgcttttg atcaaagagt ctgagagaat aggtatttta 111660ggcttgctat cttttctaat agtctgatgg aagcagaagg ctacatggag ctgatgaggt 111720ctttttaata taaagctcaa gagatcaaat gatcaaatac ttagagtgcc attctacaag 111780gctcataaaa gatcaatgca ctctttcacc catgcaattc tatcattcta acctcccttc 111840tctgaaatga aggctttttg ccatttttgt catgggtcac aagtaaataa ttcacatgta 111900tatgagtata tatataacca ggtgtgttta ttcagactag tatgtatata tatacatata 111960tatgttcata taagttagta ttcatatata tgttcatata tatatgttca tacagactag 112020tattcatata tatatacata tatatataca cacacatata tatatatata tatatgttct 112080agggaaacat gcaaggtttt tatgtctgtc cctgactgat gaccaaatac cctatagcct 112140gcacagctgc aagctgtata gccatacaat ttgcaggaca cacacacata cacacacaca 112200cacacacaca cacacactaa catataatat aatataatat aatataatat aatataatat 112260aatataatat aattaatata tataaacctg tgtgaacaca ctgggttcta agctccagtt 112320ttctgaaggg atatgggttg ccaggagagg aagagcaaaa gcaagaatgt agatgagaat 112380taggaagtaa acagatatgg agattaaaat gggcaggtac atggacaaaa aaccaggtct 112440gacaaaaact ggctttctgc cataaatgac tataaaagat attaaaaaac actttccaca 112500tgttggacaa gagacagtac aggactgaga taatttagaa aaggaaatga atgagcgcaa 112560ctccgtaact attatgactt tcttcctgga gaaccttcct ggactgaagg gcaaggaatt 112620ggagccaaag ccaaccacag cagtcttgct gaactgagga aagagactgg agtttgggat 112680agctaagaaa atgtgtattt tctatgctag gtaataatga gaaagaattt gtggtgaaaa 112740ggagctgaag gaatatgcat ggaagtctaa tataaactgc atatgcacag ggagaaattc 112800tacaaagtgg gacagagaac cactactggg gaaaggacaa attcagggaa acagtgagct 112860caatggtgac gccagagctc acgtagcact gggggatacc ggggttctga tcagcccgag 112920gagagacacc tcattgaaca tctcgggcat tcagtagaga ccccagaaaa gtcatacttt 112980aggagtagga tttatgcctt cttagaataa agactacccc agaaacaccc tagtaaagct 113040taaaaaccaa gtctaaaagg acccaaatga tctccaagta aattaactgc ctgacagaag 113100aaaactcaac catcactgga ggtaaataac atgattacag tgctctgtaa tgttgcattc 113160acaaggagtg acatcattta aaaatttatg aggcaggaaa aagcaattag tgtgatccat 113220aactaggaga aaaaccagtc aatacaaata gaccaagaaa tagtagaaac gatggaattg 113280acaaagaaat taaaactgta tatatgataa ttgtgttcaa agatttaaag aaaacatgaa 113340catgagggaa acaaatgcag aatataaaaa aaagcaaatg cgtaaaacaa ccaaatggaa 113400attaaagaac tacaaaaaag tataacctta ataaaatact cactggatgg ccttaatatt 113460agtttataca ttacagaaga aaaagtgaac cagaagataa ctcaatgaaa gccatacaat 113520ctgtaagaca cacacacacg cacacgcgcg cgcgcgcaca cacacacaca cacagagaga 113580gagagagaga gaaagagaga gagagaaagg ctgaaaaaaa taaatagaac cttaaggata 113640tcagtgaaaa tagcaaaaga tttaatatat gggtaaagca agtcacagaa ggacgggaag 113700gagatattgg gacagaaaaa aatactcaaa gcaatgatgg ctgaagactt tacacgtatg 113760aagaaaatga taaactcaca gtcaagaagc tcaatgaatc agaaatagta tttttaaaag 113820caaaactcta tgatttactt gggtacatta tagataaatc gtccaacatc aaagataaca 113880aggataatct tataagccag aggaaaacaa tatcatttac atagagggac agtaatgaaa 113940gtgaccgatg ccttctcctt ggaaacaatg gcataacatc tttaaagtga taaagagaaa 114000taaaaacaga tcaacctagg acgacatgtc cagccaaaac aaacaaataa acaaaaaaac 114060cctttaaaat aaacgtgatg taaatacgta ttctgccacc tccagaggaa acaagcaaaa 114120aaacaaaaga atgtttccaa ggcaggcttc tgtattaaaa gattttaagg aaagttattc 114180aggtagaaga aaaataatac cagatgggaa ctttaatcca tactaagtaa tgaagagccc 114240tggaaatggc aaatggcaat gtcaatataa aatactctta tttatctaat ttttaaatgt 114300atttaaagga caatttgtga tattaattaa aataatagga atatattgtt gtttcaacgt 114360atgtagtagt aaaattcata aaaacagtag cacaaataat gcagatgata actggaagta

114420tactgttaat gagttttttg cattatccat gaagttatat aatattaata gatggttgaa 114480tgtgatagtt taaggtggga tattataaat cctaggacaa ccaaaaaaat ttaaactgag 114540aggaatggat agtaagagga atagtccttt tatgcaaaag aaggaagaaa aagaggaata 114600aagaatataa aagatatggt gtaaacagaa aatacatagc attattgtag acacaaactg 114660aactacctta tgagtatatt aaatataaaa ggattaagca ttacaaataa aaggcagaga 114720ttgtaaattg aataaaaacc acagctaagt gtgttctttt tagaataaat actctttaag 114780tgtaaagatc tactttaaac accaaaatat gaaaaaggat atataccatg aaaacctgaa 114840tcataaataa gctggagtgg tgattaatgg atgcaggcac tcctaaagac taataagtga 114900atgtggtcaa attgaagaaa caaaagtata tacgtgctca atgtgcaaaa actttttctg 114960tatacatgct atgatccttt ggaaaattaa agttttaaag caatatcact gacaatagta 115020tcaaaaccaa aaaatattta gtgataaatt tcacacacta tgctcaagga ctatacacct 115080tgcactagaa aacaatgttg aggaaagaat taaaagatct aaatatacac catgcttata 115140gattaaaaga ctccatatca gttctcgtga aattgatctt tggatgaaac ccacacccaa 115200gcactattgc aacagtcctt ttttggaaaa aaaaattgga ggacttatat accttaatat 115260aaagacttat aaaagtacag gaatcaagac atgtggtatt ggcctggccc cttggctcat 115320gcctgttacc ccaacatttt gggaggctga gtctggagga tggcttgagc ccagatgttc 115380aagaccagcc ttagcaacag agtgagaccc tctctctaca aaaaataaac aattagatcg 115440atgtgatgac ttgcacatgt agtttcagct actcggaatg ctgaggtgag aggattgctt 115500gactcaggag gtctagccat gagtgagcat tgatcatgcc tctgcattcc agcctggatg 115560atggaatgag acactgtctc aaaaaaaaaa aaaaaaaagg atatgtgtta ttggccaaaa 115620aagtatgcaa acctaaaaag ggatggccca ccaccagacc cacatacata tatggtaaat 115680ggattttccg tatagatggc aaagcaattc aatggagaca aaaatgtttt acaaaatcat 115740tctgaaccat ttggatatcc atgatacaaa acaaaagcag aacttgactt ttgcttttca 115800tctcaaatta ttttgatatc tcttccacct aagtgtcaga gctaaaactg aacctgaaat 115860atgaaagttc catgaaaaaa tataaaatct tcacaacctt ggagaaggca aacttttttg 115920aggcaggagt ctgtaaacac tcactataaa ataaaacaaa ttataatgtg ggctttcatg 115980aaaactcatg cttaccaaaa gtcattgtta agaaaataaa taggcaagta acacatgaga 116040agaaaaatgc tctctgtcca tatatctgac aaatggcttg tgtccagaat ataggaacat 116100ttctcccact cactaaacag aggacaaaca actaatgggc aacagattga ataggcattt 116160cttggggata gatagatgta cacatagcca ataagcacct gaaaaaatgt ccagtatctc 116220agccatgaaa aataaagagt tataatcatc atgagatgtc accaaacacc caatggacat 116280ggatattatt aagaagacac cacagtaact gatgtcactg atgtagagca aggatgtgaa 116340actctctcat atgctggtga aagtgcaaaa tgatacaacc acttttgaaa tcagtctgat 116400agtttctcca aaagttcaat aaatgcactt ttaccctaca aacctgcaat cctgtttgtg 116460aatatttacc ccacagaaat ggaaacataa gtccacgaag acatctccaa gaatattcat 116520agcagcttta ttttttataa ccccaaactg tagacaattt caatgtcaat caataagaaa 116580atgaataaat aatttgtgaa ctagtcatac aatggcatac tgttcagcaa taaaagggag 116640catgtttttg atactctcaa atagtatgga agatgctcaa aaatattaca ttaaagaaag 116700atgccagata acaaaaatga acattatgta tgagtctatt gatgtaaggt tccagaaagg 116760taaaactaat ttctggtgaa agaaaccaat atcatttgcc tctggccatg ggaagagagt 116820agcagagatt gattgagcag taaaacgaag tttttttctg gggtgatgta aatgtcctgt 116880attgtgattg aagtgtgagt tacacaagtg tacatgttca tcagaagtca tcaaactaca 116940tctaagatct gtgcatttga ctatacatga aaatatacct cagttgaaaa tagatcaata 117000acctccctca tatactatac ttgctaacac agccagctgc ttggagaacc agcttgctgg 117060aatggagaat ctgggcttga gactgggtca catgtataga gtctctacag agacaatgtt 117120gcattcccac ggtacataat acatttcaag gtttctcaga cagccacatg tcatgaatgt 117180gaggattctg agaggttgga gcaacattcc tgggaggaac gaaggggagc acattctcca 117240agatccccca ccaccggggt cctcaccggc tgtgcttttt tttttttttt tcttgacaga 117300gtctcgctct gtcgccaggc aggagtgtaa tggcccaatc tcggctgatt gcagcctcca 117360actccagggt tcaagagatt ctcctgcctc agcttcatga gtagctggga ctacagatgt 117420gcgccactgc gcccagctaa tttttgtatt tttagtagag acggggtttt gccatgttgg 117480ccaagatggt ctcgctctgt tgacctcgtg atccacccgc cttggcttcc caaagtgctg 117540ggattacagg cgtgagccaa agcacccagc ctgtgcctct cacttactca attgtttttc 117600tgaaccctcc atagctggtg gaccttttca gatcccatag tctagccagc cctctcactt 117660tatgccttgg gtcccactgt tccttcatct catccccctt ctgtcagtcc cgcagtggct 117720gtggccagta gaggatggac tgagagtagg agaggaggtt ctgcccagga acccatccta 117780gagaaacagc atcctgcctg ggacctagtc ttccaggtca gcttttataa gtcttttaga 117840ctcaaactca cttgacccac ctgaagtggt attgacaata atgctatttt catggttgtt 117900tttcactgta aatgcagagc cttttagcta cacgactagt acagagagta agggaggctg 117960gcctgggaat gatatcatct tggatggcat ttcctccttg gagaaatata tgttagttcc 118020aactcacatg ttactataca gtcctgtaga aagagataca gagagttaga caggtataga 118080cgcatttgta tatgcataac aatctataag acacacatca aaatccgtat accggttcct 118140ctaggggtat gtgcttggca gaaggtagaa ggagggtatt ctggttcctt tcttttgcac 118200atttatgtat gatctcagtt tttatatgga gcattgatag ggtttggcta tgtccccacc 118260caaaatctca tcttgacttg taatctctat aatcctgata atccccatgt gtcaagggca 118320ggaccaggtg gaggtaactg gatcatgggg gcagtttctc ccaggctgtt ctcatgacag 118380tgagagagtc tcctgagatc tgatggtttt gtaagtgtct ggcatttccc ctacttgcac 118440ttactctgtc ctgccgcctg tgaagaaggt gcctgtttct cccttgcctt ctgccatgac 118500tgtaaatttc cagaggcctc cccagcaatg tggaactgtg agtcaattaa aactcttttc 118560tttgtaactt acccagtctg tctcgggtat ttcctcatag caatgtgaga acgggctaat 118620acaagcatat actacttttg atattttaaa ataaaaatta tcatctatct ttgaaaggca 118680tgcacaaatg ggaagttgag gaacatttgt gttgtggcaa ttgtatgata cctttaatgg 118740gaatatttca aagacacttg ttaagacttt gttagaacaa aatgtagagg gtgctggatg 118800tccctgaata ttcttccgcc tcctgtaact tgtattgctt tggaatttcc agtggcctga 118860caatgaacta ctgcaggaat ccagatgccg atacaggccc ttggtgtttt accatggacc 118920ccagcatcag gtgggagtac tgcaacctga cgcgatgctc agacacagaa gggactgtgg 118980tcgctcctcc gactgtcatc caggttccaa gcctagggcc tccttctgaa caaggtaaga 119040agtctgtgtc ttaccttgtc tagcacatac ctctctatgt gcttggacaa cgggatgaaa 119100agacatgaaa aaccacactg atgcagaagc ctttagtgct acacgggagc tcgagtgttg 119160gttgaggttc tgccatgacc aaggaagtct cagtgccgtc cctgggaaag ccagagctgt 119220gatttttggc acaacttgtg ggagtagtga ctttaggact ggcgcaaaac ctccagggtg 119280ctcaacttaa ccactcacct tattctaaaa tgggttattt cagtgtccca gtcaaattcc 119340tattctaaca tgctgtcaac tgtgtgatta tttccaagcc aataagcatt tccagtaatt 119400tcttaaaata gtgttcattg cagtcttcag cgttgtggct cctgagggat gtggcccctg 119460attctgtcgt cctagagaag cctgacatga ctgcattgat tctgtatcgt cctgggtcta 119520tgtggctgcc tggctgtctg taatcatctg ttttattttt atttttttct acagactgta 119580tgtttgggaa tgggaaagga taccggggca agaaggcaac cactgttact gggacgccat 119640gccaggaatg ggctgcccag gagccccata gacacagcac gttcattcca gggacaaata 119700aatgggcagg tctggaaaaa aatgtaagcc actttgattt ggactctttt tccctttgct 119760gacaaatctt ttcaaacaga agaggggcag aggaaaatac tggaaagact tcaggaggct 119820aagcgtaatt agccttagca tggaaagtgc aagcagcaca ggccagcaaa gccccacgcg 119880tgtgggggtt ctcaggcctc ttctcttttg acatttcttt actgtttcca ttgttgggtg 119940ctgtttctcg tttctagtgc ttgtcctcta agccaggggt ccccactcca gtactggtac 120000tggtactggt actggaactg gtaattatct gtggcctgtt aggaactggg ctgcacagca 120060ggaggtgagc ttcgggggag caaacaaagc ttcatctgta ttttctgctg cttcccatca 120120ctctcatagc tgcctgagct ctgccagctg tcagatcaga ggcagcatta gattatcata 120180gcacaaaccc tattgtgaac tgcacatgtg aggaatctag attgcatgct ccttatgaga 120240atctaatgcc tgatgatctg tcatgcttcc atcaccccca gatgggacca cctacttgca 120300ggaaaattag ctcagggctc ccactgattt taccttatgg tgagatgcac atttatttca 120360ttatatatta caatgtaata ataattgaaa taaagtgcac gataaatgga aggtacttga 120420gtcatccttt aaccatcgcc ccctcacccc aggtgcacag aaaaattgcc ttttatgaaa 120480ctggtctctg gtgccaaaaa agttggggaa ccacactgct ctgggttcta gtagtcagag 120540atgccctcta tgaggcttaa gtcagatttt tctagaaaag atttggatgg gccatcaggt 120600caccatgaga cttcccttag cctcatgcat tctctgtgat ggtttacttt ggggcctatg 120660aatagggaag actgagatat aggaaaaacc aaagtgtctg tgttccccca ctctcacacc 120720catgtaacat aacacttctc acaccagata tggggggatt tctcctcaca ccccaagcga 120780gtctccagca gataccagct gggtgtccta caatgtaact cggtcctgac actctatctg 120840gagacagtgt cagatcccac aagttaaggc tcagtcctac aagactgccc cactgcagat 120900gccaatccca agttgcaggc tgtgacctgt acttctgccc agctggataa agatctgttt 120960ttctatatga ccctccatgg gtttgattac tttgctagag tggctcacag aactcaggga 121020aacacgttac ttttatttac ccatttatta taaaagatat taaaaaggat cctggtgaac 121080agccaggtgg aagagatgca cagggcaagg cacgtgggaa ggggctcaga gcctctatgc 121140cctctccagt gcaccagtcc ccagtaccct aagtgttcag caacccagaa gctctccaag 121200tgcagtcttg ttgggttttt atggaggctt cattacagag gcacagttga ttacatcatt 121260ggccatcggt gatcggctca ccttcggccc ctcttccctc cctggaggtt ggagggtggg 121320gctgaacagt tccaaccctc aagtcacatg gttggttccc ttggcaacca gcccctgggg 121380ctatccagga acccaccaag agttgcttca ttgcagctcc cttcacccag gaaactccaa 121440gggatttagg agctctgtgt taagaactgg ggggcagaga cccaatatac atttcttatt 121500ctatcacaat atcacaggaa gctaaggatg atactgcctt tgtgtgtctt ggctgtggat 121560ggtgcataat gcatggaagt aagcatttct gaatcaacag caaacaggct ttatcaggta 121620gaagacccct cagcgcccca gggacaaagc tcatcaatga tgtcccactg tcctctgagg 121680ctctagctct aagacctcca gtgggtcaag ctcctggaga agtggcacat tctccaaaga 121740cccttcaggg tcaccacacc ctggttaagg gtgtggcctc ataactcctt ttgactatga 121800ctgatggctt acagcataga aagaaataac tttgtcaaaa aatataataa tgatagaaag 121860gaagaaggaa cgctcccttt tgtcttctaa gaatagatgt gaaatgtgtg tgccttagaa 121920tatcttctcc ctctcctgct ccacgtgagc tggagcttac atgcctgctt gttttcagta 121980ctgccgtaac cctgatggtg acatcaatgg tccctggtgc tacacaatga atccaagaaa 122040actttttgac tactgtgata tccctctctg tggtaagttg ccttctgttt tggtaaggaa 122100actgcttcct taatatggat ttggaaaaaa aaaagcaaaa aaaacagaaa atggcttttg 122160agctgagtgc ttctggggag gagatggctg ccctctccac cagagcctgc ttttcatcat 122220ggccaccttg aacctgccct actattggcc ccatttgtta ggaaaacacc cgcccctccc 122280accacacaca cataaataaa ataaatgtca aattcccaaa gggcaaactt agaggtgatc 122340taatcagccc gggatagtcc caccgaaccc ttctttgtct agcgtgggat gcatgaaaaa 122400caaatttaga gtcattatga tgaaaaactg tcctcttctg cagctgagaa gaaaaaaaaa 122460atacgagcag caggaaacag ctaagcatgt aatgcacatt gtaaacctca gatggccatc 122520ctaggaaatc aatgaagggt agtgcagctc tttagcccca gatggccttt ctcgtaagat 122580tactactcat gagtcccatt agcgacattg cttagagact gcttgttagg ttccttcctc 122640attgctctga gactcttatt gggagtatga ggcttggatc aggggaaggg gaattgacat 122700tagatcttaa atgattgggg taacaaatcc atgggggaaa aaaagccact tgtacttgtt 122760ccctattttc ttcctgctga ccaatcaact tgtctgtccg agttacagaa caccaccctg 122820gacttttctt ttgtgtaatt tggttgcttg tggttgggtc tgccatgtga agggaccttg 122880agctggggga agaaggttgg cctccaagtc cactgaagac cagcatcctg agattgcctg 122940gggaggtggt acagggcagt gatgaagatc atgggagcca cactgcccat cgtcacattt 123000gggccactcc tggggagagc aagagggaag aaggagaggt tagggtgata ggaaagattc 123060tacttggcca atattattat aatgtggcat tgtggtctct ggatttagtg tgagttgata 123120gctgactttt ttctcgagtg ggtgcttttg ttctattttg tcggtgctat tgcagaagca 123180tcttggtggt tcctctacct caaagtctct tgatggggtc agttccagtt ctccgcttct 123240ggccccatct agtacacgcc actgcctctc actgcctggg ctctctatcc ttgacaggct 123300gccttgaatt taagcccagt ctgacttacc tgcctcaaac acccacagta gtgcctggga 123360ctcatgcacc tttgactccc atggaaggga agtgcagtag cttcccaggt gcaattctgc 123420tgtcctcacc cacattgagg atgtatgaga atcaggttct tagagattgg agaaagaagg 123480aagaatggga acaagatttc ttccaatgga ctgtgaggtt ccccacctta ctttgatgta 123540agacaagtga ggttaacccc aagcctggtg aggagggttc ccatcagaca cttggaaatc 123600ctgaggactg tttcctgcag aaggatgtgg ttggtgggat attcaggttt gactcatgat 123660tgagaaagtt agagcctctg gttggagaaa gagtttaata actatttcat ttccaccaac 123720acattcagta cgaataataa ataagtaaaa ataaatagaa acattcagtt ttattttgaa 123780tagtaggagt agggtataat ttctgtagtt actcttttag tacaatgatg catgtttact 123840gtatgtaagg catactagca gaaattgagc tcagcactag aaaagatgat tgcattccat 123900gccatgcttc ttttttacaa aagacttcta tagatagatt ctcaaaacaa cccacagcaa 123960atgaaaagtt atttggaaaa ctcaggttcc agattcactg gagtgtagaa tctctggttg 124020gttggggagg aatttcctct tgcagttgtt attaataatt atatgaataa ttattaacta 124080tattaatatt tatagttttg aagaccttga agggctggag acaacagaga agcatttttg 124140aacaccctct gtagcccctg cactgttgta ggcattgatg ggtggtacca aagatgggac 124200actttcccta cctccagaga ccttgtgggc ttgctgcaga gagaaggcag ggaggaggaa 124260aagaagaata gaggcacatg tgtgtaaatt acccccacag cagtcagtta gtcatgggag 124320gctccccaga agaactgtcc tgaagctggc tgagagaagg caacatttca acataggaca 124380gttatccttg ctacataaaa tcacatacac acatgcacat atgtccacac acagagactc 124440acatgcaaaa gaatcctttg tgcctttcag taaactttac atggtttaga aagaacttat 124500atttccttga aaggagagtg tcctttgttg tttactacca ctttttaaac ttagaaagaa 124560aaatctaaag agtgtttatg attttaccat ttaatttcac ctttgagatg tgaaaaacta 124620gtgcttggaa ttcgtcctga attaaacgac acaattgcta acttggactc aaatgcgact 124680tcttttccca ccttgtgcca cagcatcctc ttcatttgat tgtgggaagc ctcaagtgga 124740gccgaagaaa tgtcctggaa gcattgtagg ggggtgtgtg gcccacccac attcctggcc 124800ctggcaagtc agtctcagaa caaggtaaga acaggcccag aaaccatcta tactgtcctt 124860ccatgtaagc cccacaaaac ccttctacat ttacacagaa cccacacagc tgatgcatca 124920atacctgcct ctctgttttc tgaaggagga aaaaatatag aaaaattaaa aaaagttata 124980ttattatagg ttctctactt ggaaaatagc caaaatacaa atctttttct tgatctgggc 125040agttccatca aaatctgtag gcacagtgat ttgcaccaag ttccaatact tttggaaaat 125100attgaagatg ctctgagggt ttctatggat atccattgtc tcactgtcag atgaaaagaa 125160agggaagttt ttagaaatgt gacactttgc agtgagggag gacaagagca aacttaccta 125220cagtctatca caggcacaga ttttttttta cacttttgtg aatcattgaa ttcaatgccg 125280aggctattca tctattcaca aacacatgaa caaattatgg gttgtgatcc ccataaatga 125340agagtaatca gtccgaaccc acagaacctg gacattttgg gtatcgtttc agtggaacat 125400gcaattcgta agttcagttt gcttgggtgt ctcttaggaa gaacacatag gacacagacc 125460catctgcctg catgttttgc ttcctcatct cctttctaca ccagggcacc tgtgctcaat 125520tgctgttctc ctctaaagag acttccttct gtaagtttgt gaaatgccat cgacaaacct 125580gatcgcatcg catttcactc tgctgttgag ttgatttttc tttactttat cgtttgtaac 125640ttcttgctct acagagcttt caccttccac atatttcaga ttcattcttt cctaaactgt 125700gtggtggtct atgtcctcac tgactatcaa catactgcca tcatgcactt cctatctcta 125760ttcctcttcg ttgcaatctg gctccaagtg gctcacacca ttattctgat ctatcaactg 125820cctacacagt cctagaaagt aagtgagtca agaaacatcc cccaaaagta aacttttcag 125880gtaagatcag aagaccctca tgagtcactg ctgctcagga tcgtatctgg ctccttgaag 125940agtgaccttg catagatctt gtcataaaaa atgaaagaga ccttgggaag gtcttgggct 126000ggtcactttt gtcagagtcc agggctgtgg ggtgaaagcc acagctatag agcttcattc 126060tggagtcact tagctttgct ctcctgggga caggctgtgc ctattcttgc ctcaggcatc 126120aaaaaaagtg gcacagatgg gcccttctga aaaatctcac tactggagca cagctcgaag 126180tttctactat cctgacgttg ggcggtagtc ctttgctttg ggaatatgaa catgatcaaa 126240actgagtgaa cttgtcttcc tggctttctg tacaatgaag tagaacaaac catccaattt 126300gaccaaagcc ttggcatgtt ttctttctag gtttggaaag cacttctgtg gaggcacctt 126360aatatcccca gagtgggtgc tgactgctgc tcactgcttg aagaagtacg tttaagggaa 126420aactgacatg gggtcttatc ttcaagactt ttttcctccc tctcttcctc catcccttct 126480ttcttcccac cctccccttc cttcctcccc acctctcttc cttttctgga aggaacacta 126540ggaaccaggg aatgcatgca gaatcctgag gcagaatttc cagggcaatt ggatgagaga 126600ggagggaagt gtttctagag ggaatctgca gagggaagac ccagtgcaag tgattttttg 126660gacctgtata aaccgcagga cagagctgtt cactaccaga ggcatcaatc tgtattgcat 126720tgctctagag caatatctga ggctgaataa tttataaaga aaagagttta attggcacat 126780gtttctgcag gctttacagg aagcaggatg ctgtcatctc ctctgcttct gtgtgggcct 126840aaggaagatt acaatcatgg tggagggcaa agtgggagca ggcatgtcac atggccagag 126900caggagcaag agacagagag agatggggtg ggggtgctgc acaataccaa atgaccagac 126960tttgcaagaa ctaagagtga gagctcactg atcaccatga agatgtggcc caagccattc 127020aagagggatg cacctctatg atccaaaccc ctttcacagg ccatagctcc atcactgggg 127080actacagttg aacacgagat ttaggtgggg acaaatatac aaactatatc acagtctctg 127140atgaaacaga ttgagaacag accttaactg tcagtttcca gcaaattgtg aattttgttt 127200cttgccactc ataagtcact gattctgggt ggccgagggt gtcagaggga cagcgccaag 127260ttcatggcac agaggatacc tgaaggggct ggaccatatt tttctcttga catcctcatc 127320ttttctaggt cctcaaggcc ttcatcctac aaggtcatcc tgggtgcaca ccaagaagtg 127380aacctcgaat ctcatgttca ggaaatagaa gtgtctaggc tgttcttgga gcccacacaa 127440gcagatattg ccttgctaaa gctaagcagg tactcgctca cctgtggtct tcaccccacg 127500ctggtgaaga tatttgcttt atgtctgggt tttatgggcc atggccactg catggcagtg 127560gggaggaact gtctatcaca tgaaaggctc aagggctttg gggacagcat caatcttcaa 127620ccccagccct gccacatgtt agttgtgctc tttaaaaagg cagaaggatt cgtttcctca 127680cgtggaaaaa gagataccct gttacccgta aaacttactt aatgttcacc agttcatcca 127740cattcatgat cagggaaagg ttgttattcc aggctaacta ttctcctttc ataataatat 127800gctggagaga atcaaatgag attgcatttc aaagcgcttg aaaaaccacc atatcgagcc 127860atgcttagtg tgggcgcctc taatcactgc tattcaggag gctgacgagg aagaattgct 127920tgagcccagg acttcaaggc tgtaggcagc tatgattgtg ccactgcact ccaggctggg 127980tgacagatca agaccctgtc tcaacaaaag aaaagaaaac aaaacaaatg aacagaaata 128040ttccacaatg tcaaaaaaaa aaaaaaccca cacaacatac aatttacaaa tgcaaataat 128100aatattattg ttgtcttctt tgattttctc tttcctggtg aaattttgtt ttattaagcc 128160tgacaaagtg atacctttgc ttacatcact taaagttagt ctatttggac ctaggtgaca 128220gtacaatcag ctaagaaaca gtatttgtag gagaggcagg tttgggacag gtgacaaggc 128280atgtggggtg ctcgctgtgc tggtggctct ggaaggcagg gtgtcaatgc agacagggat 128340gagcatggcc tggttgggaa ggcatggggc aggcaggagc ctgagctgct ctcctgggcc 128400tggtcacaag cccatggcag cttctctggg tctgtgaact gaggggtgat gtcctggaat 128460cctctgacac tctaggaagg agagaagggc ctttctggct cagcctttat aaacagtagc 128520tgatctccct cttgctcccc agggtcctcc ccaccatccc agcaaatgtg caaatacaag 128580atctctgctc ctcatggtcc tcagagagct ggggtgttct gatggcttga acaagtcact 128640taggaaatgt ggggttttgg aggcattctc tgataggctg atacgttttg agtttagagt 128700tcccaccgca catccccaca cccctagagt ctagggcatt tagtgctcca tgagggaacc 128760tgtagagtga ggacatctgc atcacaggct gggccttcta gtgtccagaa gcagaaagtg 128820tgtctgcttc aaagttggtg ctaatgatga tttttggtca gaatacggca tttctcattt 128880ccattccttt atccccttga acttactaaa gtagaatcag gtctaaaaac cagagttcta 128940atctttaaga gtccctggga ttctaaggta tatgaatgtc cttggaaaac aataccattt 129000agttcatgca aggtgcttat ttcccatcct ctttcatttg atgtctagca ttttactgca 129060ttcttaccac cacggtttag taacattcac gaggaggaag tggaggatcc agatggagca 129120acttgctctg ggcacacaag gcatttgcaa ttttataccc tcttgatgat gtctcagcca 129180gacattctgc ccagtcatca atgccctctt caattaatat gaaaggacac acttggcatg 129240agattccaat cgtgcacaga atatacatga gaagtgtgcc tttgtcatcc ctactttcaa 129300aggctaaggc caccctcagt ttcttgcatg caactgatgc ctttcaaatg aaaccttaca 129360tctgtgtagt ccataggcaa ccacaggcaa atgtgagggt gaaacgctgt gttctacatt 129420gttctgtgtc agtgaagcaa ggcagtgcca gctcagaggg ctctggggct tcaaggcagg

129480gatgcctggt tgtaggtact gccacttcca gctgggcagt gaaacataac tgctaatact 129540ttccttacag gcctgccgtc atcactgaca aagtaatgcc agcttgtctg ccatccccag 129600actacatggt caccgccagg actgaatgtt acatcactgg ctggggagaa acccaaggtg 129660agatcaattc cattgcccac gtaacaaatt gtttttgacc ttcagtgcat gttacaaaat 129720gagcattttg gagatagttg tacaaattcc tacccatgaa tgtggtctac ccactcctga 129780ctttgcctgg acacctgtct atgtctccat aatcagtctt caagggactt gggcaagggg 129840agcggtgcca tttccttgag tctctctctt ttttgttttc agaatctttt aatttttttt 129900gtaatgattg tatgtttccc ttacaacaaa aacaaacacc agtagaggtc tttgagtctc 129960ttaatcataa tttcagcatt catattgctt ccccaggtaa gtggggtttt gacccagccc 130020tcaagttaag ggtgttagat tatttttcat gtgaaattag acagactgcg tttctaaaca 130080tggtgcaaaa cagtaacgac aaaagttgta attaaactat tcttcttccc aaatacccac 130140atgtctaatg tgtgtgtgag ggtgttaggc aggggacctg aagctggggg agaggcagac 130200agttcccatg gccccaagtc taggatggca tttggtattg gttgatgggt gagagcaaga 130260gagggaatat ttttgtgcat gatgtggtat cagcacctgt actacatttt atggattcct 130320tcttctcttt gcggtatgcc ctgacaataa ttatatccgt cagccttacc cccttggcag 130380taggaaaact gaaactgtct taaagtctca gctctacttt ctcagaggtg caggcaaggg 130440cactgggagt ctggggccct ggaaaactgt tctgactctg ccacttgcca gatagacctg 130500aactagacac gttacctctt tgtaccactt ggctctaatc ccttatctgt aaaaccagca 130560ttttcaaatg gtgctttgca catcagcctt ttgcataagc tttgatttga taaaatgttt 130620tttgtgtttt taaaaagatt aaaaaccaca ggtttagata atttcaaagt aggcttccct 130680ttttctgtca ttttcctatt atttttaaaa cctcacctcc ttgactcctt gttccctttt 130740tctgcactgc tgagtctggg agcactgagg ccaggtaaaa ggaaacttgg caaatgaggg 130800gcacctatgg gtgtgggagg ctgctcctgg tgtttgcata ttttaaaatt taaatgctac 130860aaaccactgt gagttaggta ttattgttcc tattttacca ttgaggaagc tggggctcag 130920agaaggtgga gggtggtaca gacaaacctg aattggaacc ctggctcctg cctatgggct 130980gtcaggactt agaaaagtcg tgagctctcg ctgattgttt cctcagctga tgtgggctgc 131040agggctgtta tgggggaaat aataagaaag tgcatcaagt gctgagcaca tcctaagcac 131100tccatcatgg cagctcctac tactaataaa gaatagaatt atatctaaca tgattctttc 131160ttgcaagtga cagaaaatcc aactcaaatt ggattaagca aaacaaggga aattcttagt 131220gagctgcaaa gttttcaggc tcacatgatg gccccaaatc ccaggtcctc ccaatcatgg 131280agtaggcact atttgggggc acaaaggtga cattcccatg gctgcagatg ctgtggtgct 131340gtggctgtac cgggaaagaa taagaaaggc cactctccca attatgtgaa caatagtctg 131400cccactctga gaagtcaaac ttgggtcaca gtcctgcccc tgaacccatc actgactggc 131460tctgacctgc accaattgtt ccatgttgga ggtgaaggca agaccccact aatacccata 131520aggggcaaaa gttagataga tccttcaaga ggattatggg aggtagggca aaaagctgct 131580gggcagccag aaagcaaaca gagcctctat gatacctcaa ctgatgaaag catgaagcta 131640aaatcataag gatctgggtg tgagttctgg ctctcccatc ttccatgtga cattgggcag 131700ttatttaatc tcttttagcc tccgctttct catcttacat atgagataat tgtgaggatt 131760aagattacac ataatcatca tcatcaccgt ccaccactac caccatcatc cccatcaaca 131820tcatcgccac cactatcatc attcttactg gcactaccat caccatcacc accattccac 131880caccatcacc aatatcatca ctgtcaacat cattaccacc atcaccatca ccaccaccat 131940catcattact accactacca ctactaccac catcaccatc accaccattc caccaccatc 132000accaatatca tcactctcaa catcatcacc atcaccatca ccaccaccat catcatcatt 132060actaccacta ccactactac caccatcacc atcaccactg tcccactact atcagcatga 132120catcaccatc accaccacca tcatcattac caccgctact accaacatca ccatcaccac 132180aattctactg ccatcaccat taacattacc accaccatca tcactatcac catcaccacc 132240atcatcacca ctgccattat cactgccacc atcatcacta tcctctatat ttcctcatct 132300gtattatcat tactaccacc atcactatca ccaccatcgt caccatcata atcaccatca 132360acaccatctc caataccacc atcactgtaa ccatcatcac caccaccatg atcactatca 132420ccatcatcac aatgatcact gtaaccatca ttactaccca ccaccatcac cactactcca 132480ccaccatcac cattatcatt accatcacca ttatcaccac catcatcatc accagcacca 132540ccatcatcac cagcaccacc atcaccatca ccatcattaa caccatcact atcaccattg 132600gtttaatcat caccaccatc atcataaata aacatcacat aaccagggtg tagctgggtg 132660ttgaccccag agcccactca ctgtttcctc tctcccaccc ccatccacac atttctaacc 132720accatcctgc actgggctcc cagtctcctc tggtctcacc cacatgtcca ctgagaaaag 132780gattttcaga acaccaacta gaccaggagg agccacatac ataactcagg cctgcttatc 132840aactttctac atgttaataa tgacatcaga tcaatgggtg ttctcagctt ctcagaagga 132900ggtcaaaatt ctccccctct ccccttcatg tgtccagacc ttcccggatt tggatgtacc 132960aagtgcagag tggtgttgag gccaaggggc tcatccatgt aagtctcatc tgcaatcact 133020gggctgatcc cgtggccctg tctccagggc gccatcagag agggcttcaa tcctcaggtt 133080acctgtggcc caccctgccc tcagaggtgc catctctaca ttggccacga gatggcagca 133140catactcata gactgcatta atttcccagc aactcctggt gggttttccc tcttatcagg 133200atgtttgcct tgctcagaga gcaaatctga gagcagtgac acctaactta actttcagca 133260aaatattttg agaagggtgc ccctttacac atctgtgcag tccaggtgat gcatcccatg 133320cccaatgctc ggtagtcagg aggagcttcc tccatgcagc tctgcggaag agactcttcc 133380acgctgctca tgtaaactcc agattcggtg tcagttttct gacaccgaag acaatgatct 133440aagtgcagtc aagggctttg gggaaagcag gagagagtgc ctcagttcta gcctgtgcca 133500tgcttgcaaa gttttgcaaa attctaatga gagctgggct tgcaacattg gaaacttgga 133560ttatttgtga gagcactgag aaatccctgg gcatgtccat ctggaaaaac agcatttcct 133620ctggcacttt agcagaggtt ctgtttcaat ttggcgaagg aaattaagca gtttttcaca 133680aaagaagaac tacaacgagg agaattgtcc ctagtatttc ttctccctaa ttgtcaagga 133740agtgtaaatt agaaaatgaa tcaggacaat ttccacctac tatgttagct aatattttaa 133800aaattgaata tcacaagggt gaggcaaagt aattgttttc cagtgacatt ttccactgtc 133860acaccctttt agagaataat ttggcaatgt tactgtgaga tagaaatatg tctatataat 133920tatgggaact gagacttcag aaagtaataa ggaataagaa tgaaatttat gaacaaacat 133980gtggaaggtt ggaagcaaga gtggggccaa cacgcatggg gaggaagcat ttgggcagcg 134040actccgcaga cccagactca agctgagcta tacaacctcc ttacgcctca gtttcctcaa 134100ctgaagaaca ggaatgacaa gtgcctgttt cataggaccg ttgtgaggat taagtgagat 134160ataccacatt atgagcttgt gcctggaaag gttgattctt agtaaatgat gactattctt 134220ttttattgca ataaaattta tacaacatag agttactatt ttaaccattt ttgcaggtac 134280cactgagtgg cattcagtac attcacaatg gtgtgcaacc gtcaccatat ttccaggaca 134340tttttctcat ccccaaagga aacctcatgc ccattaagca gtcactcctc attaaaatat 134400tagttatgaa gactgtagca tttttttaaa aactcatgat ataacattga ttgaaaaaat 134460cagtatagga aattgtgcat tatgatgtaa tagtaaaaga agcatataaa aatctgaaaa 134520aagtatataa aaagaatagc aattgtattt ctcagactct ctttacattg taaaaatcat 134580tttgatagct tcaaaagaaa agcaaaaagt acacaaacaa caaccaaccc caaagcagca 134640tgacaaagcc cagattgttg aatccaggtc ttgggaacat aaaatcttat atgacatttg 134700cactttaatg ggtcagagag tccagtggca ttgggagctg ccttgtgttc tgcagcctca 134760cggacagaca ggaggtccag ctccactgct ctgttcttct ggaatttcct cgtgaacaag 134820ctttggcctc agtaaccatt tctttcatct ttttaaacac aggtaccttt gggactggcc 134880ttctcaagga agcccagctc cttgttattg agaatgaagt gtgcaatcac tataagtata 134940tttgtgctga gcatttggcc agaggcactg acagttgcca ggtaagaaaa gatcaataga 135000tcaaagtctt gtgctctccc gtctcagtct cagtccctta gacgtcagtc ccaaagtggc 135060aaattcagga aggttttgtc agtggaagac cccagtctaa gtgttgctca gaaactcccc 135120agatctgtcc ctgaatgcat attcagatca tctaaggaga cgtcttgggg cttgagttcc 135180agatccatag caagggagcc gtaagtgcca taactacctc aggccactca ccttcctggt 135240gtgtgctggt caccagtgac tgaagtggtg gcttttccag tagagaggaa ggtagagggt 135300acaggaccga gacaaattac acacacttaa caatgatgtc caggctagcc cagtctaaag 135360gaaacaccaa gttaggaagc aatgcatgca ggattcacaa gggattattt tttttcccag 135420gaaaaaacta agtgatgtgg ttttgttgaa tagactttgc taagtactta agcactgcag 135480atgcttgagt aatatgctca taagttcctt tctgatttga attactggga aaatgtacat 135540atggataaga gaaggatggc atcccatatt aaaaggttgg cagcttaaag ctcacatgaa 135600ttttccccta cctctgttta gggtgacagt ggagggcctc tggtttgctt cgagaaggac 135660aaatacattt tacaaggagt cacttcttgg ggtcttggct gtgcacgccc caataagcct 135720ggtgtctatg ctcgtgtttc aaggtttgtt acttggattg agggaatgat gagaaataat 135780taattggacg ggagacagag tgaagcatca acctacttag aagctgaaac gtgggtaagg 135840atttagcatg ctggaaataa tagacagcaa tcaaacgaag acactgttcc cagctaccag 135900ctatgccaaa ccttggcatt tttggtattt ttgtgtataa gcttttaagg tctgactgac 135960aaattctgta ttaaggtgtc atagctatga catttgttaa aaataaactc tgcacttatt 136020ttgatttgaa ttaattttgg ttttggtctt caaaattttc atgctctttt catcccatct 136080atttttattt ttatttttta gactttacgt cctggggtac atgtgcagaa tgtgcaggtt 136140tgttacatag atgtacacgt gccatggtag tttgctgcac ccatcaacct gtcatctaat 136200tcggtatttc ttttagttct atccctcccc tagccctcca ccccttgaca ggcccaggtg 136260tgtgatgttg ccctccctgt gtccatgtgt tctcattgtt caactcacac ttatgagtga 136320gaacatgccg tgtttgtttt tctgttcttg tgttagtttg ctgagaatga tagtttccag 136380cttcatccat gtccctgcaa aggacatgaa ctcatccttt tttatggctg catagaattc 136440catggtgtat atgtgccaca ttttatccaa tctaacattg atgggcaatt gggttggttc 136500caactctttg ctattgtgaa tagtgccaca ataaacatac gtgtgcatgt gttttcatag 136560cagaatgatt tataatcctc tgggtatata cccagtaatg ggattgcagg gtcaaatggt 136620gtttctggtg ctagatcttt gaggaatcac cacactgtct tccacaatgg ttgaactaat 136680ttatgctccc accaacaata tcaaggcatt cctatttctc cacatcctct ccagcatctg 136740ttgtttcctg actttttaat gatcgccatt ctaactggca tgagatggta tctcattgtg 136800gttttgattt gcatttctct aatgatcagt gatgatgagc ttttctcata tgtttgttgg 136860ctgcataaat gccttttttg gagaagcatc tgttcatatc ctttgcccac tttttgatgg 136920tgttgttttt ttctggtaaa tttgtttaag ttctttgtag attctggata ttagcctttt 136980gtcagatgga tagatggcaa aaattttatc ctattatgta ggttgcctgt tcactccgat 137040gatagtttct tttgctgtgc agaagctctt tggtttaatt agatctcatt tgtctatttt 137100ggcttttgtt accattgctt ttagtgtttt agtcatgaag tcttctccca tgctatgtcc 137160tgaatggtat tgcctaagtt ttcttccagg gtttttatgg ttttaggttt tgcatttaag 137220tctttaatcc atcttgagtt aatttttgta taagtaatgc ccttctttgt ctcttttgat 137280ctttgttggc ttaaagtata ttttatcaga gactagaatt gcaatccctg cttttttttt 137340tctttttgct ttccttttgc ttggtaaata ttcttccatc cctttatttt gagcctatgt 137400atgtctgcac atgagatagg tttcctgaat acagcacacc aatgggtctt gactctttat 137460tcaatttgcc agtctgtgtc ttttaattgg gggcatttag tccatttaca tttaaggtta 137520atattgttat gtgtgaattt gatcctgtca ttatgatgct agcgggttat tttgcccatt 137580agttgatgca gtttcttcat agtgtggatg gcctttacaa tttggtagtt tttgcagtgg 137640ctggtaccaa ttgttccttt ccatgtttag tgcttcgttc aggagctctt gtgaggcagg 137700ccttgtggtg acaaaatctt tcagcatttg cttgtctgta aaggatttta tttctccttt 137760gcttatgaag cttagtttcg ctgggtatga aattctgggt tgaaaattat tttcttttag 137820aatgttgaat attggccccc actctcttcg ggcttgttgg gtttctgcag agagatccac 137880tgttagtctg attggcttcc ctttccgggt aacccaacct ttctctctgg ctgcccttag 137940aaatttttcc ttcatttcaa ccttggtgaa tctgacgatt atgtcttgag gtggctcttc 138000t 138001413938DNAHomo sapiens 4ctgggattgg gacacacttt ctggacactg ctggccagtc ccaaaatgga acataaggaa 60gtggttcttc tacttctttt atttctgaaa tcagcagcac ctgagcaaag ccatgtggtc 120caggattgct accatggtga tggacagagt tatcgaggca cgtactccac cactgtcaca 180ggaaggacct gccaagcttg gtcatctatg acaccacatc aacataatag gaccacagaa 240aactacccaa atgctggctt gatcatgaac tactgcagga atccagatgc tgtggcagct 300ccttattgtt atacgaggga tcccggtgtc aggtgggagt actgcaacct gacgcaatgc 360tcagacgcag aagggactgc cgtcgcgcct ccgactgtta ccccggttcc aagcctagag 420gctccttccg aacaagcacc gactgagcaa aggcctgggg tgcaggagtg ctaccatggt 480aatggacaga gttatcgagg cacatactcc accactgtca caggaagaac ctgccaagct 540tggtcatcta tgacaccaca ctcgcatagt cggaccccag aatactaccc aaatgctggc 600ttgatcatga actactgcag gaatccagat gctgtggcag ctccttattg ttatacgagg 660gatcccggtg tcaggtggga gtactgcaac ctgacgcaat gctcagacgc agaagggact 720gccgtcgcgc ctccgactgt taccccggtt ccaagcctag aggctccttc cgaacaagca 780ccgactgagc aaaggcctgg ggtgcaggag tgctaccatg gtaatggaca gagttatcga 840ggcacatact ccaccactgt cacaggaaga acctgccaag cttggtcatc tatgacacca 900cactcgcata gtcggacccc agaatactac ccaaatgctg gcttgatcat gaactactgc 960aggaatccag atgctgtggc agctccttat tgttatacga gggatcccgg tgtcaggtgg 1020gagtactgca acctgacgca atgctcagac gcagaaggga ctgccgtcgc gcctccgact 1080gttaccccgg ttccaagcct agaggctcct tccgaacaag caccgactga gcaaaggcct 1140ggggtgcagg agtgctacca tggtaatgga cagagttatc gaggcacata ctccaccact 1200gtcacaggaa gaacctgcca agcttggtca tctatgacac cacactcgca tagtcggacc 1260ccagaatact acccaaatgc tggcttgatc atgaactact gcaggaatcc agatgctgtg 1320gcagctcctt attgttatac gagggatccc ggtgtcaggt gggagtactg caacctgacg 1380caatgctcag acgcagaagg gactgccgtc gcgcctccga ctgttacccc ggttccaagc 1440ctagaggctc cttccgaaca agcaccgact gagcaaaggc ctggggtgca ggagtgctac 1500catggtaatg gacagagtta tcgaggcaca tactccacca ctgtcacagg aagaacctgc 1560caagcttggt catctatgac accacactcg catagtcgga ccccagaata ctacccaaat 1620gctggcttga tcatgaacta ctgcaggaat ccagatgctg tggcagctcc ttattgttat 1680acgagggatc ccggtgtcag gtgggagtac tgcaacctga cgcaatgctc agacgcagaa 1740gggactgccg tcgcgcctcc gactgttacc ccggttccaa gcctagaggc tccttccgaa 1800caagcaccga ctgagcaaag gcctggggtg caggagtgct accatggtaa tggacagagt 1860tatcgaggca catactccac cactgtcaca ggaagaacct gccaagcttg gtcatctatg 1920acaccacact cgcatagtcg gaccccagaa tactacccaa atgctggctt gatcatgaac 1980tactgcagga atccagatgc tgtggcagct ccttattgtt atacgaggga tcccggtgtc 2040aggtgggagt actgcaacct gacgcaatgc tcagacgcag aagggactgc cgtcgcgcct 2100ccgactgtta ccccggttcc aagcctagag gctccttccg aacaagcacc gactgagcaa 2160aggcctgggg tgcaggagtg ctaccatggt aatggacaga gttatcgagg cacatactcc 2220accactgtca caggaagaac ctgccaagct tggtcatcta tgacaccaca ctcgcatagt 2280cggaccccag aatactaccc aaatgctggc ttgatcatga actactgcag gaatccagat 2340gctgtggcag ctccttattg ttatacgagg gatcccggtg tcaggtggga gtactgcaac 2400ctgacgcaat gctcagacgc agaagggact gccgtcgcgc ctccgactgt taccccggtt 2460ccaagcctag aggctccttc cgaacaagca ccgactgagc aaaggcctgg ggtgcaggag 2520tgctaccatg gtaatggaca gagttatcga ggcacatact ccaccactgt cacaggaaga 2580acctgccaag cttggtcatc tatgacacca cactcgcata gtcggacccc agaatactac 2640ccaaatgctg gcttgatcat gaactactgc aggaatccag atgctgtggc agctccttat 2700tgttatacga gggatcccgg tgtcaggtgg gagtactgca acctgacgca atgctcagac 2760gcagaaggga ctgccgtcgc gcctccgact gttaccccgg ttccaagcct agaggctcct 2820tccgaacaag caccgactga gcaaaggcct ggggtgcagg agtgctacca tggtaatgga 2880cagagttatc gaggcacata ctccaccact gtcacaggaa gaacctgcca agcttggtca 2940tctatgacac cacactcgca tagtcggacc ccagaatact acccaaatgc tggcttgatc 3000atgaactact gcaggaatcc agatgctgtg gcagctcctt attgttatac gagggatccc 3060ggtgtcaggt gggagtactg caacctgacg caatgctcag acgcagaagg gactgccgtc 3120gcgcctccga ctgttacccc ggttccaagc ctagaggctc cttccgaaca agcaccgact 3180gagcaaaggc ctggggtgca ggagtgctac catggtaatg gacagagtta tcgaggcaca 3240tactccacca ctgtcacagg aagaacctgc caagcttggt catctatgac accacactcg 3300catagtcgga ccccagaata ctacccaaat gctggcttga tcatgaacta ctgcaggaat 3360ccagatgctg tggcagctcc ttattgttat acgagggatc ccggtgtcag gtgggagtac 3420tgcaacctga cgcaatgctc agacgcagaa gggactgccg tcgcgcctcc gactgttacc 3480ccggttccaa gcctagaggc tccttccgaa caagcaccga ctgagcaaag gcctggggtg 3540caggagtgct accatggtaa tggacagagt tatcgaggca catactccac cactgtcaca 3600ggaagaacct gccaagcttg gtcatctatg acaccacact cgcatagtcg gaccccagaa 3660tactacccaa atgctggctt gatcatgaac tactgcagga atccagatgc tgtggcagct 3720ccttattgtt atacgaggga tcccggtgtc aggtgggagt actgcaacct gacgcaatgc 3780tcagacgcag aagggactgc cgtcgcgcct ccgactgtta ccccggttcc aagcctagag 3840gctccttccg aacaagcacc gactgagcaa aggcctgggg tgcaggagtg ctaccatggt 3900aatggacaga gttatcgagg cacatactcc accactgtca caggaagaac ctgccaagct 3960tggtcatcta tgacaccaca ctcgcatagt cggaccccag aatactaccc aaatgctggc 4020ttgatcatga actactgcag gaatccagat gctgtggcag ctccttattg ttatacgagg 4080gatcccggtg tcaggtggga gtactgcaac ctgacgcaat gctcagacgc agaagggact 4140gccgtcgcgc ctccgactgt taccccggtt ccaagcctag aggctccttc cgaacaagca 4200ccgactgagc aaaggcctgg ggtgcaggag tgctaccatg gtaatggaca gagttatcga 4260ggcacatact ccaccactgt cacaggaaga acctgccaag cttggtcatc tatgacacca 4320cactcgcata gtcggacccc agaatactac ccaaatgctg gcttgatcat gaactactgc 4380aggaatccag atgctgtggc agctccttat tgttatacga gggatcccgg tgtcaggtgg 4440gagtactgca acctgacgca atgctcagac gcagaaggga ctgccgtcgc gcctccgact 4500gttaccccgg ttccaagcct agaggctcct tccgaacaag caccgactga gcaaaggcct 4560ggggtgcagg agtgctacca tggtaatgga cagagttatc gaggcacata ctccaccact 4620gtcacaggaa gaacctgcca agcttggtca tctatgacac cacactcgca tagtcggacc 4680ccagaatact acccaaatgc tggcttgatc atgaactact gcaggaatcc agatgctgtg 4740gcagctcctt attgttatac gagggatccc ggtgtcaggt gggagtactg caacctgacg 4800caatgctcag acgcagaagg gactgccgtc gcgcctccga ctgttacccc ggttccaagc 4860ctagaggctc cttccgaaca agcaccgact gagcaaaggc ctggggtgca ggagtgctac 4920catggtaatg gacagagtta tcgaggcaca tactccacca ctgtcacagg aagaacctgc 4980caagcttggt catctatgac accacactcg catagtcgga ccccagaata ctacccaaat 5040gctggcttga tcatgaacta ctgcaggaat ccagatgctg tggcagctcc ttattgttat 5100acgagggatc ccggtgtcag gtgggagtac tgcaacctga cgcaatgctc agacgcagaa 5160gggactgccg tcgcgcctcc gactgttacc ccggttccaa gcctagaggc tccttccgaa 5220caagcaccga ctgagcaaag gcctggggtg caggagtgct accatggtaa tggacagagt 5280tatcgaggca catactccac cactgtcaca ggaagaacct gccaagcttg gtcatctatg 5340acaccacact cgcatagtcg gaccccagaa tactacccaa atgctggctt gatcatgaac 5400tactgcagga atccagatgc tgtggcagct ccttattgtt atacgaggga tcccggtgtc 5460aggtgggagt actgcaacct gacgcaatgc tcagacgcag aagggactgc cgtcgcgcct 5520ccgactgtta ccccggttcc aagcctagag gctccttccg aacaagcacc gactgagcaa 5580aggcctgggg tgcaggagtg ctaccatggt aatggacaga gttatcgagg cacatactcc 5640accactgtca caggaagaac ctgccaagct tggtcatcta tgacaccaca ctcgcatagt 5700cggaccccag aatactaccc aaatgctggc ttgatcatga actactgcag gaatccagat 5760gctgtggcag ctccttattg ttatacgagg gatcccggtg tcaggtggga gtactgcaac 5820ctgacgcaat gctcagacgc agaagggact gccgtcgcgc ctccgactgt taccccggtt 5880ccaagcctag aggctccttc cgaacaagca ccgactgagc aaaggcctgg ggtgcaggag 5940tgctaccatg gtaatggaca gagttatcga ggcacatact ccaccactgt cacaggaaga 6000acctgccaag cttggtcatc tatgacacca cactcgcata gtcggacccc agaatactac 6060ccaaatgctg gcttgatcat gaactactgc aggaatccag atgctgtggc agctccttat 6120tgttatacga gggatcccgg tgtcaggtgg gagtactgca acctgacgca atgctcagac 6180gcagaaggga ctgccgtcgc gcctccgact gttaccccgg ttccaagcct agaggctcct 6240tccgaacaag caccgactga gcaaaggcct ggggtgcagg agtgctacca tggtaatgga 6300cagagttatc gaggcacata ctccaccact gtcacaggaa gaacctgcca agcttggtca 6360tctatgacac cacactcgca tagtcggacc ccagaatact acccaaatgc tggcttgatc 6420atgaactact gcaggaatcc agatgctgtg gcagctcctt

attgttatac gagggatccc 6480ggtgtcaggt gggagtactg caacctgacg caatgctcag acgcagaagg gactgccgtc 6540gcgcctccga ctgttacccc ggttccaagc ctagaggctc cttccgaaca agcaccgact 6600gagcaaaggc ctggggtgca ggagtgctac catggtaatg gacagagtta tcgaggcaca 6660tactccacca ctgtcacagg aagaacctgc caagcttggt catctatgac accacactcg 6720catagtcgga ccccagaata ctacccaaat gctggcttga tcatgaacta ctgcaggaat 6780ccagatgctg tggcagctcc ttattgttat acgagggatc ccggtgtcag gtgggagtac 6840tgcaacctga cgcaatgctc agacgcagaa gggactgccg tcgcgcctcc gactgttacc 6900ccggttccaa gcctagaggc tccttccgaa caagcaccga ctgagcaaag gcctggggtg 6960caggagtgct accatggtaa tggacagagt tatcgaggca catactccac cactgtcaca 7020ggaagaacct gccaagcttg gtcatctatg acaccacact cgcatagtcg gaccccagaa 7080tactacccaa atgctggctt gatcatgaac tactgcagga atccagatgc tgtggcagct 7140ccttattgtt atacgaggga tcccggtgtc aggtgggagt actgcaacct gacgcaatgc 7200tcagacgcag aagggactgc cgtcgcgcct ccgactgtta ccccggttcc aagcctagag 7260gctccttccg aacaagcacc gactgagcaa aggcctgggg tgcaggagtg ctaccatggt 7320aatggacaga gttatcgagg cacatactcc accactgtca caggaagaac ctgccaagct 7380tggtcatcta tgacaccaca ctcgcatagt cggaccccag aatactaccc aaatgctggc 7440ttgatcatga actactgcag gaatccagat gctgtggcag ctccttattg ttatacgagg 7500gatcccggtg tcaggtggga gtactgcaac ctgacgcaat gctcagacgc agaagggact 7560gccgtcgcgc ctccgactgt taccccggtt ccaagcctag aggctccttc cgaacaagca 7620ccgactgagc aaaggcctgg ggtgcaggag tgctaccatg gtaatggaca gagttatcga 7680ggcacatact ccaccactgt cacaggaaga acctgccaag cttggtcatc tatgacacca 7740cactcgcata gtcggacccc agaatactac ccaaatgctg gcttgatcat gaactactgc 7800aggaatccag atgctgtggc agctccttat tgttatacga gggatcccgg tgtcaggtgg 7860gagtactgca acctgacgca atgctcagac gcagaaggga ctgccgtcgc gcctccgact 7920gttaccccgg ttccaagcct agaggctcct tccgaacaag caccgactga gcagaggcct 7980ggggtgcagg agtgctacca cggtaatgga cagagttatc gaggcacata ctccaccact 8040gtcactggaa gaacctgcca agcttggtca tctatgacac cacactcgca tagtcggacc 8100ccagaatact acccaaatgc tggcttgatc atgaactact gcaggaatcc agatgctgtg 8160gcagctcctt attgttatac gagggatccc ggtgtcaggt gggagtactg caacctgacg 8220caatgctcag acgcagaagg gactgccgtc gcgcctccga ctgttacccc ggttccaagc 8280ctagaggctc cttccgaaca agcaccgact gagcaaaggc ctggggtgca ggagtgctac 8340catggtaatg gacagagtta tcgaggcaca tactccacca ctgtcacagg aagaacctgc 8400caagcttggt catctatgac accacactcg catagtcgga ccccagaata ctacccaaat 8460gctggcttga tcatgaacta ctgcaggaat ccagatgctg tggcagctcc ttattgttat 8520acgagggatc ccggtgtcag gtgggagtac tgcaacctga cgcaatgctc agacgcagaa 8580gggactgccg tcgcgcctcc gactgttacc ccggttccaa gcctagaggc tccttccgaa 8640caagcaccga ctgagcaaag gcctggggtg caggagtgct accatggtaa tggacagagt 8700tatcgaggca catactccac cactgtcaca ggaagaacct gccaagcttg gtcatctatg 8760acaccacact cgcatagtcg gaccccagaa tactacccaa atgctggctt gatcatgaac 8820tactgcagga atccagatgc tgtggcagct ccttattgtt atacgaggga tcccggtgtc 8880aggtgggagt actgcaacct gacgcaatgc tcagacgcag aagggactgc cgtcgcgcct 8940ccgactgtta ccccggttcc aagcctagag gctccttccg aacaagcacc gactgagcag 9000aggcctgggg tgcaggagtg ctaccacggt aatggacaga gttatcgagg cacatactcc 9060accactgtca ctggaagaac ctgccaagct tggtcatcta tgacaccaca ctcgcatagt 9120cggaccccag aatactaccc aaatgctggc ttgatcatga actactgcag gaatccagat 9180gctgtggcag ctccttattg ttatacgagg gatcccggtg tcaggtggga gtactgcaac 9240ctgacgcaat gctcagacgc agaagggact gccgtcgcgc ctccgactgt taccccggtt 9300ccaagcctag aggctccttc cgaacaagca ccgactgagc agaggcctgg ggtgcaggag 9360tgctaccacg gtaatggaca gagttatcga ggcacatact ccaccactgt cactggaaga 9420acctgccaag cttggtcatc tatgacacca cactcgcata gtcggacccc agaatactac 9480ccaaatgctg gcttgatcat gaactactgc aggaatccag atgctgtggc agctccttat 9540tgttatacga gggatcccgg tgtcaggtgg gagtactgca acctgacgca atgctcagac 9600gcagaaggga ctgccgtcgc gcctccgact gttaccccgg ttccaagcct agaggctcct 9660tccgaacaag caccgactga gcagaggcct ggggtgcagg agtgctacca cggtaatgga 9720cagagttatc gaggcacata ctccaccact gtcactggaa gaacctgcca agcttggtca 9780tctatgacac cacactcgca tagtcggacc ccagaatact acccaaatgc tggcttgatc 9840atgaactact gcaggaatcc agatgctgtg gcagctcctt attgttatac gagggatccc 9900ggtgtcaggt gggagtactg caacctgacg caatgctcag acgcagaagg gactgccgtc 9960gcgcctccga ctgttacccc ggttccaagc ctagaggctc cttccgaaca agcaccgact 10020gagcagaggc ctggggtgca ggagtgctac cacggtaatg gacagagtta tcgaggcaca 10080tactccacca ctgtcactgg aagaacctgc caagcttggt catctatgac accacactcg 10140catagtcgga ccccagaata ctacccaaat gctggcttga tcatgaacta ctgcaggaat 10200ccagatcctg tggcagcccc ttattgttat acgagggatc ccagtgtcag gtgggagtac 10260tgcaacctga cacaatgctc agacgcagaa gggactgccg tcgcgcctcc aactattacc 10320ccgattccaa gcctagaggc tccttctgaa caagcaccaa ctgagcaaag gcctggggtg 10380caggagtgct accacggaaa tggacagagt tatcaaggca catacttcat tactgtcaca 10440ggaagaacct gccaagcttg gtcatctatg acaccacact cgcatagtcg gaccccagca 10500tactacccaa atgctggctt gatcaagaac tactgccgaa atccagatcc tgtggcagcc 10560ccttggtgtt atacaacaga tcccagtgtc aggtgggagt actgcaacct gacacgatgc 10620tcagatgcag aatggactgc cttcgtccct ccgaatgtta ttctggctcc aagcctagag 10680gctttttttg aacaagcact gactgaggaa acccccgggg tacaggactg ctactaccat 10740tatggacaga gttaccgagg cacatactcc accactgtca caggaagaac ttgccaagct 10800tggtcatcta tgacaccaca ccagcatagt cggaccccag aaaactaccc aaatgctggc 10860ctgaccagga actactgcag gaatccagat gctgagattc gcccttggtg ttacaccatg 10920gatcccagtg tcaggtggga gtactgcaac ctgacacaat gcctggtgac agaatcaagt 10980gtccttgcaa ctctcacggt ggtcccagat ccaagcacag aggcttcttc tgaagaagca 11040ccaacggagc aaagccccgg ggtccaggat tgctaccatg gtgatggaca gagttatcga 11100ggctcattct ctaccactgt cacaggaagg acatgtcagt cttggtcctc tatgacacca 11160cactggcatc agaggacaac agaatattat ccaaatggtg gcctgaccag gaactactgc 11220aggaatccag atgctgagat tagtccttgg tgttatacca tggatcccaa tgtcagatgg 11280gagtactgca acctgacaca atgtccagtg acagaatcaa gtgtccttgc gacgtccacg 11340gctgtttctg aacaagcacc aacggagcaa agccccacag tccaggactg ctaccatggt 11400gatggacaga gttatcgagg ctcattctcc accactgtta caggaaggac atgtcagtct 11460tggtcctcta tgacaccaca ctggcatcag agaaccacag aatactaccc aaatggtggc 11520ctgaccagga actactgcag gaatccagat gctgagattc gcccttggtg ttataccatg 11580gatcccagtg tcagatggga gtactgcaac ctgacgcaat gtccagtgat ggaatcaact 11640ctcctcacaa ctcccacggt ggtcccagtt ccaagcacag agcttccttc tgaagaagca 11700ccaactgaaa acagcactgg ggtccaggac tgctaccgag gtgatggaca gagttatcga 11760ggcacactct ccaccactat cacaggaaga acatgtcagt cttggtcgtc tatgacacca 11820cattggcatc ggaggatccc attatactat ccaaatgctg gcctgaccag gaactactgc 11880aggaatccag atgctgagat tcgcccttgg tgttacacca tggatcccag tgtcaggtgg 11940gagtactgca acctgacacg atgtccagtg acagaatcga gtgtcctcac aactcccaca 12000gtggccccgg ttccaagcac agaggctcct tctgaacaag caccacctga gaaaagccct 12060gtggtccagg attgctacca tggtgatgga cggagttatc gaggcatatc ctccaccact 12120gtcacaggaa ggacctgtca atcttggtca tctatgatac cacactggca tcagaggacc 12180ccagaaaact acccaaatgc tggcctgacc gagaactact gcaggaatcc agattctggg 12240aaacaaccct ggtgttacac aaccgatccg tgtgtgaggt gggagtactg caatctgaca 12300caatgctcag aaacagaatc aggtgtccta gagactccca ctgttgttcc agttccaagc 12360atggaggctc attctgaagc agcaccaact gagcaaaccc ctgtggtccg gcagtgctac 12420catggtaatg gccagagtta tcgaggcaca ttctccacca ctgtcacagg aaggacatgt 12480caatcttggt catccatgac accacaccgg catcagagga ccccagaaaa ctacccaaat 12540gatggcctga caatgaacta ctgcaggaat ccagatgccg atacaggccc ttggtgtttt 12600accatggacc ccagcatcag gtgggagtac tgcaacctga cgcgatgctc agacacagaa 12660gggactgtgg tcgctcctcc gactgtcatc caggttccaa gcctagggcc tccttctgaa 12720caagactgta tgtttgggaa tgggaaagga taccggggca agaaggcaac cactgttact 12780gggacgccat gccaggaatg ggctgcccag gagccccata gacacagcac gttcattcca 12840gggacaaata aatgggcagg tctggaaaaa aattactgcc gtaaccctga tggtgacatc 12900aatggtccct ggtgctacac aatgaatcca agaaaacttt ttgactactg tgatatccct 12960ctctgtgcat cctcttcatt tgattgtggg aagcctcaag tggagccgaa gaaatgtcct 13020ggaagcattg taggggggtg tgtggcccac ccacattcct ggccctggca agtcagtctc 13080agaacaaggt ttggaaagca cttctgtgga ggcaccttaa tatccccaga gtgggtgctg 13140actgctgctc actgcttgaa gaagtcctca aggccttcat cctacaaggt catcctgggt 13200gcacaccaag aagtgaacct cgaatctcat gttcaggaaa tagaagtgtc taggctgttc 13260ttggagccca cacaagcaga tattgccttg ctaaagctaa gcaggcctgc cgtcatcact 13320gacaaagtaa tgccagcttg tctgccatcc ccagactaca tggtcaccgc caggactgaa 13380tgttacatca ctggctgggg agaaacccaa ggtacctttg ggactggcct tctcaaggaa 13440gcccagctcc ttgttattga gaatgaagtg tgcaatcact ataagtatat ttgtgctgag 13500catttggcca gaggcactga cagttgccag ggtgacagtg gagggcctct ggtttgcttc 13560gagaaggaca aatacatttt acaaggagtc acttcttggg gtcttggctg tgcacgcccc 13620aataagcctg gtgtctatgc tcgtgtttca aggtttgtta cttggattga gggaatgatg 13680agaaataatt aattggacgg gagacagagt gaagcatcaa cctacttaga agctgaaacg 13740tgggtaagga tttagcatgc tggaaataat agacagcaat caaacgaaga cactgttccc 13800agctaccagc tatgccaaac cttggcattt ttggtatttt tgtgtataag cttttaaggt 13860ctgactgaca aattctgtat taaggtgtca tagctatgac atttgttaaa aataaactct 13920gcacttattt tgatttga 13938523DNAArtificial SequencePrimer 5acagcaatca aacgaagaca ctg 23628DNAArtificial SequencePrimer 6agcttataca caaaaatacc aaaaatgc 28727DNAArtificial SequenceProbe 7tcccagctac cagctatgcc aaacctt 27816DNAArtificial SequencePrimer 8ccacagtggc cccggt 16921DNAArtificial SequencePrimer 9acagggcttt tctcaggtgg t 211028DNAArtificial SequenceProbe 10ccaagcacag aggctccttc tgaacaag 281120DNAArtificial SequenceSynthetic oligonucleotide 11ggcaggtcct tcctgtgaca 201220DNAArtificial SequenceSynthetic oligonucleotide 12cctgtgacag tggtggagta 201320DNAArtificial SequenceSynthetic oligonucleotide 13tcctgtgaca gtggtggagt 201420DNAArtificial SequenceSynthetic oligonucleotide 14cttcctgtga cagtggtgga 201520DNAArtificial SequenceSynthetic oligonucleotide 15ccttcctgtg acagtggtgg 201620DNAArtificial SequenceSynthetic oligonucleotide 16tccttcctgt gacagtggtg 201720DNAArtificial SequenceSynthetic oligonucleotide 17gtccttcctg tgacagtggt 201820DNAArtificial SequenceSynthetic oligonucleotide 18ggtccttcct gtgacagtgg 201920DNAArtificial SequenceSynthetic oligonucleotide 19aggtccttcc tgtgacagtg 202020DNAArtificial SequenceSynthetic oligonucleotide 20caggtccttc ctgtgacagt 202120DNAArtificial SequenceSynthetic oligonucleotide 21gcaggtcctt cctgtgacag 202220DNAArtificial SequenceSynthetic oligonucleotide 22tggcaggtcc ttcctgtgac 202320DNAArtificial SequenceSynthetic oligonucleotide 23ttggcaggtc cttcctgtga 202420DNAArtificial SequenceSynthetic oligonucleotide 24cttggcaggt ccttcctgtg 202520DNAArtificial SequenceSynthetic oligonucleotide 25gcttggcagg tccttcctgt 202620DNAArtificial SequenceSynthetic oligonucleotide 26tcttcctgtg acagtggtgg 202720DNAArtificial SequenceSynthetic oligonucleotide 27ttcttcctgt gacagtggtg 202820DNAArtificial SequenceSynthetic oligonucleotide 28gttcttcctg tgacagtggt 202920DNAArtificial SequenceSynthetic oligonucleotide 29ggttcttcct gtgacagtgg 203020DNAArtificial SequenceSynthetic oligonucleotide 30aggttcttcc tgtgacagtg 203120DNAArtificial SequenceSynthetic oligonucleotide 31caggttcttc ctgtgacagt 203220DNAArtificial SequenceSynthetic oligonucleotide 32tggcaggttc ttcctgtgac 203320DNAArtificial SequenceSynthetic oligonucleotide 33ttggcaggtt cttcctgtga 203420DNAArtificial SequenceSynthetic oligonucleotide 34cttggcaggt tcttcctgtg 203520DNAArtificial SequenceSynthetic oligonucleotide 35agcttggcag gttcttcctg 203620DNAArtificial SequenceSynthetic oligonucleotide 36actatgcgag tgtggtgtca 203720DNAArtificial SequenceSynthetic oligonucleotide 37gactatgcga gtgtggtgtc 203820DNAArtificial SequenceSynthetic oligonucleotide 38cgactatgcg agtgtggtgt 203920DNAArtificial SequenceSynthetic oligonucleotide 39ccgactatgc gagtgtggtg 204020DNAArtificial SequenceSynthetic oligonucleotide 40tccgactatg cgagtgtggt 204120DNAArtificial SequenceSynthetic oligonucleotide 41gtccgactat gcgagtgtgg 204220DNAArtificial SequenceSynthetic oligonucleotide 42ggtccgacta tgcgagtgtg 204320DNAArtificial SequenceSynthetic oligonucleotide 43gggtccgact atgcgagtgt 204420DNAArtificial SequenceSynthetic oligonucleotide 44ctgctcagtc ggtgcttgtt 204520DNAArtificial SequenceSynthetic oligonucleotide 45cctctgctca gtcggtgctt 204620DNAArtificial SequenceSynthetic oligonucleotide 46gcctctgctc agtcggtgct 204720DNAArtificial SequenceSynthetic oligonucleotide 47cttccagtga cagtggtgga 204820DNAArtificial SequenceSynthetic oligonucleotide 48ttcttccagt gacagtggtg 204920DNAArtificial SequenceSynthetic oligonucleotide 49gttcttccag tgacagtggt 205020DNAArtificial SequenceSynthetic oligonucleotide 50ggttcttcca gtgacagtgg 205120DNAArtificial SequenceSynthetic oligonucleotide 51gaccttaaaa gcttatacac 205220DNAArtificial SequenceSynthetic oligonucleotide 52gtcagacctt aaaagcttat 205320DNAArtificial SequenceSynthetic oligonucleotide 53tgtcagtcag accttaaaag 205420DNAArtificial SequenceSynthetic oligonucleotide 54gaatttgtca gtcagacctt 205520DNAArtificial SequenceSynthetic oligonucleotide 55agaatttgtc agtcagacct 205620DNAArtificial SequenceSynthetic oligonucleotide 56ccttaataca gaatttgtca 205720DNAArtificial SequenceSynthetic oligonucleotide 57gctccgttgg tgcttgttca 205820DNAArtificial SequenceSynthetic oligonucleotide 58tgctccgttg gtgcttgttc 205920DNAArtificial SequenceSynthetic oligonucleotide 59ttgctccgtt ggtgcttgtt 206020DNAArtificial SequenceSynthetic oligonucleotide 60tttgctccgt tggtgcttgt 206120DNAArtificial SequenceSynthetic oligonucleotide 61ctttgctccg ttggtgcttg 206220DNAArtificial SequenceSynthetic oligonucleotide 62tcctgtaaca gtggtggaga 206320DNAArtificial SequenceSynthetic oligonucleotide 63ttcctgtaac agtggtggag 206420DNAArtificial SequenceSynthetic oligonucleotide 64cttcctgtaa cagtggtgga 206520DNAArtificial SequenceSynthetic oligonucleotide 65ccttcctgta acagtggtgg 206620DNAArtificial SequenceSynthetic oligonucleotide 66tccttcctgt aacagtggtg 206720DNAArtificial SequenceSynthetic oligonucleotide 67gtccttcctg taacagtggt 206820DNAArtificial SequenceSynthetic oligonucleotide 68tgtccttcct gtaacagtgg 206920DNAArtificial SequenceSynthetic oligonucleotide 69tggagccaga

ataacattcg 207020DNAArtificial SequenceSynthetic oligonucleotide 70cctctaggct tggagccaga 207120DNAArtificial SequenceSynthetic oligonucleotide 71agttcttcct gtgacagtgg 207220DNAArtificial SequenceSynthetic oligonucleotide 72gtccgactat gctggtgtgg 207320DNAArtificial SequenceSynthetic oligonucleotide 73ggtccgacta tgctggtgtg 207420DNAArtificial SequenceSynthetic oligonucleotide 74gggtccgact atgctggtgt 207520DNAArtificial SequenceSynthetic oligonucleotide 75cctctaggct tggaatcggg 207620DNAArtificial SequenceSynthetic oligonucleotide 76gttcagaagg agcctctagg 207720DNAArtificial SequenceSynthetic oligonucleotide 77tgttcagaag gagcctctag 207820DNAArtificial SequenceSynthetic oligonucleotide 78gcttgttcag aaggagcctc 207920DNAArtificial SequenceSynthetic oligonucleotide 79tgcttgttca gaaggagcct 208020DNAArtificial SequenceSynthetic oligonucleotide 80gtgcttgttc agaaggagcc 208120DNAArtificial SequenceSynthetic oligonucleotide 81ggtgcttgtt cagaaggagc 208220DNAArtificial SequenceSynthetic oligonucleotide 82tggtgcttgt tcagaaggag 208320DNAArtificial SequenceSynthetic oligonucleotide 83gctcagttgg tgcttgttca 208420DNAArtificial SequenceSynthetic oligonucleotide 84tgctcagttg gtgcttgttc 208520DNAArtificial SequenceSynthetic oligonucleotide 85gcttggatct gggaccaccg 208620DNAArtificial SequenceSynthetic oligonucleotide 86gcctccatgc ttggaactgg 208720DNAArtificial SequenceSynthetic oligonucleotide 87gctcagttgg tgctgcttca 208820DNAArtificial SequenceSynthetic oligonucleotide 88cctcgataac tctggccatt 208920DNAArtificial SequenceSynthetic oligonucleotide 89tcctgtgaca gtggtggaga 209020DNAArtificial SequenceSynthetic oligonucleotide 90gtaggttgat gcttcactct 209120DNAArtificial SequenceSynthetic oligonucleotide 91cgtttgattg ctgtctatta 209220DNAArtificial SequenceSynthetic oligonucleotide 92ctctgtgctt ggatctggga 209320DNAArtificial SequenceSynthetic oligonucleotide 93cctctgtgct tggatctggg 209420DNAArtificial SequenceSynthetic oligonucleotide 94gcctctgtgc ttggatctgg 209520DNAArtificial SequenceSynthetic oligonucleotide 95agaagcctct gtgcttggat 209620DNAArtificial SequenceSynthetic oligonucleotide 96ttcagaagaa gcctctgtgc 209720DNAArtificial SequenceSynthetic oligonucleotide 97gctccgttgg tgcttcttca 209820DNAArtificial SequenceSynthetic oligonucleotide 98tttgctccgt tggtgcttct 209920DNAArtificial SequenceSynthetic oligonucleotide 99gctttgctcc gttggtgctt 2010020DNAArtificial SequenceSynthetic oligonucleotide 100ggctttgctc cgttggtgct 2010120DNAArtificial SequenceSynthetic oligonucleotide 101gggctttgct ccgttggtgc 2010220DNAArtificial SequenceSynthetic oligonucleotide 102ccttcctgtg acagtggtag 2010320DNAArtificial SequenceSynthetic oligonucleotide 103tccttcctgt gacagtggta 2010420DNAArtificial SequenceSynthetic oligonucleotide 104tgtccttcct gtgacagtgg 2010520DNAArtificial SequenceSynthetic oligonucleotide 105cctctaggct tggaaccggg 2010620DNAArtificial SequenceSynthetic oligonucleotide 106tgcttgttcg gaaggagcct 2010720DNAArtificial SequenceSynthetic oligonucleotide 107gtgcttgttc ggaaggagcc 2010820DNAArtificial SequenceSynthetic oligonucleotide 108gcttggaact gggaccaccg 2010920DNAArtificial SequenceSynthetic oligonucleotide 109ctgtgcttgg aactgggacc 2011020DNAArtificial SequenceSynthetic oligonucleotide 110ctctgtgctt ggaactggga 2011117DNAArtificial SequenceSynthetic oligonucleotide 111cctgtgacag tggtgga 1711217DNAArtificial SequenceSynthetic oligonucleotide 112tcctgtgaca gtggtgg 1711317DNAArtificial SequenceSynthetic oligonucleotide 113ttcctgtgac agtggtg 1711417DNAArtificial SequenceSynthetic oligonucleotide 114cttcctgtga cagtggt 1711517DNAArtificial SequenceSynthetic oligonucleotide 115ccttcctgtg acagtgg 1711617DNAArtificial SequenceSynthetic oligonucleotide 116tccttcctgt gacagtg 1711717DNAArtificial SequenceSynthetic oligonucleotide 117gtccttcctg tgacagt 1711817DNAArtificial SequenceSynthetic oligonucleotide 118ggtccttcct gtgacag 1711917DNAArtificial SequenceSynthetic oligonucleotide 119ccgactatgc gagtgtg 1712017DNAArtificial SequenceSynthetic oligonucleotide 120gtccgactat gcgagtg 1712117DNAArtificial SequenceSynthetic oligonucleotide 121ggtccgacta tgcgagt 1712217DNAArtificial SequenceSynthetic oligonucleotide 122gtcagacctt aaaagct 1712317DNAArtificial SequenceSynthetic oligonucleotide 123aagcctctgt gcttgga 1712417DNAArtificial SequenceSynthetic oligonucleotide 124agcctctgtg cttggat 1712517DNAArtificial SequenceSynthetic oligonucleotide 125gcctctgtgc ttggatc 1712617DNAArtificial SequenceSynthetic oligonucleotide 126gctccgttgg tgcttct 1712717DNAArtificial SequenceSynthetic oligonucleotide 127ctctgtgctt ggaactg 1712817DNAArtificial SequenceSynthetic oligonucleotide 128tgcctcgata actctgt 1712917DNAArtificial SequenceSynthetic oligonucleotide 129tgtgcctcga taactct 1713017DNAArtificial SequenceSynthetic oligonucleotide 130gctcagttgg tgctgct 1713127DNAArtificial SequenceSynthetic oligonucleotide 131gcgtttgctc ttcttcttgc gtttttt 271323987DNAMacaca mulatta 132atgtatcgtt ttggaatttc cagtggcttg atcaggaact actgcaggaa tccagatcct 60gtggcagccc cttattgtta tacgatggat cccaatgtca ggtgggagta ctgcaacctg 120acacaatgct cagatgcaga agggactgcc gtcgcacctc cgaatgtcac cctggttcca 180agcctagagg ctccttccga acaatcaccg actgagcaaa ggcctggggt gcaggagtgc 240taccacggta atggacagag ttatcgaggc acatacttca ccactgtgac aggaagaacc 300tgccaagctt ggtcatctat gacaccgcac tctcatagtc ggaccccgga aaactaccca 360aatggtggct tgatcaggaa ctactgcagg aatccagatc ctgtggcagc cccttattgt 420tataccatgg atcccaatgt caggtgggag tactgcaacc taacacaatg ctcagacgca 480gaagggattg ccgtcacacc tctgactgtt accccggttc caagcctaga ggctccttcc 540aagcaagcac caactgagca aaggcctggt gtccaggagt gctaccatgg taatggacag 600agttatcgag gcacatactt caccactgtg acaggaagaa cctgccaagc ttggtcatct 660atgacaccac attctcatag tcgtacccca gaaaactacc caaatggcag tccgacctct 720tcagatctct tagtctaccc tgccgtcttc cttgatgcca tgggtcccac tgttctttca 780actcatccgc tttccctcag tcccggagtg gctgcgacca gcagaggata tattgagagc 840aagagagaag caccgactga gcaaaggcct ggggtgcagg agtgctacca cggtaatgga 900cagagttatc gaggcacata cttcaccact gtgacaggaa gaacctgcca agcttggtca 960tctatgacac cgcactctca tagtcggacc ccggaaaact acccaaatgg tggcttgatc 1020aggaactact gcaggaatcc agatcctgtg gcagcccctt attgttatac catggatccc 1080agtgtcaggt gggagtactg caacctgaca caatgctcag acgcagaagg gactgccgtc 1140gcacctccga atgtcacccc ggttccaagc ctagaggctc cttctgagca agcaccaact 1200gagcaaaggc ttggggtgca ggagtgctac cacagtaatg gacagagtta tcgaggcaca 1260tacttcacca ctgtgacagg aagaacctgc caagcttggt catctatgac accacactct 1320catagtcgga ccccagaaaa ctacccaaat gctggcttgg tcaagaacta ctgccgaaat 1380ccagatcctg tggcagcccc ttggtgttat acaacggatc ccagtgtcag gtgggagtac 1440tgcaacctga cacgatgctc agatgcagaa gggactgctg tcgtgcctcc aaatattatt 1500ccggttccaa gcctagaggc ttttcttgaa caagaaccga ctgaggaaac ccccggggta 1560caggagtgct actaccatta tggacagagt tatagaggca catactccac cactgttaca 1620ggaagaactt gccaagcttg gtcatctatg acaccacacc agcatagtcg gaccccaaaa 1680aactatccaa atgctggcct gaccaggaac tactgcagga atccagatgc tgagattcgc 1740ccttggtgtt ataccatgga tcccagtgtc aggtgggagt actgcaacct gacacaatgt 1800ctggtgacag aatcaagtgt ccttgaaact ctcacagtgg tcccagatcc aagcacacag 1860gcttcttctg aagaagcacc aacggagcaa agtcccgagg tccaggactg ctaccatggt 1920gatggacaga gttatcgagg ctcattctcc accactgtca caggaaggac atgtcagtct 1980tggtcctcta tgacaccaca ctggcatcag aggacaacag aatattatcc agatggtggc 2040ctgaccagga actactgcag gaatccagat gctgagattc gcccttggtg ttataccatg 2100gatcccagtg tcaggtggga gtactgcaac ctgacacaat gtccagtgac agaatcaagt 2160gtcctcgcaa cgtccatggc tgtttctgaa caagcaccaa tggagcaaag ccccggggtc 2220caggactgct accatggtga tggacagagt tatcgaggtt cattctccac cactgtcaca 2280ggaaggacat gtcagtcttg gtcctctatg acaccacact ggcatcagag gaccatagaa 2340tactacccaa atggtggcct gaccaagaac tactgcagga atccagatgc tgagattcgc 2400ccttggtgtt ataccatgga tcccagagtc agatgggagt actgcaacct gacacaatgt 2460gtggtgatgg aatcaagtgt ccttgcaact cccatggtgg tcccagttcc aagcagagag 2520gttccttctg aagaagcacc aactgaaaac agccctgggg tccaggactg ctaccaaggt 2580gatggacaga gttatcgagg cacattctcc accactatca caggaagaac atgtcagtct 2640tggttgtcta tgacaccaca tcggcatcgg aggatcccat tacgctatcc aaatgctggc 2700ctgaccagga actattgcag aaatccagat gctgagattc gcccttggtg ttacaccatg 2760gatcccagtg tcaggtggga gtactgcaac ctgacacaat gtccagtgac agaatcaagt 2820gtcctcacaa ctcccacggt ggtcccggtt ccaagcacag aggctccttc tgaacaagca 2880ccacctgaga aaagccctgt ggtccaggat tgctaccatg gtgatggaca gagttatcga 2940ggcacatcct ccaccactgt cacaggaagg aactgtcagt cttggtcatc tatgatacca 3000cactggcatc agaggacccc agaaaactac ccaaatgctg gcctgaccag gaactactgc 3060aggaatccag attctgggaa acaaccctgg tgttacacga ctgatccatg tgtgaggtgg 3120gagtactgca acctgacaca atgctcagaa acagaatcag gtgtcctaga gactcccact 3180gttgttccgg ttccaagcat ggaagctcat tctgaagcag caccaactga gcaaacccct 3240gtggtccagc agtgctacca tggtaatgga cagagttatc gaggcacatt ctccaccact 3300gtcacaggaa ggacatgtca atcttggtca tccatgacac cacaccagca taagaggacc 3360ccggaaaacc acccaaatga tggcttgaca atgaactact gcaggaatcc agatgctgac 3420acaggccctt ggtgttttac catggacccc agcgtcaggc gggagtactg caacctgacg 3480cgatgctcag acacagaagg gactgtggtc acacctccga ctgttatccc ggttccaagc 3540ctagaggctc cttctgaaca agtgcttgga attcatcctg aattaaacga cacaattgct 3600aacttggact caaaggtgaa ttctttccca ccttgtgcca cagcatcctc ttcatttgat 3660tgtgggaagc ctcaagtgga gccaaagaaa tgtcctggaa gcattgtagg tgggtgtgtg 3720gcccacccac attcctggcc ctggcaagtc agtcttagaa caaggtttgg aaagcacttc 3780tgtggaggca ccttaatatc cccagagtgg gtgctgactg ctgcttgctg cttggagacg 3840ttctcaaggc cttccttcta caaggtcatc ctgggtgcac accaagaagt gaatctcgaa 3900tctcatgttc aagaaataga agtgtctagg ttgttcttgg agcccatagg agcagatatt 3960gccttgctaa agctaagcag gtactaa 398713320DNAArtificial SequenceSynthetic oligonucleotide 133ggttcttcca gtgacagtgg 2013420DNAArtificial SequenceSynthetic oligonucleotide 134atgcctcgat aactccgtcc 20

Claims

1. A compound, or a salt thereof, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 3900 to 3919 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1.

2. The compound of claim 1, wherein the modified oligonucleotide consists of 15 to 30, 18 to 24, 19 to 22, 13 to 25, 14 to 25, 15 to 25, 16 to 20 linked nucleosides.

3. The compound of claim 1, wherein the modified oligonucleotide comprises a nucleobase sequence comprising a portion of at least 10, at least 12, at least 14, at least 16, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 1.

4. (canceled)

5. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 1000% complementary to SEQ ID NO: 1.

6-7. (canceled)

8. The compound of claim 1, wherein the modified oligonucleotide is single-stranded.

9. The compound of claim 1, wherein at least one internucleoside linkage is a modified internucleoside linkage.

10. The compound of claim 9, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

11. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar.

12. The compound of claim 11, wherein at least one modified sugar is a bicyclic sugar.

13. The compound of claim 11, wherein at least one modified sugar comprises a 2'-O-methoxyethyl, a constrained ethyl, a 3'-fluoro-HNA or a 4'-(CH.sub.2).sub.n--O-2' bridge, wherein n is 1 or 2.

14. The compound of claim 1, wherein at least one nucleoside comprises a modified nucleobase.

15. The compound of claim 14, wherein the modified nucleobase is a 5-methylcytosine.

16. The compound of claim 1, wherein the modified oligonucleotide consists of 12 to 20 linked nucleosides and comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

17. The compound of claim 16, wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises: a gap segment consisting of ten linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; a 3' wing segment consisting of five linked nucleosides; wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate and wherein each cytosine residue is a 5-methylcytosine.

18. The compound of claim 16, wherein the modified oligonucleotide consists of 20 linked nucleosides.

19. (canceled)

20. A composition comprising a compound according to claim 1, or a salt thereof, and a pharmaceutically acceptable carrier or diluent.

21. A method of treating, preventing, or slowing progression of a disease related to elevated apo(a) and/or elevated Lp(a) in a patient in need thereof, comprising administering the composition according to claim 20, or a salt thereof.

22. A method of treating, preventing, or slowing progression of a disease related to elevated apo(a) and/or elevated Lp(a) in a patient in need thereof, comprising administering a compound according to claim 1, or a salt thereof.

23. The method of claim 21, wherein the disease is an inflammatory, cardiovascular or metabolic disease, disorder or condition.

24. The method of claim 22, wherein the disease is an inflammatory, cardiovascular or metabolic disease, disorder or condition.