Methods and compositions for measuring and managing oxidative stress levels

Abstract

Provided herein are methods for providing personalized antioxidant supplement blend for an individual subject based on the levels of antioxidant biomarkers, prooxidant biomarkers, and genetic statuses. The antioxidant supplement blend includes suggestions for one or more of diet, supplements, and / or life style changes for the individual.

Description

Attorney Ref: VIB-029WO METHODS AND COMPOSITIONS FOR MEASURING AND MANAGING OXIDATIVE STRESS LEVELS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to the U.S. Provisional Patent Application No. 63 / 561,648, filed on March 5, 2024, the entire content of which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Aging is a complex process involving a gradual decline in organ function, leading to mortality. Oxidative damage to cellular biomolecules, such as lipids, DNA, and proteins, is considered to play a central role in the aging process. In particular, reactive species (e.g., reactive oxygen species (ROS) and reactive nitrogen species (RNS)) can damage cells and stop proliferation. The human body has an antioxidant system to counteract this damage, but when oxidant levels exceed the body’s ability to neutralize them, oxidative stress results. This stress contributes to the aging process and is linked to age-related diseases (e.g., cardiovascular disease, neurodegenerative disorders, and cancer). Therefore, methods for conducting an effective diagnosis of an individual’s deficiencies and combat oxidative damage to potentially slow down aging are required. SUMMARY

[0003] Disclosed herein are personalized antioxidant supplement blends that can help improve an individual’s aging process based on a particular individual’s health profile. Such personalized antioxidant supplement blend can effectively reduce oxidative stress and provide personalized anti-aging products, dietary, supplement, and lifestyle suggestions along with routine monitoring strategies in accordance with an individual’s health profile. Further disclosed herein are methods for determining quantities of each active element to be included in the personalized antioxidant supplement blends.

[0004] In one aspect, provided herein is a method for determining a personalized antioxidant supplement blend for an individual, the method comprising: (a) obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for the individual; (b) determining an antioxidant score from the antioxidant biomarker values and a first set of genetic information; (c) determining a prooxidant score from the prooxidant biomarker values and a second set of genetic information;Attorney Ref: VIB-029WO (d) determining a personalized factor for the individual using the antioxidant score and the prooxidant score; and (e) identifying the personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor.

[0005] In one aspect, the method further comprises repeating steps (a)-(e) every three or four months.

[0006] In one aspect, an antioxidant biomarker value comprises a quantitative measurement of an enzyme, a small molecule, a non-enzymatic protein or combinations thereof from a sample obtained from the individual.

[0007] In one aspect, the sample comprises one or more of serum, plasma, erythrocytes, white blood cells, whole blood, tissues, or urine.

[0008] In one aspect, the enzyme is selected from the group consisting of Superoxide dismutase, Catalase, Glutathione peroxidase and Glutathione reductase or combinations thereof.

[0009] In one aspect, the small molecule is selected from the group consisting of Glutathione, Glutathione disulfide, Glutathione:Glutathione disulfide, Uric acid, Coenzyme Q10, Vitamin A, Vitamin C, Vitamin E and Selenium or combinations thereof.

[0010] In one aspect, the non-enzymatic protein is Oxidized albumin or Ceruloplasmin or a combination thereof.

[0011] In one aspect, the antioxidant biomarker value is obtained using mass spectroscopy.

[0012] In one aspect, a prooxidative marker value comprises a quantitative measurement of a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker or combinations thereof from a sample obtained from the individual.

[0013] In one aspect, the sample comprises one or more of serum, plasma, erythrocytes, saliva, Peripheral lymphocyte, cerebrospinal fluid (CSF), whole blood, tissue, or urine.

[0014] In one aspect, the lipid peroxidation markers are selected from the group consisting of Malondialdehyde, 4-Hydroxynonenal, 8- Isoprostaglandin F-2α, 11β- Prostaglandin F-2α, 15(R)- Prostaglandin F-2α and 8-Iso-15(R)- Prostaglandin F-2α or combinations thereof.

[0015] In one aspect, the nucleic acid damage marker is a DNA damage marker, an RNA damage marker or combinations thereof.

[0016] In one aspect, the DNA damage marker is selected from the group consisting of 8- Hydroxy-2' -deoxyguanosine, 8-Hydroxyguanine and 8-Nitroguanine or combinations thereof.Attorney Ref: VIB-029WO

[0017] In one aspect, the RNA damage marker is selected from the group consisting of 8- Hydroxyguanosine and 8-Nitroguanosine or combinations thereof.

[0018] In one aspect, the protein damage marker is selected from the group consisting of Allantoin, o, o'-Dityrosine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine and N-(1- Carboxymethyl)-L-lysine or combinations thereof.

[0019] In one aspect, the prooxidative biomarker value is obtained using mass spectrometry.

[0020] In one aspect, the genetic information is determined based on a presence or absence of a polymorphism in an antioxidant gene or in a prooxidant gene from a sample obtained from the individual.

[0021] In one aspect, an antioxidant gene polymorphism is selected from the group consisting of SOD1 (rs2234694), SOD2 (rs4880), SOD3 (rs1799895, rs8192287), GSTM1 (rs366631), GSTM5 (rs3754446), CAT (rs7943316, rs4756146, rs1001179), GPX1 (rs1050450, rs1987628), GPX2 (rs4902346, rs2071566), GPX4 (rs713041), GSR (rs8190955), GSS (rs121909307), GLUL (rs10911021), GSTP1 (rs1695), SELENOP (rs3877899), TXNRD1 (rs7310505), TXNRD2 (rs1548357), TrxR2 (rs4485648), HMOX1 (rs2071746) and PRKAA2 (rs2796498, rs10789038) or combinations thereof.

[0022] In one aspect, a prooxidant gene polymorphism is selected from the group consisting of XDH (−337GA), CYB5R3 (rs916321), CYP1A1 (rs1048943), CYBA (rs4673, A-930G) and COX-2 (rs20417) or combinations thereof.

[0023] In one aspect, the genetic information is obtained from a polymerase chain reaction (PCR) analysis.

[0024] In one aspect, the PCR analysis is a reverse transcription (RT) PCR analysis.

[0025] In one aspect, the method further comprises: determining a plurality of individual antioxidant biomarker scores based on the antioxidant biomarker values; and calculating an antioxidant biomarker score by combining the plurality of individual antioxidant biomarker scores.

[0026] In one aspect, determining the plurality of individual antioxidant biomarker scores comprises: for each of one or more of the antioxidant biomarkers, assigning an individual antioxidant biomarker score for the antioxidant biomarker based on whether the measurement value of the antioxidant biomarker falls below a lower limit (LL), between the LL and an upper limit (UL), or above the UL of a range defined for the antioxidant biomarker.

[0027] In one aspect, the method further comprises:Attorney Ref: VIB-029WO determining a plurality of individual antioxidant single nucleotide polymorphisms (SNP) scores based on the first subset of genetic information; and calculating an antioxidant genetic score by combining the plurality of individual antioxidant SNP scores.

[0028] In one aspect, determining the plurality of individual antioxidant SNP scores further comprises: categorizing each individual antioxidant SNP into a group based on the obtained genetic information; and assigning a value as an individual antioxidant SNP score based on the group.

[0029] In one aspect, the group includes a poor function group, a moderately affected group, and an optimal function group.

[0030] In one aspect, the method further comprises determining an antioxidant score by combining the antioxidant biomarker score and the antioxidant genetic score.

[0031] In one aspect, the method further comprises: determining a plurality of individual prooxidant biomarker scores based on the prooxidant biomarker values; and calculating a prooxidant biomarker score by combining the plurality of prooxidant biomarker scores.

[0032] In one aspect, determining the plurality of individual prooxidant biomarker scores comprises: for each of one or more of the prooxidant biomarkers, assigning an individual value as an individual prooxidant biomarker score for the prooxidant biomarker based on whether the measurement value of the prooxidant biomarker falls below a upper limit (UL), above the UL and within a pre-defined range, or above the UL and beyond the pre-defined range.

[0033] In one aspect, the method further comprises: determining a plurality of individual prooxidant SNP scores based on the second subset of genetic information; and calculating a prooxidant genetic score by combining the plurality of prooxidant antioxidant SNP scores.

[0034] In one aspect, determining the plurality of individual prooxidant SNP scores comprises: categorizing each individual prooxidant SNP into a group based on the obtained genetic information; and assigning a value as an individual prooxidant SNP score based on the group.Attorney Ref: VIB-029WO

[0035] In one aspect, the group includes an optimal function group, a moderately affected group, and an altered function group.

[0036] In one aspect, the method further comprises determining a prooxidant score by combining the prooxidant biomarker score and the prooxidant genetic score.

[0037] In one aspect, the method further comprises determining a redox ratio representing a measure of prooxidant to antioxidant activity in the individual.

[0038] In one aspect, the redox ratio is a ratio of the prooxidant score and the antioxidant score.

[0039] In one aspect, prior to determining the redox ratio, the prooxidant score and the antioxidant score are normalized.

[0040] In one aspect, the method further comprises: determining an antioxidant biomarker score based on values of antioxidant biomarkers; determining an antioxidant genetic score based on the first set of genetic information; and calculating an antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

[0041] In one aspect, the method further comprises: determining a lipid peroxidation biomarker score based on values of lipid peroxidation biomarkers; determining a lipid peroxidation genetic score based on lipid peroxidation genetic information included in the second set of genetic information; and calculating an individual lipid peroxidation score based on the lipid peroxidation biomarker score and the lipid peroxidation genetic score.

[0042] In one aspect, the method further comprises: determining a nucleic acid biomarker score based on values of nucleic acid biomarkers; determining a nucleic acid genetic score based on nucleic acid genetic information included in the second set of genetic information; and calculating an individual nucleic acid score based on the nucleic acid biomarker score and the nucleic acid genetic score.

[0043] In one aspect, the method further comprises: determining a protein damage biomarker score based on values of protein damage biomarkers;Attorney Ref: VIB-029WO determining a protein damage genetic score based on protein damage genetic information included in the second set of genetic information; and calculating an individual protein damage score based on the protein damage biomarker score and the protein damage genetic score.

[0044] In one aspect, the method further comprises: identifying a reference range for each of the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score; and determining an actual marker zone (AMZ) based on the respective individual score and respective reference range.

[0045] In one aspect, the method further comprises: identifying a target marker zone (TMZ) for each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score; and determining the personalized factor respectively for each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score, based on a number of zone transitions from the AMZ to TMZ.

[0046] In one aspect, the method further comprises identifying the dosages of one or more nutrients on each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score using the respective personalized factor.

[0047] In one aspect, the method further comprises: obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for a population including the individual; ividual; determining a reference antioxidant score from the antioxidant biomarker values and a third set of genetic information for the population including the individual; and determining a reference prooxidant score from the prooxidant biomarker values and a fourth set of genetic information.

[0048] In one aspect, the method further comprises: determining an antioxidant biomarker score based on the values of antioxidant biomarkers associated with the population;Attorney Ref: VIB-029WO determining an antioxidant genetic score based on the third set of genetic information associated with the population; and calculating the reference antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

[0049] In one aspect, the method further comprises: determining a prooxidant biomarker score based on the values of prooxidant biomarkers associated with the population; determining a prooxidant genetic score based on the fourth set of genetic information associated with the population; and calculating the reference prooxidant score based on the prooxidant biomarker score and the prooxidant genetic score.

[0050] In one aspect, the method further comprises: determining an antioxidant biomarker score based on values of antioxidant biomarkers for the individual; ntioxidant biomarkers for the individual; determining an antioxidant genetic score based on the first set of genetic information for the individual; and calculating an antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

[0051] In one aspect, the method further comprises: determining a prooxidant biomarker score based on values of prooxidant biomarkers for the individual; determining a prooxidant genetic score based on the first set of genetic information for the individual; and calculating a prooxidant score based on the prooxidant biomarker score and the prooxidant genetic score.

[0052] In one aspect, the method further comprises: identifying a first percentile ranking of the individual antioxidant score relative to the reference antioxidant score; identifying a second percentile ranking of the individual prooxidant score relative to the reference prooxidant score; and determining the personalized factor based on one or more of the first and second percentile rankings.Attorney Ref: VIB-029WO

[0053] In one aspect, identifying the personalized antioxidant supplement blend comprises determining a personalized intervention.

[0054] In one aspect, the personalized intervention comprises recommendations selected from the group consisting of diet, supplements, physical exercise and lifestyle changes and combinations thereof.

[0055] In one aspect, the supplements for improving a level of Prooxidant enzyme SNPs comprises one or more of Quercetin, Aqueous extract of Carica papaya mature leaves, Alpha lipoic acid, Dealcoholized red wine, red grape juice, Catechins, Myricetin, Epicatechin, Indole-3-carbinol, Soybean, Green tea, Curcumin, Garlic, Fish oil, Rosemary Astaxanthin, Vitamin D, Pycnogenol, and β-carotene.

[0056] In one aspect, the supplements for improving a level of SOD comprises one or more of Copper, Manganese, Vitamin E, Vitamin D3, Vitamin C, Selenium, Green tea extract, Curcumin, Coenzyme Q10, and N-Acetyl Cysteine.

[0057] In one aspect, the supplements for improving a level of CAT comprises one or more of Alpha-lipoic acid, Vitamin D3, Vitamin E, Coenzyme Q10, Vitamin C, Vitamin A, Selenium, and Manganese.

[0058] In one aspect, the supplements for improving a level of GPX comprises one or more of Selenium, Vitamin C, Vitamin D, Lutein, Selenium, and Glutathione.

[0059] In one aspect, the supplements for improving a level of GSTM comprises one or more of broccoli, S-Adenosyl methionine, pomegranate-Black carrot juice, and grape pomace extract.

[0060] In one aspect, the supplements for improving a level of GLUL comprises aged garlic extract.

[0061] In one aspect, the supplements for improving a level of HMOX1 comprises one or more of aged garlic extract and resveratrol extra virgin olive oil.

[0062] In one aspect, the supplements for improving a level of SELENOP comprises Selenium.

[0063] In one aspect, the supplements for improving a level of CYB5R3 comprises one or more of Vitamin C and Glutathione.

[0064] In one aspect, the supplements for improving a level of PRKAA2 comprises one or more of folic acid, Alpha lipoic acid, Magnesium, and Vitamin C.

[0065] In one aspect,the supplements for improving a level of TXNRD1 comprises one or more of Quercetin, Seleno, and methionine.Attorney Ref: VIB-029WO

[0066] In one aspect, the supplements for reducing a level of Malondialdehyde (MDA) in improving lipid peroxidation effect comprises one or more of Magnesium, Vitamin E, Olive oil, Melatonin, Vitamin C, Beta-carotene, grape seeds, green tea extract, Neem, Curcumin, Holy basil, Ashwagandha, Selenium, and Glutathione.

[0067] In one aspect, the supplements for reducing a level of 4-hydroxynonenal (4-HNE) in improving lipid peroxidation effect comprises one or more of Vitamin C, Anthocyanins, Vitamin E, Beta-carotene, Lutein, grape seed. Scutellaria baicalensis, Korean red ginseng, Ashwagandha, Carnosine, Quercetin, Epigallocatechin gallate, Selenium, Manganese, Green tea extract, Curcumin, and Glutathione.

[0068] In one aspect, the supplements for reducing a level of 4-Hydroxynonenalmercapturic acid (4-HNE-MA) in improving lipid peroxidation effect comprises Vitamin C.

[0069] In one aspect, the supplements for reducing a level of Lipid Hydroperoxides (LOOH) in improving lipid peroxidation effect comprises one or more of Aged garlic supplement, Tea polyphenols, Vitamin E, and Coenzyme Q10.

[0070] In one aspect, the supplements for reducing a level of Oxidised LDL (oxLDL) in improving lipid peroxidation effect comprises one or more of L-carnitine, Vitamin E, Beta- carotene, Hydroxytyrosol, Vitamin C, 1,27-dihydroxy vitamin D3 and omega-3 fatty acids, Hazelnut, and green tea.

[0071] In one aspect, the supplements for reducing a level of 8-iso-prostaglandin F2α (8-iso- PGF2α) in improving lipid peroxidation effect comprises one or more of Vitamin C, Vitamin E, Omega-3 fatty acid, Lycopene, Beta-carotene, and Selenium.

[0072] In one aspect, the supplements for reducing a level of 11-β-prostaglandin F2α (11- PGF2α) in improving lipid peroxidation effect comprises Omega-3 fatty acid.

[0073] In one aspect, the supplements for reducing a level of 8-Hydroxy-2’-deoxyguanosine (8-OHdG) in improving DNA damage comprises one or more of Alpha-tocopherol, Garlic extract, Coenzyme Q10, Curcumin, Red yeast rice-olive extract, Creatine, Resveratrol, and Vitamin C.

[0074] In one aspect, the supplements for reducing a level of 8-Hydroxyguanine (8-OHG) in improving DNA damage comprises Selenium.

[0075] In one aspect, the supplements for reducing a level of 8-Nitroguanine (8-NO2-G) in improving DNA damage comprises one or more of Curcumin, Dihydrolipoic acid, N-acetyl- L-cysteine, and folic acid.

[0076] In one aspect, the supplements for reducing a level of 8-hydroxyguanosine (8-oxoG) in improving DNA damage comprises Tart cherry juice.Attorney Ref: VIB-029WO

[0077] In one aspect, the supplements for reducing a level of Dityrosine in improving protein damage comprises one or more of Nitisinone and N-acetyl cysteine (NAC).

[0078] In one aspect, the supplements for reducing a level of Nitrotyrosine in improving protein damage comprises one or more of Resveratrol, Vitamin C, Vitamin E, Tetrahydropterin, L-Arginine, and Glycoxidation.

[0079] In one aspect, the supplements for reducing a level of Carboxymethyl lysine (CML) in improving protein damage comprises one or more of Epigallocatechin gallate, Quercetin, Alpha lipoic acid, and Vitamin D.

[0080] In one aspect, the supplements for improving small enzymes of antioxidant markers comprises one or more of Vitamin C, Vitamin E, Calcium ascorbate, Apple polyphenols, Curcumin, Selenium, N-acetylcysteine (NAC), Astaxanthin, Glutathione, Glycine, Lutein, and Beta carotene.

[0081] In one aspect, the supplements for improving proteins of antioxidant markers comprises one or more of Chitosan, N-acetylcysteine (NAC), Zinc, Copper, and Vitamin C.

[0082] In one aspect, the method further comprises administering or having administered the personalized antioxidant supplement blend to the individual. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0083] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0084] FIG. 1 depicts a system overview for determining a personalized antioxidant supplement blend for an individual, in accordance with an embodiment.

[0085] FIGS. 2A and 2B illustrate exemplary comparison and percentile-based categorization, in accordance with an embodiment

[0086] FIG. 3 provides a flowchart of various exemplary methods for determining a personalized antioxidant supplement blend for an individual, in accordance with an embodiment.

[0087] FIG. 4 illustrates an example computing device for implementing systems and methods described in FIGS. 1-3.Attorney Ref: VIB-029WO DETAILED DESCRIPTION Definitions

[0088] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0089] Abbreviations used in this application include the following:

[0090] The terms “marker,” “markers,” “biomarker,” and “biomarkers” encompass, without limitation, lipids, lipoproteins, proteins, cytokines, chemokines, growth factors, peptides, nucleic acids, nutrients, genes, and oligonucleotides, together with their related complexes, metabolites, mutations, variants, polymorphisms, modifications, fragments, subunits, degradation products, elements, and other analytes or sample-derived measures. A marker can also include mutated proteins, mutated nucleic acids, variations in copy numbers, and / or transcript variants, in circumstances in which such mutations, variations in copy number and / or transcript variants are useful for indicating the aging-related health conditions of a subject.

[0091] The term “antioxidant biomarker” is a measurable indicator in biological samples (e.g., blood, urine, or tissues) that reflects the body’s antioxidant status and ability to counteract oxidative stress. An antioxidant biomarker includes an enzymatic antioxidant biomarker or a non-enzymatic antioxidant biomarker.

[0092] An enzymatic antioxidant biomarker is a measurable enzyme in biological samples that helps neutralize reactive oxygen species (ROS) and reduce oxidative stress, including superoxide dismutases (SODs), thioredoxin reductase and catalase (CAT), etc.

[0093] A non-enzymatic antioxidant biomarker is a measurable molecule in biological samples that helps ROS and reduces oxidative stress without enzymatic activity. The non- enzymatic antioxidant biomarker includes a small molecule (e.g., Glutathione (GSH), uric acid, Coenzyme Q10 (CoQ10), Vitamins A, C, E, etc.) or protein (e.g., oxidized albumin, Ceruloplasmin).

[0094] The term “prooxidant biomarker” is a measurable biological indicator that reflects oxidative stress levels in the body. The prooxidant biomarker includes a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker.

[0095] A lipid peroxidation marker is a measurable biomolecule that indicates oxidative damage to lipids,

[0096] A nucleic acid damage marker is a measurable biomolecule that indicates oxidative, chemical, or enzymatic damage to DNA or RNA. A protein damage marker is a biomoleculeAttorney Ref: VIB-029WO that indicates structural or functional modifications to proteins due to oxidative stress, glycation, nitration, or other damaging processes.

[0097] The term “supplement” is a product taken to supplement a person’s diet.

[0098] The term “product” is any product intended to promote antioxidant defense and slow down the aging process. Depending on its purpose and effect, it can be cosmetics or medications.

[0099] The term “ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, lessening in the severity or progression, remission, or cure thereof.

[0100] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to change aging condition of a subject.

[0101] The term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease. A therapeutically effective amount can be a “prophylactically effective amount” as prophylaxis can be considered therapy.

[0102] The phrase “obtaining or having obtained” encompasses the active step of obtaining certain information and / or a step of instructing e.g., a third party to obtain the information.

[0103] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context explicitly dictates otherwise. Overview

[0104] Aging is a multifactorial process characterized by the gradual and progressive loss of organ function, ultimately leading to mortality. Various theories have been hypothesized to explain aging, with the oxidative theory of aging being one of the most compelling theories. This theory postulates that age-related functional deterioration results from the accumulation of oxidative damage to cellular biomolecules, including lipids, nucleic acids (DNA and RNA), and proteins, caused by oxidant species. The oxidative theory recognizes the mitochondria as primary organelle contributors to the aging process due to the significant role of the mitochondria in generating oxidant species in a body. Consequently, mitochondrial dysfunction is considered a hallmark of aging.

[0105] Although the precise mechanisms linking oxidative stress to aging remain unclear, it is hypothesized that the accumulation of reactive species and their damaged products might induce cellular senescence, which can lead to a decline in physiological functions. Oxidant species can promote cellular senescence by inducing the expression of the senescence-Attorney Ref: VIB-029WO associated secretory phenotype (SASP). SASP involves the secretion of soluble factors (e.g., interleukins, chemokines, and growth factors), degradative enzymes (e.g., matrix metalloproteases (MMPs)), and insoluble proteins / extracellular matrix (ECM) components. These elements can damage a cell, halting cellular proliferation and ultimately leading to cellular senescence. Assessing oxidative stress can help elucidate how this phenomenon leads to aging and aid in developing strategies for mitigation measures, thereby reducing cellular damage and promoting longevity.

[0106] Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, leading to an increase in oxidant species. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules (reactive radical and non- radical species) derived from oxygen and nitrogen, respectively, and are key contributors to oxidative stress. ROS includes superoxide radicals (O2•−), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and singlet oxygen (1O2), while RNS primarily includes nitric oxide radical (•NO).

[0107] These reactive species can originate from both endogenous and exogenous sources. Metabolism is a primary endogenous source that produces reactive species in the body, with inflammation also contributing to their production. Additionally, various exogenous sources such as toxins, ultraviolet (UV) radiation, tobacco and alcohol consumption, and environmental pollutants can further elevate ROS and RNS levels (or production of reactive species). At low to moderate levels, these free radicals can play beneficial roles in the body by participating in immune functions and cellular signaling pathways. However, the elevated levels of oxidant species can be detrimental to the body, as ROS and RNS can attack cellular biomolecules such as lipids, DNA, RNA, and proteins. This can impact the functionality of cellular biomolecules and lead to a decline in physiological processes.

[0108] To counteract the harmful effects of oxidant species, a body is equipped with an antioxidant defense system including endogenous and exogenous antioxidants. Endogenous antioxidants are innately present in the body, whereas exogenous antioxidants need to be acquired through dietary sources. The key exogenous antioxidants that help neutralize reactive species in the body may include vitamins A, C, and E, as well as selenium. The endogenous antioxidants can be enzymatic and non-enzymatic. A primary enzymatic antioxidant defense system includes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), which serve as the body’s first line of defense against oxidative stress by scavenging and neutralizing reactive species. The thioredoxin family,Attorney Ref: VIB-029WO including a group of redox proteins such as thioredoxins (TRXs), glutaredoxins (GLRXs), and peroxiredoxins (PRDXs), also aid in cellular antioxidant function. Glutathione (GSH) is an important endogenous non-enzymatic antioxidant in the body, which along with its various enzymes plays a critical role in cellular defenses against oxidative stress. Other endogenous antioxidants include alpha-lipoic acid, L-arginine, and coenzyme Q10.

[0109] When the level of oxidants surpasses the body’s antioxidant capacity, oxidative stress occurs. Reactive species can attack lipids, initiating the process of lipid peroxidation and generating oxidative damage by-products (e.g., cytotoxic oxidative by-products). Nucleic acids, including DNA and RNA, are also susceptible to oxidative damage, yielding damaged products that can contribute to genomic instability and mutagenesis. Oxidant species can attack proteins, altering the conformation of proteins and impairing enzymatic activity, which ultimately results in oxidative protein damage and the formation of damaged end products. The attack on fundamental biomolecules and the accumulation of damaged products can trigger cell death via apoptosis or necrosis, giving rise to various pathologies. The pathologies can include cardiovascular diseases (CVD), neurodegenerative diseases, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), diabetes, and cancer. Moreover, the progressive, age-associated accumulation of oxidative damage to macromolecules that leads to functional loss is believed to drive the aging process. This implies that aging is associated with oxidative stress, which increases the susceptibility to age-related diseases.

[0110] Due to increasing awareness of the importance of overall health, there has been a significant rise in products aimed at improving various aspects of well-being. However, many of these products still fall short of addressing the specific needs of an individual’s health on a deeper, cellular level. To effectively support and enhance the aging process, a more personalized approach is necessary. As aforementioned, anti-aging approaches can focus on reducing oxidative damage, as oxidative stress is a key contributor to the aging process. Factors such as genetics, immune function, oxidative stress, cellular degradation, and mitochondrial function can be analyzed to create a tailored regimen (e.g., nutritional blend) that targets an individual’s unique health needs. By considering these personalized elements, customized strategies to combat oxidative damage and promote cellular repair can be developed, ultimately contributing to a healthier and more resilient aging process.

[0111] Reference is made to FIG. 1 which depicts a system overview for determining a personalized antioxidant supplement blend for example individual 110, in accordance with an embodiment. FIG. 1 introduces an individual 110 who may undergo one or more assay(s)Attorney Ref: VIB-029WO 120 to determine factors that are informative for determining a personalized blend. As described herein, example factors include one or more of antioxidant biomarkers, prooxidant biomarkers, genetics, and possible other factors (e.g., hormones, metabolism, nutrients, and gut microbiome, etc.).

[0112] FIG. 1 further introduces a personalized antioxidant supplement system 130. Generally, system 130 analyzes the various factors and determines a personalized antioxidant supplement blend 140 that is personalized for the individual 110. Example compositions of personalized antioxidant supplement blends are disclosed herein. In various embodiments, the personalized antioxidant supplement blend is provided to the individual 110. Personalized blend

[0113] In one aspect, provided herein are ‘personalized blends’ or ‘customized blends’ comprising antioxidant nutrients in dosages calculated based on the amount required to minimize an individual’s oxidative stress and optimize the individual’s nutrient values (e.g., bring the individual’s nutrient levels into the optimum nutrient zone), as determined by the ‘Dosage’ formula (e.g., Equations 1-22 below).

[0114] In one aspect, the personalized blend includes personalized diet, exercise, supplementation plan, and lifestyle changes, whereas the supplementation plan includes the customized dosage of antioxidant nutrient supplements. Methods

[0115] The present disclosure relates to the field of oxidative stress, particularly the effective assessment of oxidative stress followed by an effective personalized antioxidant supplement blend that is customized to reduce oxidative stress and meet an individual’s health goals. The supplement blend also takes into account the genetics (e.g., redox genetics), extracellular assessment values (serum nutrient levels), intracellular assessment values (e.g., red blood cells (RBC) and white blood cells (WBC) nutrient levels), whole blood analysis (e.g., of antioxidants), urine analysis (e.g., of oxidative damage markers), absorption factor, body metrics, nutrient metrics, symptoms, conditions, comorbidities, and supporting health factors that will aid in a holistic approach to reducing oxidative stress in the body and promoting healthy aging.

[0116] Provided herein are methods of assessing and estimating oxidative stress by analyzing redox genetics and measuring antioxidant levels along with oxidative damage markers. Blood analysis, including serum, RBC, WBC, and whole blood, may be performedAttorney Ref: VIB-029WO to assess the levels of various antioxidants in the body, depending on their applicability. These antioxidants play a crucial role in neutralizing reactive oxygen species (ROS) and mitigating oxidative damage. In some embodiments, the methods may also include urine analysis, which is conducted to measure biomarkers associated with lipid peroxidation, nucleic acid damage, and protein damage. In some embodiments, the methods may further include genetic testing for redox genes. This genetic assessment may help decipher an individual’s innate redox status, understanding the individual’s natural ability to manage oxidative stress. These assessments and measurements (extracellular and / or intracellular testing) indicate the degree of oxidative stress in the body.

[0117] The method for providing an antioxidant supplement for a subject (e.g., a human subject) as disclosed herein is based on a comprehensive panel that assesses intracellular and extracellular levels of biomarkers. In some embodiments, by integrating an individual’s chronological age with biomarker assessments, the individual’s redox scores may be determined. This score may then be compared with an established redox score for that age group. Based on where the individual’s biomarker scores lie for that age, the intensity of the personalized intervention to reduce oxidative stress can be determined accordingly. These personalized interventions are tailored to the individual’s innate redox potential and current oxidative state (as reflected by the biomarkers). In some embodiments, the personalized interventions may include dietary modifications, supplementation, physical exercise, and lifestyle adjustments. The intensity of the interventions may also be modulated based on the desired target levels for oxidative stress reduction.

[0118] Oxidative stress is inevitable; however, excessive oxidative stress can accelerate aging and increase the risk of age-associated conditions. Therefore, effective management of oxidative stress is important. Reducing the oxidative burden in the body may help mitigate the risk of oxidative stress-related conditions. ROS and RNS are key contributors to oxidative stress. However, assessing the level of oxidative stress by directly quantifying these species is challenging due to their high reactivity, short lifespan, and the limitations of conventional qualification techniques. Instead, as described herein, oxidative stress is assessed indirectly by measuring antioxidant levels and biomarkers of oxidative damage.

[0119] Given that various endogenous and exogenous factors are affecting age-associated conditions, the present disclosure proposes methods and protocols that comprehensively assess overall health using specific serum / urine biomarkers, genetic predispositions, and other various intrinsic and extrinsic aging factors to create personalized nutritional productsAttorney Ref: VIB-029WO and establish a personalized antioxidant supplement blend (including dietary and lifestyle interventions), thereby effectively improving an individual’s aging process.

[0120] In some embodiments, the methods described herein measure and evaluate genetic, serum, and urine biomarkers that reflect the status of an individual’s overall health (e.g., cellular health, aging-related diseases) using a specific panel. These markers are tested using various applicable microarray or mass-spectrometry techniques. The test panel also assesses genetic polymorphisms in an antioxidant gene or in a prooxidant gene. In some embodiments, genetic testing may be conducted using reverse transcription polymerase chain reaction (RT PCR). Overall, this panel can assess the status of the individual’s oxidative stress along with the genetic susceptibility to various aging factors.

[0121] In some embodiments, a questionnaire may be designed to gauge the individual’s aging concerns, lifestyle factors, health comorbidities, and aging-care (e.g., antioxidant defense) goals. The methods provided herein take the results from the biomarker and genetics tests along with the inferences from the questionnaire to establish a personalized antioxidant supplement blend. The methods may include creating personalized products, dietary and lifestyle suggestions, antioxidant defense suggestions, and recommendations for regular nutrient monitoring strategies.

[0122] In some embodiments, the method for providing an antioxidant supplement disclosed herein can be used to identify nutrient deficiencies and design personalized supplementation diets comprising supplements and nutrient-rich food sources. The method for providing a personalized antioxidant supplement disclosed herein can subsequently establish the effectiveness of the given diet and supplement plan by monitoring the improvement in patients’ symptoms. In some embodiments, the subjects can undergo additional testing to optimize the nutritional needs of the subject. Such testing can be performed every 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or yearly to modulate the levels of nutrients needed to restore nutritional health continually in a subject and to promote healthy aging. Antioxidant Analysis

[0123] In one aspect, provided herein are methods for determining a personalized antioxidant supplement blend for an individual, the method comprising: obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for the individual; determining an antioxidant score from the antioxidant biomarker values and a first set of genetic information; determining a prooxidant score from the prooxidantAttorney Ref: VIB-029WO biomarker values and a second set of genetic information; determining a personalized factor for the individual using the antioxidant score and the prooxidant score; and identifying the personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor.

[0124] In one aspect, an antioxidant biomarker value comprises a quantitative measurement of an enzyme, a small molecule, a non-enzymatic protein or combinations thereof from a sample obtained from the individual.

[0125] In one aspect, the sample comprises one or more of serum, plasma, erythrocytes, white blood cells, whole blood, tissues, or urine .

[0126] In one aspect, the enzyme is selected from the group consisting of Superoxide dismutase, Catalase, Glutathione peroxidase and Glutathione reductase or combinations thereof.

[0127] In one aspect, the small molecule is selected from the group consisting of Glutathione, Glutathione disulfide, Glutathione:Glutathione disulfide, Uric acid, Coenzyme Q10, Vitamin A, Vitamin C, Vitamin E and Selenium or combinations thereof.

[0128] In one aspect, the non-enzymatic small protein is Oxidized albumin or Ceruloplasmin or a combination thereof.

[0129] In one aspect, the the antioxidant biomarker value is obtained using mass spectroscopy.

[0130] Measuring antioxidant levels can help determine the degree of oxidative stress by assessing the body’s antioxidant capacity. In some embodiments, blood samples are collected, and analysis of serum, RBC, WBC, and whole blood are performed to evaluate the levels of various enzymatic antioxidants, small molecule antioxidants, and protein antioxidants, as shown in Table 1. In some embodiments, antioxidant quantification is carried out using mass spectroscopy-based techniques. The tests can be conducted using different collection methods such as ethylenediaminetetraacetic acid (EDTA), serum separator tube (SST), Ficoll tubes, etc.

[0131] Oxidative stress occurs when the production of ROS and RNS exceeds the body’s ability to neutralize them with antioxidants. Measuring the levels of nutrient (antioxidants) provides insight into the body’s defense system against oxidative damage. Table 1 provides an exemplary set of antioxidants that can be tested, as well as the tissue source (serum, RBC, WBC, or whole blood). This set includes enzymatic antioxidants, which are proteins that directly neutralize ROS / RNS, thereby preventing oxidative damage. For example, superoxide dismutase (SOD) converts superoxide radicals into hydrogen peroxide, reducingAttorney Ref: VIB-029WO oxidative stress. Catalase (CAT) breaks down hydrogen peroxide into water and oxygen, preventing cellular damage. Glutathione peroxidase (GPx) reduces hydrogen peroxide and lipid peroxides, protecting cell membranes. The set in Table 1 also includes non-enzymatic antioxidants, which are small molecules that help neutralize free radicals. For example, glutathione (GSH) is a key intracellular antioxidant that supports detoxification and cellular defense. Vitamin C (ascorbic acid) is a water-soluble antioxidant that neutralizes free radicals and regenerates vitamin E. Vitamin E is a lipid-soluble antioxidant that protects cell membranes from oxidative damage. Coenzyme Q10 (CoQ10) plays a role in mitochondrial energy production and acts as an antioxidant. The set further includes protein-based antioxidants, which contribute to redox balance and repair oxidative damage. For example, oxidized albumin can bind and neutralize free radicals in circulation.

[0132] By analyzing the antioxidant markers in Table 1, the present system can estimate an individual’s antioxidant capacity and determine an oxidative stress level. For example, low antioxidant levels indicate an impaired defense system, increasing susceptibility to oxidative damage and related diseases. In some embodiments, the antioxidant marks in Table 1 may be assessed against specific reference values or ranges, allowing oxidative stress levels to be categorized into various categories (e.g., normal, moderate, or high). This categorization helps guide personalized intervention strategies.

[0133] In some embodiments, the method provided herein assesses the antioxidant levels in subject samples via any protein detection method known in the art. In some embodiments, the detection method is mass spectrometry. In some embodiments, the detection method is Liquid chromatography-mass spectrometry (LC–MS), Gas chromatography-mass spectrometry (GC-MS), or Inductively coupled plasma-mass-spectrometry (ICP-MS). In some embodiments, the detection method is Liquid chromatography-mass spectrometry (LC– MS). In some embodiments, the detection method is Gas chromatography–mass spectrometry (GC-MS). In some embodiments, the detection method is Inductively coupled plasma-mass-spectrometry (ICP-MS).

[0134] In some embodiments, the method provided herein evaluates nutrient levels, both in extracellular serum and inside (intracellular) red blood cells (RBC), white blood cells (WBC), and / or whole blood. The nutrients listed in Table 1 focus on antioxidants. The extracellular antioxidant levels provide a snapshot of the status of nutrient baseline levels at a given time. These extracellular nutrient levels are a reflection of a person’s diet over a narrow period of time. In contrast, RBCs have a normal lifespan of 120 days, and thus intracellular assessments for nutrients in RBCs can provide information on nutrients overAttorney Ref: VIB-029WO longer periods. Additionally, the intracellular levels of nutrients provide information on the absorbed levels of nutrients, thus accounting for factors such as, but not limited to, aging, lifestyle, chronic illness, and medication, that can interfere with absorption and can change the functional nutritional levels. Moreover, actual nutrient utilization occurs inside the cell owing to cellular metabolic processes. At times, nutrients could be present in serum, but poor cellular uptake may result in cells being devoid of these nutrients, thus giving rise to nutrient deficiencies owing to affected cellular activities. For example, poor cellular uptake of vitamin B1 via the thiamine transporter protein can give rise to vitamin B1 deficiency irrespective of its prevalence in serum. Similarly, the affected uptake of vitamin C via the vitamin C transporter protein results in the reduced active transport of vitamin C across the cell membrane which can give rise to a vitamin C deficiency as the cells are not able to get appropriate levels of vitamin C for their function. As a result, it is important to assess nutrients intracellularly in addition to extracellularly. Thus, the intracellular assessment provides information on cellular uptake and utilization of nutrients at the most fundamental level, enabling an understanding of the root cause of nutrient deficiencies.

[0135] In some embodiments, the antioxidant biomarkers (e.g., enzymes, small molecules, proteins) in Table 1 can be quantified in various biological samples as shown in Table 2. Therefore, appropriate biological samples can be selected and tested in assessing oxidative stress and antioxidant levels in clinical, research, and diagnostic settings. For example, protein antioxidants may be detected in serum, plasma, whole blood, tissues, and urine, offering insights into oxidative modifications of proteins and their role in antioxidant defense.

[0136] In some embodiments, one or more antioxidant biomarker scores are determined based on assessment of the antioxidant biomarkers. The determination of the antioxidant biomarker scores listed in Table 3 will be described below. Oxidative Damage Marker Analysis

[0137] In one aspect, provided herein are methods for determining a personalized antioxidant supplement blend for an individual, the method comprising: obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for the individual; determining an antioxidant score from the antioxidant biomarker values and a first set of genetic information; determining a prooxidant score from the prooxidant biomarker values and a second set of genetic information; determining a personalized factorAttorney Ref: VIB-029WO for the individual using the antioxidant score and the prooxidant score; and identifying the personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor.

[0138] Prooxidative biomarkers or oxidative damage markers include substances that can be measured in an individual’s samples to indicate the presence or effects of ROS and RNS in biological systems. Oxidative damage markers may help with health diagnosis, prognosis, and treatment of oxidative damage to lipids, DNA, proteins, etc. Oxidative damage markers are being studied in clinical practice, which are used in combination with other tests and clinical findings to make a diagnosis or prognosis of health conditions (e.g., associated with oxidative damages).

[0139] Table 4 provides an exemplary set of oxidative damage markers, including damage products of lipids, nucleic acids, and proteins to provide insight into the extent of oxidative stress in the body. Over time, oxidative stress leads to cellular damage, accelerating aging and increasing the risk of chronic conditions such as neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes, which may be indicated by the oxidative damage markers in Table 4. In some embodiments, samples can be analyzed using mass spectroscopy-based techniques. The testing can be conducted using different collection methods such as EDTA, SST, Ficoll tubes, etc.

[0140] Table 4 categorizes the exemplary oxidative damage markers into three groups of lipid peroxidation markers, nucleic acid damage markers, and protein damage markers. Lipid is useful for maintaining cell membrane integrity. Oxidative damage to lipids may lead to the formation of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and isoprostanes, which cause cellular dysfunction and inflammation. This lipid peroxidation damage is linked to conditions such as atherosclerosis, neurodegeneration (e.g., Alzheimer’s), and skin aging. Nucleic acid damage markers in Table 4 include DNA damage markers and RNA damage markers. For example, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanine indicate oxidative damage to DNA, leading to mutations, genomic instability, and accelerated cellular aging. RNA damage markers (e.g., 8-hydroxyguanosine and 8-nitroguanosine) are indicators of increased oxidative burden, which impair protein synthesis and mitochondrial function. Additionally, DNA and RNA oxidation are associated with cancer, neurodegenerative diseases, and immune system decline. Protein damage markers reflect the oxidative damage that leads to structural changes and affects enzymatic activity and signaling pathways. For example, the markers such as nitrotyrosine, chlorotyrosine, and o,o’- dityrosine indicate oxidative modifications that contribute to loss of muscle function, immuneAttorney Ref: VIB-029WO system deterioration, and chronic inflammation, and N-(1-Carboxymethyl)-L-lysine is an advanced glycation end-product (AGE) associated with diabetes, kidney disease, and cognitive decline.

[0141] Chronic oxidative damage is linked to mitochondrial dysfunction (a key hallmark of aging). Measuring the oxidative damage markers as listed in Table 4 provides a non- invasive method to assess the body’s oxidative burden. These measurements allow for early interventions through dietary antioxidants, supplements, exercise, and lifestyle modifications to slow down the aging process, and can further be used to develop personalized anti-aging strategies by targeting oxidative damage and improving redox balance.

[0142] In some embodiments, the prooxidant biomarkers or oxidant damage markers in Table 4 can be quantified in various biological samples as shown in Table 5. Certain biological samples can be selected and tested in assessing oxidative stress and cellular damage in clinical, research, and diagnostic settings. For example, RNA damage markers that affect protein synthesis and cellular function are primarily detected in urine, making them accessible markers for non-invasive testing. In contrast, protein damage markers that reflect oxidative modifications to proteins and cause structural changes and impaired enzymatic activity, can be measured in serum, plasma, whole blood, tissue, and urine.

[0143] In some embodiments, one or more prooxidant biomarker scores are determined based on assessment of the prooxidant biomarkers. The determination of the prooxidant biomarker scores listed in Table 6 will be described below.

[0144] In one aspect, a prooxidative marker value comprises a quantitative measurement of a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker or combinations thereof from a sample obtained from the individual.

[0145] In one aspect, the sample comprises one or more of serum, plasma, erythrocytes, saliva, Peripheral lymphocyte, cerebrospinal fluid (CSF), whole blood, tissue, or urine.

[0146] In one aspect, the lipid peroxidation markers are selected from the group consisting of Malondialdehyde, 4-Hydroxynonenal, 8- Isoprostaglandin F-2α, 11β- Prostaglandin F-2α, 15(R)- Prostaglandin F-2α and 8-Iso-15(R)- Prostaglandin F-2α or combinations thereof.

[0147] In one aspect, the nucleic acid damage marker is a DNA damage marker, an RNA damage marker or combinations thereof.

[0148] In one aspect, the DNA damage marker is selected from the group consisting of 8- Hydroxy-2' -deoxyguanosine, 8-Hydroxyguanine and 8-Nitroguanine or combinations thereof.Attorney Ref: VIB-029WO

[0149] In one aspect, the RNA damage marker is selected from the group consisting of 8- Hydroxyguanosine and 8-Nitroguanosine or combinations thereof.

[0150] In one aspect, the protein damage marker is selected from the group consisting of Allantoin, o, o'-Dityrosine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine and N-(1- Carboxymethyl)-L-lysine or combinations thereof.

[0151] In one aspect, the prooxidative biomarker value is obtained using mass spectrometry. Genetic Analysis

[0152] In one aspect, the method for determining a personalized antioxidant supplement blend for an individual, the method comprising: obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for the individual; determining an antioxidant score from the antioxidant biomarker values and a first set of genetic information; determining a prooxidant score from the prooxidant biomarker values and a second set of genetic information; determining a personalized factor for the individual using the antioxidant score and the prooxidant score; and identifying the personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor.

[0153] In one aspect, the genetic information is determined based on a presence or absence of a polymorphism in an antioxidant gene or in a prooxidant gene from a sample obtained from the individual.

[0154] Numerous genes play a crucial role in maintaining the balance between prooxidant production and antioxidant defense mechanisms. Genetic polymorphisms that alter the functionality of the encoded proteins can disrupt this balance, leading to oxidative stress. Polymorphisms in the genes responsible for free radical production, such as xanthine dehydrogenase (XDH) and cytochrome b-245 Alpha chain (CYBA), can significantly impact cellular redox balance, contributing to the increased production of ROS and leading to oxidative stress-related diseases. Additionally, the impaired antioxidant function can reduce the body’s ability to quench or neutralize free radicals, further exacerbating oxidative stress. Genetic polymorphisms in primary antioxidant enzyme genes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), may impair their antioxidative capacity, leading to cellular damage and increasing the risk of various pathologies.Attorney Ref: VIB-029WO

[0155] Assessment of genetic variations in prooxidant and antioxidant genes, as shown in Table 7, serves as an effective tool for determining an individual’s inherent redox status. Genetic analysis helps identify the underlying causes of elevated oxidative stress, which may predispose individuals to the risk of diseases. Moreover, genetic testing for oxidative stress- related polymorphisms can facilitate the development of targeted interventions and personalized therapies to mitigate the harmful effects of oxidative stress. In some embodiments, genetic testing in an oxidative stress panel may be performed using saliva samples. Genetic testing can be carried out using any appropriate method known in the art, including but not limited to, reverse transcription polymerase chain reaction (RT-PCR) or quantitative-PCR (qPCR)

[0156] Table 7 provides a list of genetic variations or single nucleotide polymorphisms (SNPs) associated with oxidative stress regulation, categorized into antioxidant and prooxidant genes. The antioxidant genes encode enzymes and proteins that neutralize free radicals and protect against oxidative damage, helping reduce oxidative stress. As shown in Table 7, these genes include SOD genes (e.g., SOD1, SOD2, and SOD3) that convert superoxide radicals into hydrogen peroxide, reducing oxidative stress. Additionally, CAT can break down hydrogen peroxide into water and oxygen, preventing oxidative damage. GPX genes (e.g., GPX1, GPX2, and GPX4) play a role in detoxifying hydrogen peroxide and lipid peroxides. Glutathione reductase (GSR) and glutathione synthetase (GSS) helps maintain glutathione levels, a crucial antioxidant. Selenoprotein P (SELENOP) supports antioxidant defenses and protects cells from oxidative stress. Thioredoxin reductase (TXNRD) and TrxR2 can maintain redox homeostasis and help reduce oxidative damage. Heme Oxygenase 1 (HMOX1) helps protect against oxidative stress by degrading free heme.

[0157] Prooxidant genes are involved in ROS production and processes that increase oxidative burden, contributing to oxidative stress. As shown in Table 7, the prooxidant genes may include XDH that helps uric acid metabolism and ROS production, cytochrome b5 Reductase (CYB5R3) that plays a role in redox reactions and electron transport, cytochrome P450 family 1 subfamily A member 1 (CYP1A1) that metabolizes toxins but generates ROS as a byproduct, CYBA used in NADPH oxidase for generating ROS, and cyclooxygenase-2 (COX-2) that are involved in inflammation and oxidative stress-related processes.

[0158] In some embodiments, one or more redox genetic scores are determined based on assessment of the redox genes with respect to oxidative stress. The determination of the redox genetic scores listed in Table 8 will be described below.Attorney Ref: VIB-029WO

[0159] In one aspect, an antioxidant gene polymorphism is selected from the group consisting of SOD1 (rs2234694), SOD2 (rs4880), SOD3 (rs1799895, rs8192287), GSTM1 (rs366631), GSTM5 (rs3754446), CAT (rs7943316, rs4756146, rs1001179), GPX1 (rs1050450, rs1987628), GPX2 (rs4902346, rs2071566), GPX4 (rs713041), GSR (rs8190955), GSS (rs121909307), GLUL (rs10911021), GSTP1 (rs1695), SELENOP (rs3877899), TXNRD1 (rs7310505), TXNRD2 (rs1548357), TrxR2 (rs4485648), HMOX1 (rs2071746) and PRKAA2 (rs2796498, rs10789038) or combinations thereof.

[0160] In one aspect, a prooxidant gene polymorphism is selected from the group consisting of XDH (−337GA), CYB5R3 (rs916321), CYP1A1 (rs1048943), CYBA (rs4673, A-930G) and COX-2 (rs20417) or combinations thereof.

[0161] In one aspect, the genetic information is obtained from a polymerase chain reaction (PCR) analysis. Determination of Biomarker Scores & Genetic Scores

[0162] As discussed above, assessments are conducted for serological antioxidants, urological prooxidants (or oxidative damage markers), and redox genetics. Based on these evaluations, one or more antioxidant biomarker scores, prooxidant biomarker scores, and redox genetic scores are calculated to quantify and reflect the levels of each respective biomarker. Antioxidant Biomarker Scores

[0163] The levels of various antioxidants (e.g., SOD, CAT, GPx, vitamins A, etc.) are assessed in serum or cellular samples. Based on an individual’s test results, each antioxidant biomarker can be evaluated and assigned a specific risk score. As shown in Table 3, the antioxidant biomarker reference range is categorized into multiple levels (e.g., low, moderate, or high), with a risk score being assigned to each range. A lower antioxidant level corresponds to a higher risk score, indicating greater susceptibility to oxidative stress. A higher antioxidant level receives a lower risk score, suggesting sufficient antioxidant defense.

[0164] An antioxidant biomarker score can then be calculated by averaging the risk scores of all individual antioxidants in accordance with Equation (1). This final score is useful in determining the appropriate dosage for a personalized antioxidant supplement blend. Antioxidant Biomarker Score = Average (Individual Antioxidant Biomarker Score) (1)Attorney Ref: VIB-029WO Prooxidant Biomarker Scores

[0165] The levels of various prooxidants (e.g., MDA, 4-HNE, 8-OHdG, etc.) are assessed in urine or blood samples. Similar to antioxidants, these biomarkers are scored based on their concentration levels, with higher scores reflecting greater oxidative damage. As shown in Table 6, the prooxidant biomarker reference range is categorized into multiple levels (e.g., low, moderate, or high), with a risk score being assigned to each range. A higher prooxidant level corresponds to a higher risk score, indicating greater susceptibility to oxidative stress. A lower prooxidant level receives a lower risk score, suggesting lower oxidative damage.

[0166] A prooxidant biomarker score can then be calculated by averaging the risk scores of all individual prooxidants in accordance with Equation (2). This final score helps to personalize supplement dosages for optimal redox balance. Prooxidant Biomarker Score = Average (Individual Prooxidant Biomarker Score) (2) Redox Genetic Scores

[0167] A redox genetic score quantifies an individual’s genetic predisposition to oxidative stress by assessing variations in antioxidant and prooxidant genes. These scores, referred to as antioxidant genetics score and prooxidant genetics score, are determined by evaluating single nucleotide polymorphisms (SNPs) associated with the body’s redox potential. For example, genetic variations in enzymes such as SOD, GPX, CAT, and GST affect antioxidant defense mechanisms, while SNPs in XDH, CYB5R3, CYP1A1, and NADPH oxidase genes influence prooxidant activity, contributing to oxidative stress. As shown in Table 8, each SNP is assigned a genotype score based on its impact on redox potential. Alleles predisposing the body to low, moderate, or high oxidative stress receive scores of 1, 2, or 3, respectively. In this way, the effect of the SNP is accurately reflected.

[0168] The antioxidant genetics score and prooxidant genetics score are combined with measured biomarker levels to assess an individual’s redox status. In some embodiments, the antioxidant genetics score is calculated by averaging the scores of all antioxidant-related SNPs, while the prooxidant genetics score is derived from the average of all prooxidant SNP scores, according to Equations (3) or (4) below. Antioxidant Genetics Score = Average (Individual Antioxidant SNP Score) (3) Prooxidant Genetics Score = Average (Individual Prooxidant SNP Score) (4)

[0169] In some embodiments, the antioxidant genetics score and prooxidant genetics score are multiplied by the biomarker scores for antioxidants and prooxidants, contributing toAttorney Ref: VIB-029WO an overall redox ratio. The redox ratio helps determine a personalized, genetics-based strategy for managing oxidative stress, optimizing antioxidant supplementation, and reducing the risk of oxidative damage-related diseases. Score-Based Optimization

[0170] Based on the assessment of biomarkers (e.g., regarding serological antioxidants, urological prooxidants, and redox genetics) and determination of biomarker and genetic scores, a personalized supplementation blend or plan is developed, including the appropriate supplements and dosages tailored to individual needs. Various strategies or approaches are offered to optimize the body’s redox balance for improved health and oxidative stress management. In some embodiments, these approaches include a redox-ratio approach, an individual-score approach, and a score-comparison approach. Redox-Ratio Approach for Custom Dosage Optimization

[0171] The first approach focuses on optimizing the body’s redox balance by calculating a redox ratio. In some embodiments, the customized dosage for an antioxidant supplement blend is determined using a multiplication factor, which adjusts actual antioxidant levels to align with target antioxidant zones for optimal balance.

[0172] In some embodiments, an antioxidant total score and a prooxidant total score can be calculated to quantify an individual’s oxidative stress balance by integrating biomarker levels and genetic predispositions. In some embodiments, the antioxidant total score is derived by multiplying an antioxidant biomarker score by an antioxidant genetics score in accordance with Equation (5), reflecting both measured antioxidant levels and genetic efficiency in antioxidant defense. Similarly, the prooxidant total score is obtained by multiplying a prooxidant biomarker score by a prooxidant genetics score in accordance with Equation (6), indicating oxidative stress potential based on biomarker data and genetic risk factors. Antioxidant Total = Antioxidant Biomarker Score × Antioxidant Genetics Score (5) Prooxidant Total = Prooxidant Biomarker Score × Prooxidant Genetics Score (6)

[0173] As discussed above, a redox ratio quantifies the body’s overall redox balance, representing the relationship between oxidative damage (prooxidants) and antioxidant defense mechanisms (e.g., obtained by combining the biomarkers and SNPs, respectively). In some embodiments, the redox ratio is calculated by dividing the prooxidant total score by the antioxidant total score in accordance with Equation (7).Attorney Ref: VIB-029WO Redox Ratio = Prooxidant Total / Antioxidant Total (7)

[0174] A higher redox ratio indicates increased oxidative stress, suggesting a greater need for antioxidant intervention, while a lower ratio reflects a more balanced redox state.

[0175] A customized supplement dosage is designed to optimize antioxidant levels, strengthening the body’s defense against oxidative stress. This optimization takes into account the antioxidant range, ensuring appropriate supplementation. Additionally, the personalized antioxidant supplement blend includes components that mitigate oxidative damage and support cellular repair, ultimately reducing the body’s oxidative burden.

[0176] To personalize the antioxidant supplement blend, in some embodiments, a target antioxidant zone (TAZ) may be determined based on an individual’s current antioxidant status, which is referred to as an actual antioxidant zone (AAZ). The number of zone transitions needed to move the antioxidant from AAZ to TAZ determines a multiplication factor (MF). Table 9 illustrates zone transitions. It indicates the greater the gap between AAZ and TAZ, the higher the MF, ensuring individuals receive adequate supplementation to restore redox balance. For example, zone 1 transition (MF=1.5) shows minor adjustment is needed since antioxidant levels are close to the target range, while other transition zones 1 and 2 respectively show moderate or significant adjustments due to the larger gap from the optimal range.

[0177] For a given supplement, a redox optimization factor (RAF) can then be calculated by multiplying the redox ratio by the multiplication factor (MF), in accordance with Equation 8. Redox Optimization Factor (RAF)i = Redox Ratio × MF (8)

[0178] In some embodiments, the RAF is multiplied by the recommended dietary allowance (RDA) to determine the final dosage of the customized antioxidant supplement blend, according to Equation (9). Customized Blendi = RAF × Starting Dosage (9)

[0179] Here, the starting dosage is RDA. It should be noted that the RAF can be multiplied by the RDA or any selected starting dosage to arrive at the customized blend dosage. While the starting dosage may vary, equation (9) remains the same to determine a customized blend dosage.Attorney Ref: VIB-029WO Individual-Score Approach for Custom Dosage Optimization

[0180] The second approach is to optimize the body’s redox balance by calculating individual redox scores. In some embodiments, the appropriate dosage of the personalized antioxidant supplement blend is determined using a multiplication factor, which adjusts actual marker zones to align with target marker zones for optimal redox regulation.

[0181] In this approach, individual scores for antioxidants, lipid peroxidation markers, nucleic acid damage markers, and protein damage markers are calculated. Using established reference ranges, an actual marker zone (AMZ) is identified and a target marker zone (TMZ) is determined (e.g., by a physician) for each redox marker. Based on this assessment, a personalized antioxidant supplement blend or customized intervention plan is developed to optimize redox balance.

[0182] Individual redox scores are personalized metrics used to assess an individual’s oxidative stress levels by analyzing antioxidant capacity and oxidative damage markers. These scores help determine whether an individual’s oxidative stress levels are within a normal range or if interventions are needed to restore balance.

[0183] A total individual antioxidant score, ΣAi, measures the individual’s ability to neutralize oxidative stress by assessing antioxidant levels. Serological analysis (blood tests) measures antioxidant enzyme activity and non-enzymatic antioxidants, and genetic assessment identifies polymorphisms in antioxidant-related genes (e.g., SOD, CAT, GPX). In some embodiments, serological and genetic assessment carried out for an individual can be applied to determine the individual’s antioxidant marker levels, which gives the total individual antioxidant score (ΣAi) for the individual as calculated according to Equation (10). Individual Antioxidant Total Score (ΣAi) = Antioxidant Biomarker Score × Antioxidant Genetics Score (10)

[0184] A higher ΣAi score indicates strong antioxidant defense, meaning lower susceptibility to oxidative stress-related damage. A lower ΣAi score suggests reduced antioxidant capacity, increasing the risk of oxidative stress and related diseases.

[0185] A total individual lipid peroxidation score, ΣLPiassesses an individual’s oxidative damage to lipids, which can compromise cell membrane integrity and lead to inflammation. In some embodiments, urological assessment of lipid peroxidation damage markers (e.g., MDA, 4-HNE, etc.) is conducted to determine an individual’s ΣLPiscore. In some embodiments, the total individual lipid peroxidation score ΣLPi is calculated in accordance with Equation 11.Attorney Ref: VIB-029WO Individual Lipid Peroxidation Total Score (ΣLPi) = Lipid Peroxidation Biomarker Score × Lipid Peroxidation Genetics (11)

[0186] A high ΣLPi score indicates excessive lipid peroxidation, which can contribute to diseases such as atherosclerosis, neurodegeneration, and metabolic disorders. A low ΣLPiscore suggests minimal lipid oxidation and better cellular integrity.

[0187] A total individual nucleic acid damage score ΣNAi measures an individual’s oxidative damage to DNA and RNA, which can lead to mutations, genomic instability, and aging-related diseases. In some embodiments, urological analysis is applied to detect DNA and RNA oxidation markers (e.g., 8-OhdG, 8-hydroxyguanine) to determine a ΣNAi for an individual. In some embodiments, the total individual nucleic acid damage score ΣNAiis calculated in accordance with Equation 12. Individual Nucleic Acid Damage Total Score (ΣNAi) = Nucleic Acid Damage Biomarker Score × Nucleic Acid Damage Genetics Score (12)

[0188] A high ΣNAiscore suggests increased oxidative stress on genetic material, raising risks for cancer, neurodegenerative diseases, and impaired cellular function. A low ΣNAi score indicates better genomic stability and a lower risk of mutation-driven diseases.

[0189] A total individual protein damage score ΣPDievaluates oxidative modifications to proteins, which can disrupt enzymatic activity, cellular communication, and immune response. In some embodiments, urological analysis is utilized to measure protein oxidation markers (e.g., nitrotyrosine, bromotyrosine, etc.,) to determine a ΣPDifor an individual. In some embodiments, the total individual protein damage score, ΣPDiis calculated in accordance with Equation 13. Individual Protein Damage Total Score (ΣPDi) = Protein Damage Biomarker Score × Protein Damage Genetics Score (13)

[0190] A high ΣPDi score indicates significant protein oxidation, which can contribute to chronic inflammation, immune dysfunction, and neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s). A low ΣPDiscore suggests minimal protein oxidation and better maintenance of cellular function.

[0191] Once individual redox scores (e.g., ΣAi, ΣLPi, ΣNAi, and ΣPDi) are determined, based on a reference range and for each redox marker, an actual marker zone (AMZ) can be identified, and a target marker zone (TMZ) can be determined (e.g., by a physician). In some embodiments, the number of zone transitions required to move from AMZ to TMZ defines a multiplication factor (MF). Table 10 illustrates zone transitions. It indicates the greater theAttorney Ref: VIB-029WO gap between AMZ and TMZ, the higher the MF, ensuring individuals receive adequate supplementation to restore redox balance.

[0192] The MF for each individual redox score may then be multiplied by a starting dosage for the corresponding supplement. This calculation determines a customized Blend (CB) dosage for each supplement, ensuring a personalized and optimized intervention to restore redox balance. In some embodiments, the CB dosages for different redox scores are calculated according to Equations 14 through 17. Customized Blend (CB) Ai = MF × Starting Dosage (14) Customized Blend (CB) LPi = MF × Starting Dosage (15) Customized Blend (CB) NAi = MF × Starting Dosage (16) Customized Blend (CB) PDi = MF × Starting Dosage (17) Score-Comparison Approach for Custom Dosage Optimization

[0193] The third approach includes optimizing the body’s redox balance by calculating individual antioxidant and prooxidant scores and comparing them to age-based population reference scores. A customized blend dosage can be determined using a multiplication factor designed to adjust the current biomarker levels to the target range.

[0194] In some embodiments, to evaluate oxidative stress and determine a personalized antioxidant supplement blend, reference redox scores across different age groups and personalized redox scores (e.g., discussed above in the second approach) for an individual are determined. The analysis of personalized scores based on the reference scores helps determine if an individual’s oxidative balance is within a healthy range and / or if targeted interventions are needed.

[0195] Reference redox scores provide standardized benchmarks for assessing oxidative stress and antioxidant capacity across different age groups.

[0196] In some embodiments, a total reference antioxidant score (ΣAr) is determined, measuring the body’s ability to counteract oxidative stress by evaluating antioxidant levels. In some embodiments, serological and genetic assessments are conducted across the population, which can help determine antioxidant marker levels in relation to chronological age. A comprehensive analysis of this data enables the establishment of a standardized reference antioxidant score (ΣAr) for different age groups. In some embodiments, the ΣAr score can be calculated in accordance with Equation 18.Attorney Ref: VIB-029WO Reference Antioxidant Total Score (ΣAr) = Antioxidant Biomarker Score × Antioxidant Genetics Score (18)

[0197] In some embodiments, assessment (e.g., urological assessment) of prooxidants or oxidative damage markers (e.g., lipids, DNA, RNA, protein) in the population is conducted, which provides insights into the average levels of these markers relative to chronological age. This helps create a comprehensive reference prooxidant score, ΣPr, that represents the expected levels of prooxidants for various age groups, providing a benchmark for comparison in future health assessments. In some embodiments, the ΣPr score can be calculated in accordance with Equation 19. Reference Prooxidant Total Score (ΣPr) = Prooxidant Biomarker Score × Prooxidant Genetics Score (19)

[0198] In addition to the reference scores ΣAr and ΣPr, individual redox scores may be determined. These individual scores can be compared against the reference scores to assess an individual’s oxidative stress levels. In some embodiments, the individual redox scores include an individual antioxidant score and an individual prooxidant score. The individual antioxidant score can be determined using Equation (10) as discussed above, which is reproduced here: Individual Antioxidant Total Score (ΣAi) = Antioxidant Biomarker Score × Antioxidant Genetics Score (10)

[0199] The individual prooxidant score, measuring an individual’s overall oxidative damage marker level, can be calculated in accordance with Equation 20. Individual Prooxidant Total Score (ΣPi) = Prooxidant Biomarker Score × Prooxidant Genetics Score (20)

[0200] In some embodiments, one or more individual scores can be compared to the corresponding reference scores (age-related benchmarks) to guide the determination of a personalized antioxidant supplement blend. In some embodiments, the percentile ranking of an individual’s score relative to a reference score may determine the intensity of the personalized intervention. FIG. 2A illustrates an exemplary comparison and percentile-based categorization 200, where the individual scores are evaluated against the reference scores across different percentile ranges (10th to 90th percentile).

[0201] In FIG. 2A, the intervention intensity is represented by the number of dots, with more dots indicating a higher percentile and a greater need for intervention. For example, aAttorney Ref: VIB-029WO low percentile (10th percentile or below) of prooxidant scores ΣPiindicates low oxidative stress, requiring only maintenance-based interventions. This intervention may include a balanced diet (rich in natural antioxidants), basic nutritional supplementation, moderate exercise to sustain oxidative balance, and healthy lifestyle modifications to prevent oxidative stress buildup. A high percentile (90th percentile or above) of prooxidant scores ΣPi indicates high oxidative stress, requiring intensive mitigation strategies to reduce oxidative stress. This intervention may include targeted dietary plans, specialized antioxidant supplementation, structured physical activity (designed to enhance redox balance), and lifestyle modifications to reduce exposure to oxidative stress triggers (e.g., smoking, pollution, processed foods). On the other hand, antioxidant scores ΣAifalling below the 10th percentile indicate high oxidative stress, while those ΣAiabove the 90th percentile denote strong antioxidant defenses. As a result, the CB dosages are calculated according to Equations 21 and 22. Customized Blend (CB) Ai = MF × Starting Dosage (21) Customized Blend (CB) Pi = MF × Starting Dosage (22)

[0202] Here, the multiplication factor MF may also be determined based on a zone transition from an actual marker zone to an actual marker zone, where the zone may be associated with the categorization of percentile.

[0203] The robustness of the intervention can also be subject to the individual’s health goals. If a middle-aged person (e.g., 50 years old) wants to align their oxidative stress levels with those of a younger age group (e.g., 30–40 years), their redox scores can be compared to that reference range. In such cases, more aggressive interventions are recommended to reduce oxidative stress to levels typically seen in younger individuals.

[0204] This structured approach allows for precision health management, enabling individuals to actively monitor and control their oxidative stress levels for improved cellular health, aging prevention, and disease mitigation. Alternative Score-Comparison Approach

[0205] In addition to computing a comprehensive prooxidant score (ΣPr), in some embodiments, a respective reference lipid peroxidation damage score (ΣLPr), reference nucleic acid damage score (ΣNAr), and reference protein damage score (ΣPDr) can be determined to specifically quantify oxidative damage in different biological conditions, providing a more granular approach for better assessing and managing health risks related to oxidative stress.Attorney Ref: VIB-029WO

[0206] In some embodiments, a reference prooxidant score (ΣLPr) evaluates oxidative damage to lipids, which affects cell membranes and contributes to inflammation and aging. In some embodiments, urinary analysis of lipid peroxidation damage markers across the population is conducted, which provides insights into the levels of these markers concerning chronological age. Through extensive data analysis, a standardized reference lipid peroxidation score (ΣLPr) is established for various age ranges.

[0207] In some embodiments, a reference nucleic acid damage score (ΣNAr) measures oxidative damage to DNA and RNA, which can cause mutations, genomic instability, and age-related diseases. In some embodiments, urinary assessment of nucleic acid damage, including DNA and RNA damage markers, is carried out to help determine the marker levels relative to chronological age. By analyzing this data comprehensively, a total reference nucleic acid damage score (ΣNAr) is developed for different age groups.

[0208] In some embodiments, a reference protein damage score (ΣPDr) evaluates oxidative modifications to proteins, which can disrupt enzymatic function, cellular signaling, and immune responses. In some embodiments, urinary analysis of protein damage markers within the population aids in determining their levels based on chronological age. A thorough evaluation of this data facilitates the creation of a standardized reference protein damage score (ΣPDr) across various age groups.

[0209] In some embodiments, one or more comparisons selected from the group consisting of ΣArvs ΣAi, ΣLPrvs ΣLPi, ΣNArvs ΣNAiand ΣPDrvs ΣPDican be performed to determine a recommended personalized intervention. FIG. 2B illustrates an exemplary comparison and percentile-based categorization 250, where the individual scores are evaluated against the reference scores across different percentile ranges (10th to 90th percentile) for key oxidative stress markers. For example, if an individual has higher-than- normal oxidative damage scores (e.g., ΣLPi, ΣNAi, ΣPDi) and a lower antioxidant score (ΣAi), it may indicate an increased need for antioxidant interventions such as dietary changes, supplementation, etc. If the lower score ΣAiis attributed to a deficiency in antioxidant enzymes, the personalized supplements may include increased CoQ10 and selenium. However, if the ΣAi value is primarily related to the absence of non-enzymatic antioxidants, this particular individual is suggested to enhance the intake of vitamins C and E (e.g., from fruits and nuts). In this way, personalized strategies are developed to mitigate oxidative stress and promote healthy aging.

[0210] This alternative approach allows for a more detailed and precise assessment of health risks associated with oxidative stress, facilitating better management strategies.Attorney Ref: VIB-029WO Example Scoring Methodology

[0211] An example methodology for scoring biological indices used to evaluate oxidative burden is described herein. The indices include serological antioxidants, urological and serological prooxidants, oxidative damage markers, and redox genetics.

[0212] For serological antioxidants, scoring is determined based on marker levels. A value below a lower limit (LL) is assigned a score of 1, while a value between the LL and a upper limit (UL) receives a score of 5. If the value exceeds the UL, it is given a score of 10. A higher antioxidant score reflects a stronger antioxidant defense system. The LLs, ULs, and corresponding scores for each serological antioxidant are listed in Table 19.

[0213] In the case of urological prooxidants and oxidative damage markers, a value below the UL is scored as 1. If the value surpasses the UL but remains within 10% above it, the score is 10, whereas any value exceeding 10% above the UL is assigned a score of 20. A higher prooxidant score corresponds to an increased oxidative burden. Table 20 lists the LLs, ULs, and corresponding scores for each urological prooxidant and oxidative damage marker.

[0214] For antioxidant genetic polymorphisms, the scoring is based on allele functionality. An allele associated with poor function receives a score of 1, while an allele with moderately affected function is assigned a score of 2. An allele linked to optimal function is given a score of 3. A higher antioxidant genetic score indicates a more effective antioxidant genetic function.

[0215] Similarly, scoring for prooxidant genetic polymorphisms is determined by allele functionality. An allele associated with optimal function is assigned a score of 1, while an allele with moderately affected function receives a score of 2. An allele linked to increased prooxidant function is scored as 3. To calculate the prooxidant total genetics score, each prooxidant allele score is multiplied by 3. A higher prooxidant genetic score signifies an increased prooxidant burden or activity within the body. The scoring methodology for each serological antioxidant genetic polymorphism and prooxidant genetic polymorphism are listed in Table 21. Calculations

[0216] In some embodiments, two approaches can be applied for score determination. Approach 1: Defined Multiplication FactorAttorney Ref: VIB-029WO

[0217] As discussed above in Equations (1) and (3), an antioxidant biomarker score and an antioxidant genetics score can be determined by averaging the scores assigned to each antioxidant biomarker and antioxidant genetic polymorphism, based on the results obtained from serological and genetic testing, respectively. An overall antioxidant score or antioxidant total score is then calculated by multiplying these two scores, as shown in Equation (5), which is reproduced below. Antioxidant Total = Antioxidant Biomarker Score × Antioxidant Genetics Score (5)

[0218] Similarly, a prooxidant biomarker score and a prooxidant genetics score can be calculated by averaging the scores assigned to each prooxidant biomarker and prooxidant genetic polymorphism, respectively. The resulting prooxidant total score is determined using Equation (6) reproduced below: Prooxidant Total = Prooxidant Biomarker Score × Prooxidant Genetics Score (6)

[0219] To standardize these values, an antioxidant normalization factor is derived by dividing the antioxidant total score by the total number of antioxidant biomarkers. In various embodiments, the standardization involves dividing the antioxidant total score by a total number of antioxidant biomarkers 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200. A prooxidant normalization factor is calculated by dividing the prooxidant total by the total number of prooxidant biomarkers. In various embodiments, the standardization involves dividing the prooxidant total score by a total number of antioxidant biomarkers 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200. The calculation is shown in Equations (23) and (24). Antioxidant Normalization Factor = Antioxidant Total / N (23) Prooxidant Normalization Factor = Prooxidant Total / M (24) where “N” refers to the total number of antioxidant biomarkers and “M” refers to the total number of prooxidant biomarkers. The ‘Redox Ratio’ (RR) is then determined by dividing the prooxidant normalization factor by the antioxidant normalization factor, similar to Equation (7) above.Attorney Ref: VIB-029WO Redox Ratio = Prooxidant Normalization Factor / Antioxidant Normalization Factor

[0220] In some embodiments, one or more predefined scale settings can be used to determine the appropriate multiplication factor (MF) based on the RR value. For example, if RR is no greater than 0. 09, the MF of 1 is specified. If RR is between 0.1 and 0.49, the MF is set to be 1.5. If RR is no less than 0.5, the MF of 2 is determined. An example mapping between RR and MF is shown in Table 22. The selected MF is then applied to the recommended daily allowance (RDA) of each supplement to calculate the customized dosage (CB), which is incorporated into the supplement blend.

[0221] The individual follows the supplement regimen for a specific period (e.g., three months), after which their serological antioxidant and urological prooxidant biomarker levels are reassessed. Since redox genetics remain unchanged, follow-up results from serological antioxidant and urological prooxidant testing, along with genetic assessments, are used to recalculate the RR and adjust the MF. These updated values help refine the CB dosage for continued supplementation. Approach 2: Exponential Multiplication Factor

[0222] Using this approach, a redox ratio is also calculated as discussed in approach 1. However, here, an MF is determined by adding a specific value (e.g., 1) to the RR, ensuring that MF increases exponentially as RR rises. This approach guarantees a proportional adjustment based on oxidative stress levels. Once the RR is calculated, the corresponding MF is obtained by summing the RR with one. The MF is then applied to the RDA of each supplement to calculate the CB, which is then integrated into the supplement blend. Example Biomarkers and Genetics

[0223] As disclosed herein, methods include analyzing exemplary biomarkers, such as antioxidant biomarkers and / or prooxidant biomarkers, for determining a personalized antioxidant supplement blend for an individual.

[0224] Exemplary antioxidant biomarkers may include biomarkers to provide a measure of the antioxidant activity in the individual. Example antioxidant biomarkers include any of Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPX), or Heme Oxygenase-1 (HO-1), as listed in Tables 23-1, 23-4, 24-1, 24-4, 25-1, 25-4, 26-1, 26-4, 27-1, 27-4, 28-1, 28-4, 29-1, 29-4, 30-1, and 30-4.Attorney Ref: VIB-029WO

[0225] In various embodiments, methods for determining a personalized antioxidant supplement blend for an individual include analyzing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 antioxidant biomarkers.

[0226] Exemplary prooxidant biomarkers may include biomarkers to provide a measure of the prooxidant activity in the individual. Example prooxidant biomarkers include any of ATRAZINE__ET, ATRAZINE_MERCAPTURATE_ET, BISPHENOL_A_BPA_ET, BUTYLPARABEN_ET, DDA_ET, DIETHYLDITHIOPHOSPHATE_DEDTP_ET, DIETHYLPHOSPHATE_DEP_ET, DIETHYLTHIOPHOSPHATE_DETP_ET, DIMETHYLDITHIOPHOSPHATE_DMDTP_ET, DIMETHYLPHOSPHATE_DMP_ET, DIMETHYLTHIOPHOSPHATE_DMTP_ET, DIPHENYL_PHOSPHATE_DPP_ET, ETHYLPARABEN__ET, FOUR_METHYLHIPPURIC_ACID_FOURMHA_ET, FOUR_NONYLPHENOL_ET, GLYPHOSATE_ET, METHYLPARABEN_ET, MONO_TWO_ETHYL_5_HYDROXYHEXYL_PHTHALATE_MEHHP_ET, MONO_TWO_ETHYL_5_OXOHEXYL_PHTHALATE_MEOHP_ET, MONO_ETHYL_PHTHALATE_METP_ET, MONO_TWO_ETHYLHEXYL_PHTHALATE_MEHP_ET, N_ACETYL_THREE_FOUR_DIHYDROXYBUTYL_CYSTEINE_NADB_ET, N_ACETYL_TWO_CYANOETHYL_CYSTEINE_NACE_ET, N_ACETYL_TWO_HYDROXYPROPL_CYSTEINE_NAHP_ET, N_ACETYL_PHENYL_CYSTEINE_NAP_ET, N_ACETYL_PROPYL_CYSTEINE_NAPR_ET, N_ACETYL_S__TWO_CARBAMOYLETHYL_CYSTEINE_NAE_ET, PERCHLORATE_ET, PHENYLGLYOXYLIC_ACID_PGO_ET, PROPYLPARABEN_ET, HREE_METHYLHIPPURIC_ACID_THREEMHA_ET, THREE_PHENOXYBENZOIC_ACID__THREEPBA_ET, TIGLYLGLYCINE_TG__ET, TRICLOSAN__ET, TWO_FOUR_DICHLOROPHENOXYACETIC_ACID_TWO_FOUR_D_ET, TWO_HYDROXYETHYL_MERCAPTURIC_ACID_HEMA_ET, TWO_HYDROXYISOBUTYRIC_ACID__TWOHIB___ET, TWO_METHYLHIPPURIC_ACID__TWOMHA___ET, BROMOTYROSINE_OS, CHLOROTYROSINE_OS, DITYROSINE_OS, EIGHT_HYDROXY_2_DEOXYGUANOSINE_OS, EIGHT_HYDROXYGUANINE_OS,Attorney Ref: VIB-029WO EIGHT_HYDROXYGUANOSINE_OS, EIGHT_ISO_PROSTAGLANDINF2A_OS, EIGHT_NITROGUANINE_OS, EIGHT_NITROGUANOSINE_OS, ELEVEN_B_PROSTAGLANDINF2A_OS, FIFTEEN_R_PROSTAGLANDINF2A_OS, GLUTATHIONE4_HYDROXYNONENAL_GS_HNE_OS, MALONDIALDEHYDE_OS, NE_CARBOXYETHYLLYSINE_CEL_OS, E_CAROBOXYMETHYLLYSINE_CML_OS, or NITROTYROSINE_OS, as listed in Tables 23-1, 23-4, 24-1, 24-4, 25-1, 25-4, 26-1, 26-4, 27-1, 27-4, 28-1, 28-4, 29-1, 29-4, 30-1, and 30-4.

[0227] In various embodiments, methods for determining a personalized antioxidant supplement blend for an individual include analyzing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 prooxidant biomarkers.

[0228] As disclosed herein, methods include analyzing exemplary biomarkers, such as genetic information including one or more mutations and / or variants, for determining a personalized antioxidant supplement blend for an individual. For example, such genetic information can include an antioxidant gene polymorphism or a prooxidant gene polymorphism. Example genetic information includes any of the antioxidant gene polymorphisms of RS1001179_OS, RS1050450_OS, RS10789038_OS, RS10911021_OS, RS121909307_OS, RS1548357_OS, RS1695_OS, RS1799895_OS, RS1987628_OS, RS2071566_OS, RS2071746_OS, RS2073316_OS, RS2234694_OS, RS2796498_OS, RS366631_OS, RS3754446_OS, RS3877899_OS, RS4485648_OS, RS4756146_OS, RS4880_OS, RS4902346_OS, or RS713041_OS. Example genetic information includes any of the prooxidant gene polymorphisms of RS1048943_OS, RS20417_OS, RS206812_OS, RS4673_OS, or RS916321_OS. These example gene polymorphisms are also listed in Tables 23-1, 23-4, 24-1, 24-4, 25-1, 25-4, 26-1, 26-4, 27-1, 27-4, 28-1, 28-4, 29-1, 29-4, 30- 1, and 30-4. Exemplary Flowchart for Calculating a Customized Blend

[0229] Referring now to FIG. 3, a flowchart of an exemplary method for determining a percentage of each active element in a personalized antioxidant supplement blend is provided, in accordance with an embodiment.

[0230] Step 310: Obtain antioxidant biomarker values, prooxidant biomarker values, and genetic information for an individual. As used herein, an antioxidant biomarker comprises aAttorney Ref: VIB-029WO quantitative measurement of an enzyme, a small molecule, a non-enzymatic protein or combinations thereof from a sample obtained from the individual. The sample comprises one or more of serum, plasma, erythrocytes, white blood cells, whole blood, tissues, or urine. In some embodiments, an antioxidant biomarker value is obtained using mass spectroscopy.

[0231] As used herein, a prooxidative marker value comprises a quantitative measurement of a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker or combinations thereof from a sample obtained from the individual. The sample is one or more of serum, plasma, erythrocytes, saliva, peripheral lymphocyte, cerebrospinal fluid (CSF), whole blood, tissue, or urine. In some embodiments, a prooxidant biomarker value is obtained using mass spectroscopy. As used herein, the genetic information is determined based on the presence or absence of a polymorphism in an antioxidant gene or in a prooxidant gene from a sample obtained from the individual. In some embodiments, the genetic information is obtained from a reverse transcription (RT) polymerase chain reaction (PCR) analysis.

[0232] Step 320: Determine an antioxidant score from the antioxidant biomarker values and a first set of genetic information. Here, the first set of genetic information includes information of antioxidant gene polymorphism selected from the group consisting of SOD1 (rs2234694), SOD2 (rs4880), SOD3 (rs1799895, rs8192287), GSTM1 (rs366631), GSTM5 (rs3754446), CAT (rs7943316, rs4756146, rs1001179), GPX1 (rs1050450, rs1987628), GPX2 (rs4902346, rs2071566), GPX4 (rs713041), GSR (rs8190955), GSS (rs121909307), GLUL (rs10911021), GSTP1 (rs1695), SELENOP (rs3877899), TXNRD1 (rs7310505), TXNRD2 (rs1548357), TrxR2 (rs4485648), HMOX1 (rs2071746) and PRKAA2 (rs2796498, rs10789038). In some embodiments, an antioxidant biomarker score is obtained by averaging individual antioxidant biomarker scores determined based on the antioxidant biomarker measurement values. An antioxidant genetic score is obtained by averaging individual antioxidant SNP scores determined from the first set of genetic information. The antioxidant score is a product of the antioxidant biomarker score and the antioxidant genetic score, reflecting the overall antioxidant level of this individual.

[0233] Step 330: Determine a prooxidant score from the prooxidant biomarker values and a second set of genetic information. Here, the second set of genetic information includes information of prooxidant gene polymorphism selected from the group consisting of XDH (−337GA), CYB5R3 (rs916321), CYP1A1 (rs1048943), CYBA (rs4673, A-930G) and COX- 2 (rs20417) or combinations thereof. In some embodiments, a prooxidant biomarker score is obtained by averaging individual prooxidant biomarker scores determined based on theAttorney Ref: VIB-029WO prooxidant biomarker measurement values. A prooxidant genetic score is obtained by averaging individual prooxidant SNP scores determined from the second set of genetic information. The prooxidant score is a product of the prooxidant biomarker score and the prooxidant genetic score, reflecting the overall oxidant damage of this individual.

[0234] Step 340: Determine a personalized factor for the individual using the antioxidant score and the prooxidant score. The personalized factor determines a CB based on a baseline or initial RDA. In some embodiments, the personalized factor is a multiplication factor. In some embodiments, a redox score is determined by dividing the prooxidant score by the antioxidant score, and the personalized factor is derived from the redox score. For example, a multiplication factor can be determined based on a mapping of the redox score in relation to a predefined range. In another example, the RR is incremented by a specific number (e.g., one) to derive a multiplication factor.

[0235] Step 350: Identify a personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor. Each active element can be determined for the exact amount to be included in the customized supplement regime, which combines with the base elements (e.g., using the personalized factor) may form a personalized antioxidant supplement blend for the individual, which can purposely address the concerns specific to the individual.

[0236] Step 360: Administering the personalized antioxidant supplement blend to the individual. In various embodiments, step 360 is an optional step or can be a step performed by e.g., the individual. The individual is administered the customized dosages of antioxidant nutrients for a specific period, after which antioxidant and / or prooxidant levels can be retested, and the dosage was recalibrated accordingly.

[0237] In various embodiments, steps 310-360 can be repeated for the individual. In various embodiments, steps 310-360 can be repeated multiple times to continuously adjust the personalized antioxidant supplement blend for the individual as the individual’s needs change. Each repeating of steps 310-360 can be separated by a specific period. In various embodiments, the specific period can be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 48 months, months, 72 months, 84 months, 96 months, 108 months, or 120 months. In various embodiments, at the subsequent retesting, the antioxidant and prooxidant levels are retestedAttorney Ref: VIB-029WO but the genetic information for the individual need not be retested. The supplement administration and the follow-up tests allow for continuous adjustments of the personalized antioxidant supplement blend to align with the individual’s evolving needs. Interventions

[0238] A personalized antioxidant supplement blend may include a recommended intervention determined based on individual redox scores. In one aspect, the recommended personalized intervention comprises customized recommendations selected from the group consisting of diet, supplements, physical exercise and lifestyle changes and combinations thereof.

[0239] Several strategies can be employed to combat oxidative damage and potentially slow down aging. An antioxidant-rich diet, consuming foods rich in antioxidants such as fruits and vegetables containing vitamins C and E, can help neutralize reactive oxygen species (ROS) and reduce oxidative stress. Certain supplements, such as vitamin C, vitamin E, coenzyme Q10, selenium, and alpha-lipoic acid, can support the body’s antioxidant defense system. Additionally, regular, moderate physical activity has been shown to improve the body’s antioxidant defenses, promote mitochondrial health, and reduce oxidative damage. However, excessive exercise can increase oxidative stress, so balance is important. Moreover, lifestyle modification can reduce environmental exposures by avoiding factors that increase oxidative stress, such as smoking, excessive alcohol consumption, pollution, and UV radiation, which can help minimize damage to cells. Other intervention strategies may include stress management, caloric restriction, and intermittent fasting, pharmacological interventions, etc. For example, practicing relaxation techniques (e.g., meditation, yoga, or deep breathing exercises) can help an individual relieve chronic stress and reduce the overall burden of oxidative damage. Reducing calorie intake or engaging in intermittent fasting may activate cellular repair mechanisms and reduce oxidative stress, potentially extending lifespan. Research is exploring drugs or compounds that target oxidative stress and enhance the body’s antioxidant capacity. These include molecules like resveratrol, spermidine, and NAD+ precursors, which have been suggested to promote longevity and reduce age-related damage. By incorporating these methods, it may be possible to reduce oxidative damage, mitigate the effects of aging, and improve overall health and longevity.Attorney Ref: VIB-029WO Diet

[0240] Diet plays an important role in regulating oxidative stress. Studies have indicated that high-fat or high-carbohydrate diets contribute to oxidative stress by elevating the levels of protein carbonylation and lipid peroxidation products and reducing the body’s antioxidant defense. Diet can help maintain cellular health and redox balance.

[0241] Plant-based diets rich in antioxidants are particularly effective in combating oxidative stress. Generally, plant polyphenols act as natural antioxidants by reducing the generation of oxidants in the body and enhancing the expression of antioxidant enzymes. Moreover, consuming foods that directly provide antioxidants offers significant benefits. Vitamin C, found in citrus fruits rich in can help reduce oxidative stress as it quenches O2•ˉ and•OH while regenerating α tocopherol (a form of vitamin E). Vitamin E, a lipid-soluble antioxidant abundant in nuts, protects lipids from peroxidative damage. Its most potent antioxidant form, α-tocopherol, is a primary peroxyl radical (ROO•) neutralizer in biological lipid molecules. Carotenoids, including carotenes and xanthophylls, are pigments present in yellow, orange, and red fruits and vegetables. They function as non-enzymatic natural antioxidants, effectively scavenging1O2 and ROO•. These findings emphasize the importance of a diet rich in antioxidant-containing foods to strengthen the body's natural defense mechanisms against oxidative stress, promoting overall health and well-being.

[0242] Considering the antioxidant properties of various foods, a personalized diet plan tailored to the individual is recommended to help lower oxidative stress and enhance the body's antioxidant potential. Supplements

[0243] While diet is a good source of antioxidants, it can be associated with various limitations. Antioxidant intake from food can be inconsistent due to dietary variability (it is practically not possible to adhere to a uniform diet). The type and quantity of antioxidants obtained from foods cannot be monitored, making it difficult to ensure that an individual gets all the necessary antioxidants. Moreover, the antioxidants obtained by the body from food are subject to variations in digestion and absorption in the body. Therefore, to overcome these limitations, targeted antioxidant supplementation is recommended in addition to an antioxidant-rich diet.

[0244] In some embodiments, supplements that serve as antioxidants (e.g., GSH, glutathione), function as antioxidants (e.g., vitamin A, E, C), and / or enhance antioxidant activity (e.g., carotenoids, polyphenols) are recommended. Various supplements, throughAttorney Ref: VIB-029WO their specific mechanism, can help counteract the effects of redox-related genetic polymorphisms. Based on the results from genetic testing, specific supplements to optimize the activity of both prooxidant and antioxidant genes. Additionally, certain supplements can help regulate biomarker levels by addressing and improving the processes associated with various oxidative damage markers, including lipid peroxidation, nucleic acid, and protein damage markers. Similarly, several supplements can enhance the levels of specific antioxidant markers, supporting the body’s overall redox balance. Various exemplary supplements are listed in Tables 11-16.

[0245] Table 11 lists genetic variations (SNPs) in prooxidant genes that contribute to oxidative stress and identifies specific supplements that help regulate the activity of prooxidant enzyme SNPs. Prooxidant genes, such as XDH, CYBA, CYP1A1, and COX-2, that are known to regulate oxidative processes in the body are listed in Table 11. Genetic variations (SNPs), such as XDH (-337A, 565+64C), CYBA (C242T, A-930G), CYP1A1 (rs1048943), and COX-2 (rs20417), which can alter gene function and increase ROS production, are also listed. Table 11 further includes various natural compounds and vitamins that help modulate the activity of prooxidant genes, reducing excessive oxidative stress. For example, supplements such as quercetin and Carica papaya extract are recommended, as they help inhibit XO conversion and thus reduce ROS production caused by XDH. For CYBA, a key ROS producer, supplements such as alpha lipoic acid, red grape juice, and quercetin are recommended to reduce oxidative stress by downregulating ROS production. CYP1A1 helps detoxify harmful compounds but can also generate oxidative stress, and, accordingly, supplements such as indole-3-carbinol, green tea, curcumin, astaxanthin, etc., are identified to enhance detoxification while reducing oxidative stress. Vitamin D, pycnogonid, and quercetin are also identified to suppress COX-2 activity, reducing inflammation and ROS production.

[0246] Table 12 lists SNPs in antioxidant genes and the supplements that enhance their activity to strengthen the body’s defense against oxidative stress. For example, for SOD genes that convert superoxide radicals (O2•−) into hydrogen peroxide (H2O2) to reduce oxidative stress, supplements including copper, manganese, vitamin E, CoQ10, etc., are identified, which enhance SOD enzyme activity to neutralize ROS. For CAT that breaks down H2O2into water and oxygen and prevents cellular damage, supplements including alpha-lipoic acid, vitamin D3, selenium, etc., are determined, which boost catalase activity to enhance antioxidant defense. As to GPX genes (GPX1, GPX2, GPX4) that detoxify H2O2 and lipid peroxides, supplements such as selenium, glutathione, vitamin C, lutein, etc., areAttorney Ref: VIB-029WO recommended, which support GPX activity to reduce oxidative stress. As to GST genes (GSTM1, GSTM5, GSTP1) involved in detoxification, supplements such as broccoli, pomegranate extract, s-adenosyl methionine, etc., are listed, which enhance GST function to detoxify harmful substances.

[0247] Lipid peroxidation occurs when ROS damage cellular lipids, leading to inflammation and chronic diseases. Table 13 lists oxidative lipid damage markers and supplements that reduce their levels. For example, malondialdehyde (MDA) is a byproduct of lipid peroxidation, indicating oxidative stress. Supplements including magnesium, vitamin E, green tea, curcumin, etc., are identified and presented to an individual to reduce MDA levels by scavenging free radicals. 4-Hydroxynonenal (4-HNE) is a toxic aldehyde formed from lipid peroxidation, and supplements such as vitamin C, quercetin, selenium, etc., can detoxify 4-HNE and prevent its accumulation. Oxidized LDL (oxLDL) is LDL cholesterol modified by oxidative stress, contributing to atherosclerosis. Supplements, including vitamin E, beta-carotene, green tea, omega-3 fatty acids, etc., are identified to protect LDL from oxidation. 8-iso-Prostaglandin F2α (8-iso-PGF2α) is a marker of lipid oxidation, and corresponding supplements such as vitamin C, omega-3, lycopene, etc., can reduce lipid peroxidation and inflammation. Lipid peroxidation contributes to heart disease, neurodegeneration, and aging, making supplementation crucial for individuals with high oxidative lipid damage markers.

[0248] Oxidative stress can damage DNA and RNA, leading to mutations, cancer risk, and aging. Table 14 lists nucleic acid damage markers (oxidative DNA / RNA damage markers) and supplements that protect genetic material. In this table, oxidative DNA damage markers are categorized into groups of 8-Hydroxy-2’-deoxyguanosine (8-OHdG), 8- Hydroxyguanine (8-OHG), and 8-Nitroguanine (8-NO2-G), and oxidative DNA damage markers include 8-hydroxyguanosine (8-oxoG). For example, for 8-OHdG, a key DNA oxidation marker, supplements can include CoQ10, curcumin, vitamin C, and resveratrol that prevent oxidative DNA damage. Regarding 8-NO2-G, a marker of RNA and DNA nitration that links to inflammation, corresponding supplements can include curcumin, n-acetyl cysteine, folic acid, etc., that protect against nitrosative damage. For individuals with high nucleic acid damage markers, supplements can protect DNA / RNA, reducing the risk of mutations and aging-related diseases.

[0249] Oxidative stress can modify proteins, affecting their function and leading to diseases (e.g., Alzheimer’s, diabetes, etc.). Table 15 categorizes specific protein oxidation markers and lists the supplements that counteract oxidative damage, along with theirAttorney Ref: VIB-029WO mechanisms of action. In Table 15, protein oxidation markers are shown in three groups: dityrosine, nitrotyrosine, and carboxymethyl lysine (CML). Dityrosine is formed when tyrosine residues in proteins undergo oxidative cross-linking, reducing protein function and contributing to aging-related disorders. Nitrotyrosine results from nitration of tyrosine residues by reactive nitrogen species (RNS), affecting protein function and signaling pathways. CML is a marker of glycoxidation, associated with diabetes and age-related diseases.

[0250] To combat the damages from these protein oxidation markers, various supplements are identified, as shown in Table 15. For dityrosine reduction, n-acetyl cysteine (NAC) can act as an antioxidant, scavenging free radicals to prevent dityrosine formation. nitisinone inhibits an enzyme involved in dityrosine formation, reducing oxidative protein damage. For nitrotyrosine reduction, supplements such as resveratrol, vitamin C, L-arginine can be taken to reduce nitric oxide-mediated protein damage. For CML reduction, quercetin, alpha-lipoic acid, and vitamin D can be used to prevent glycoxidation and oxidative protein damage. For individuals with elevated protein damage markers, supplementation prevents protein oxidation and supports cellular function.

[0251] Table 16 offers a broader view of antioxidant markers and the supplements that enhance their levels, whereas Table 12 primarily focuses on antioxidant enzyme SNPs and how specific supplements influence their activity. In Table 16, antioxidants are categorized into enzymes (e.g., SOD, catalase, GPX), small molecules (e.g., vitamin C, uric acid, glutathione), and proteins (e.g., oxidized albumin, ceruloplasmin). This table explains how different supplements contribute to increasing specific antioxidant markers and reducing oxidative stress. For example, Copper, Vitamin E, Vitamin D3, Vitamin C, Manganese, Coenzyme Q10 are applied to enhance the activity and SOD antioxidant markers' levels, which help neutralize harmful reactive oxygen species (ROS). Vitamin C is helpful because it increases antioxidant markers by directly donating electrons to neutralize free radicals, regenerating vitamin C and other antioxidants like vitamin E, and enhancing the activity of antioxidant enzymes, such as glutathione peroxidase, within cells. Thus, if an individual is found to have a biomarker or a mutation (e.g., a single nucleotide polymorphism (SNP)) that affects a particular gene, then the resulting supplement for the individual can be provided to counteract the mutation. For example, referring to Table 12, if a SNP in column 2 is found for a particular gene in column 1, then a particular corresponding supplement shown in column 3 can be selected for the individual. As another example, referring to Table 16, if anAttorney Ref: VIB-029WO antioxidant marker in column 2 is found for a particular gene in column 1 to be lacking, then a particular corresponding supplement shown in column 3 can be selected for the individual.

[0252] By analyzing genetic polymorphisms and oxidative damage markers based on the information listed in Tables 11-16, the present approaches allow individuals to target their antioxidant supplementation to reduce lipid, nucleic acid, and protein damage, improving health, longevity, and disease prevention. Personalized Physical Exercise Regimen

[0253] In addition to diet and supplements specifically tailored to an individual, a personalized physical exercise regimen is also determined based on the results from genetic assessment, serological assessment, and urological assessment.

[0254] Physical exercise is important in managing and improving oxidative stress; however, the intensity and duration of exercise significantly influence its impact on the body’s redox balance. Both acute and chronic physical training contribute to the production of ROS and RNS, leading to oxidative stress. However, regular exercise training can enhance the body’s endogenous antioxidative system, offering protection against oxidative damage.

[0255] Regular aerobic exercise boosts the body’s antioxidant defenses by triggering oxidant species production. During physical activity, the body’s energy demand increases, resulting in increased oxygen consumption to produce energy. The elevated oxygen consumption generates ROS, such as O2•ˉ , as natural byproducts of aerobic metabolism. This induces mild oxidative stress in the body (while excessive ROS can be harmful), which can act as a hermetic stressor to activate a favorable adaptive response in cells and tissues, strengthening antioxidant defenses and enhancing overall resilience to oxidative damage.

[0256] Research suggests that exercise intensity higher than 75-80% VO2maxstimulates the body’s antioxidant system, promoting the production of key enzymes such as SOD and GPx. Individuals with an appropriate oxidative stress biomarker profile and no genetic alterations in prooxidant and antioxidant genes can safely participate in high-intensity exercise routines at higher VO2maxlevels. However, individuals with elevated oxidative damage markers, reduced antioxidant markers, and / or genetic polymorphisms in the prooxidant and antioxidant genes may benefit from moderate-intensity exercise practices at lower VO2maxlevels, as their ability to counteract oxidative stress is more limited. Studies indicate that regular, progressive resistance training over time enhances antioxidant enzyme activity, further supporting the body’s defense mechanisms.Attorney Ref: VIB-029WO

[0257] Based on the genetics and biomarker profiles, individuals receive exercise recommendations tailored to their oxidative stress profile and redox potential. Individuals with a high antioxidant capacity may follow higher-intensity training regimens, whereas individuals with higher oxidative stress markers may engage in moderate-intensity workouts to prevent excessive ROS accumulation.

[0258] Additionally, antioxidant supplementation may be adjusted according to training intensity, ensuring that the body’s antioxidant defenses are adequately supported based on its metabolic demands. Table 17 lists two example cases of physical exercise regimens. If oxidate damage and related risk are determined and / or changed, the intensity of exercise (e.g., resistance training) and the dosage of antioxidant supplements will be adjusted accordingly. For example, if assessment findings show mild oxidative stress with slightly elevated lipid peroxidation markers (e.g., MDA, 4-HNE), moderate antioxidant enzyme activity with SNPs in GPX1 or SOD2 (leading to suboptimal ROS detoxification), and genetic tendency toward inflammation or muscle fatigue under prolonged exercise. Based on these assessment results, the system provided herein may recommend this particular individual to perform steady-state cardio (e.g., jogging, swimming, moderate cycling) or strength training (e.g., progressive resistance exercises). According to this exercise recommendation, antioxidant supplements can be adjusted to include selenium, vitamin D3, green tea extract, and omega-3 fatty acids. Selenium can enhance glutathione peroxidase (GPX) activity, reducing oxidative stress. Vitamin D3 helps regulate inflammation and oxidative stress in muscle tissues. Green tea extract supports fat metabolism and reduces exercise-induced oxidative stress. Omega-3 fatty acids (e.g., fish oil, flaxseed oil) reduce exercise-induced inflammation and lipid oxidation. The personalized nutrimental blend, including customized diet, exercise, and supplements, helps maintain redox balance during exercise while supporting muscle recovery and mitigating oxidative damage for this particular individual. Lifestyle

[0259] Lifestyle factors such as nutrient intake also play a major role in an individual’s overall health. Nutritional antioxidants including vitamin C, vitamin E, carotenoids, copper, and selenium may promote health by scavenging free radicals. For example, free radicals generated from endogenous metabolic pathways or exogenous factors may lead to oxidative stress, where the exogenous factors include at least exposure to UV radiation, ionizingAttorney Ref: VIB-029WO radiation, pollution, alcohol intake, or smoking. Oxidative stress results in the loss of functional characteristics and regenerative potential, exacerbating the aging process.

[0260] In some embodiments, the method described herein may recommend a lifestyle modification for an individual based on assessment results (e.g., genetic, serological, and / or urological evaluations). These recommendations may include reducing or quitting smoking and alcohol consumption, adopting healthier cooking practices, and minimizing the intake of processed foods, sugary beverages, and foods high in trans fats and refined sugars to improve overall oxidative balance and well-being. Multiplex Testing Method SOP SOP for UPLC-MS / MS Bio-diagnostic Assay Panel for Oxidative Stress Markers

[0261] The purpose of this standard operating procedure (SOP) is to define the standardized protocols for an accurate and reproducible analysis of oxidative stress markers using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS / MS). This procedure is specifically designed to assess a comprehensive panel of oxidative stress biomarkers (OSBs) and nitrative stress biomarkers (NSBs), ensuring precision and reliability in the quantification of these markers.

[0262] This SOP applies to all personnel involved in various aspects of the analytical process, including sample preparation, UPLC-MS / MS analysis, instrument maintenance, troubleshooting, safety precautions, and documentation, to maintain consistency in oxidative stress marker analysis and minimize variability in results. Pre-assay Preparation

[0263] Preparation of Mobile Phases and Diluent buffer

[0264] Prior to conducting the assay, essential preparations must be made to ensure the accuracy of the analysis. The preparation of mobile phases and diluent buffer plays a critical role in optimizing chromatographic separation and ionization efficiency.

[0265] Mobile Phase A is prepared by adding 0.1% (v / v) formic acid to high-purity water, which enhances ionization and improves chromatographic separation.

[0266] Mobile Phase B consists of a 1:1 (v / v) mixture of methanol (MeOH) and acetonitrile (ACN), facilitating the efficient elution of analytes from the UPLC column.

[0267] The diluent buffer composed of a 1:1 (v / v) mixture of methanol (MeOH) and water. This solvent is used for the preparation of calibrators and for sample dilution.Attorney Ref: VIB-029WO

[0268] Proper mixing of all solutions is required to ensure homogeneity and consistency throughout the analysis.

[0269] Preparation of Stocks and Derivatization Regents

[0270] In addition to mobile phase preparation, stock solutions and derivatization reagents are prepared before sample analysis. Standard stock solutions are formulated to establish calibration curves and quality control samples, ensuring accurate biomarker quantification.

[0271] Table 18 outlines the standard procedures for preparing stock solutions and calibrators, including the required solvents, analyte volumes, and weights necessary for their formulation. For example, the fourth column specifies the volumes needed for the preparation of calibrators at a 100x concentration factor. This increased concentration factor helps long-term storage and ensures that calibrators remain stable over time.

[0272] Before use, calibrators must be diluted 1:100 (v / v) in the diluent buffer. Once diluted, they are processed along with the samples, following the appropriate method designated for each specific analyte. The table includes key oxidative stress and nitrative stress biomarkers, such as CML, 8-HG, 8-HdG, 8-NG, CY, CEL, MDA, and PGF variants, among others. Each analyte requires a specific reconstitution buffer (e.g., water, ethanol, DMSO, methanol, PBS) and precise handling conditions, such as sonication to ensure complete dissolution before use.

[0273] This standardized approach to stock and calibrator preparation ensures consistency, accuracy, and reproducibility in the analysis of oxidative stress markers using UPLC-MS / MS technology. This approach also optimizes sample processing efficiency and enhance the reliability of biomarker quantification.

[0274] For the derivatization procedure, in some embodiments, a 0.2M DNPH solution can be prepared by dissolving 2,4-Dinitrophenylhydrazine (DNPH) in a 20% trichloroacetic acid (TCA) solution. This solution is specifically used in the derivatization of malondialdehyde (MDA) during sample processing to enhance its detection and quantification. Sample Processing

[0275] Various sample processing methods can be applied for different analytes based on their concentration requirements and chemical properties. Proper dilution ensures that the analytes fall within an instrument’s detection range, while derivatization enhances theAttorney Ref: VIB-029WO measurement of specific markers like MDA that may otherwise be difficult to quantify accurately. These standardized procedures ensure consistency and reliability in oxidative stress biomarker analysis.

[0276] Method 1: 1:3 Dilution with Diluent Buffer

[0277] To achieve an optimal concentration for analysis, samples are diluted at a 1:3 ratio (one part sample to three parts diluent buffer). This dilution method is specifically applied to analytes such as 8-Isoprostaglandin F-2α, 11β-Prostaglandin F-2α, 15(R)-Prostaglandin F-2α, and 8-Iso-15(R)-Prostaglandin F-2α. These compounds require moderate dilution to ensure accurate quantification without interference from excessive concentration or matrix effects.

[0278] Method 2: 1:20 Dilution with Diluent Buffer

[0279] For certain analytes that require a lower sample concentration for precise analysis, a 1:20 dilution (one part sample to twenty parts diluent buffer) can be performed. This method is used for analytes including 4-Hydroxynonenal-Glutathione, 8-Hydroxyguanine, 8- Hydroxyguanosine, o,o'-Dityrosine, 8-Nitroguanosine, 8-Nitroguanine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine, N-(1-Carboxymethyl)-L-lysine, and N-(1-Carboxyethyl)-L- lysine. These compounds typically exhibit higher baseline concentrations, requiring greater dilution to remain within an instrument’s dynamic range and prevent signal saturation.

[0280] Method 3: 1:3 Dilution with Diluent Buffer and Derivatization with 0.2M DNPH

[0281] For the analysis of malondialdehyde (MDA), an additional derivatization step is required to enhance detection. Samples are first diluted at a 1:3 ratio with the diluent buffer, followed by the addition of 0.2M DNPH solution. The mixture is then incubated at 50°C for two hours, allowing the derivatization reaction to take place. This process improves the stability and detectability of MDA, ensuring accurate measurement during analysis. UPLC-MS / MS Analysis

[0282] This process involves injecting the prepared samples into an advanced analytical system (UPLC-MS / MS), which is optimized to separate and detect different components of the sample. To quantify the analytes (the substances being measured), calibration curves are generated from known concentrations of standards. The resulting data is analyzed using software designed for this purpose, ensuring accurate results.

[0283] In some embodiments, the prepared samples are introduced into the UPLC- MS / MS system under carefully optimized conditions for effective chromatographicAttorney Ref: VIB-029WO separation and detection. The analytes are measured by comparing their response to calibration curves created from standard solutions. The collected data is then processed using specialized software. Computing Device

[0284] The methods described herein, including the methods of determining a personalized antioxidant supplement blend, are, in some embodiments, performed on a computing device. Examples of a computing device can include a personal computer, desktop computer laptop, server computer, a computing node within a cluster, message processors, hand-held devices, multi-processor systems, microprocessor-based or programmable consumer electronics, network PCs, minicomputers, mainframe computers, mobile telephones, PDAs, tablets, pagers, routers, switches, and the like.

[0285] FIG. 4 illustrates an example computing device 400 for implementing system and methods described in FIGS. 1-3. In some embodiments, the computing device 400 includes at least one processor 402 coupled to a chipset 404. The chipset 404 includes a memory controller hub 420 and an input / output (I / O) controller hub 422. A memory 406 and a graphics adapter 412 are coupled to the memory controller hub 620, and a display 418 is coupled to the graphics adapter 412. A storage device 408, an input interface 414, and network adapter 416 are coupled to the I / O controller hub 422. Other embodiments of the computing device 400 have different architectures.

[0286] The storage device 408 is a non-transitory computer-readable storage medium such as a hard drive, compact disk read-only memory (CD-ROM), DVD, or a solid-state memory device. The memory 406 holds instructions and data used by the processor 402. The input interface 414 is a touch-screen interface, a mouse, track ball, or other type of input interface, a keyboard, or some combination thereof, and is used to input data into the computing device 400. In some embodiments, the computing device 400 may be configured to receive input (e.g., commands) from the input interface 414 via gestures from the user. The graphics adapter 412 displays images and other information on the display 418. For example, the display 418 can show an indication of a treatment, such as a treatment validated by applying the cellular disease model. As another example, the display 418 can show an indication of a common chemical structure group likely contributes toward an outcome (e.g., favorable outcome or adverse outcome). As another example, the display 418 can show a candidate patient population that, through implementation of the cellular disease model, hasAttorney Ref: VIB-029WO been predicted to respond favorably to an intervention. The network adapter 416 couples the computing device 400 to one or more computer networks.

[0287] The computing device 400 is adapted to execute computer program modules for providing functionality described herein. As used herein, the term “module” refers to computer program logic used to provide the specified functionality. Thus, a module can be implemented in hardware, firmware, and / or software. In one embodiment, program modules are stored on the storage device 408, loaded into the memory 406, and executed by the processor 402.

[0288] The types of computing devices 400 can vary from the embodiments described herein. For example, the computing device 400 can lack some of the components described above, such as graphics adapters 412, input interface 414, and displays 418. In some embodiments, a computing device 400 can include a processor 402 for executing instructions stored on a memory 406. Embodiments of the methods described above can be implemented in computer programs executing on programmable computers, comprising a processor, a data storage system (including volatile and non-volatile memory and / or storage elements), a graphics adapter, an input interface, a network adapter, at least one input device, and at least one output device. A display is coupled to the graphics adapter. Program code is applied to input data to perform the functions described above and generate output information. The output information is applied to one or more output devices, in known fashion. The computer can be, for example, a personal computer, microcomputer, or workstation of conventional design.

[0289] Each program can be implemented in a high level procedural or object oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language can be a compiled or interpreted language. Each such computer program is preferably stored on a storage media or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The system can also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

[0290] The signature patterns and databases thereof can be provided in a variety of media to facilitate their use. “Media” refers to a manufacture that contains the signature patternAttorney Ref: VIB-029WO information of the present invention. The databases of the present invention can be recorded on computer readable media, e.g. any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic / optical storage media. One of skill in the art can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising a recording of the present database information. "Recorded" refers to a process for storing information on computer readable medium, using any such methods as known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. ADDITIONAL EMBODIMENTS

[0291] Disclosed herein are personalized antioxidant supplement blends that can help improve an individual’s antioxidant defense system and relieve oxidant stress based on a particular individual’s oxidant profile. Such personalized antioxidant supplement blend can effectively provide personalized skin products, dietary, supplement, and lifestyle suggestions along with routine monitoring strategies in accordance an individual’s profile.

[0292] In one aspect, provided herein is a method for determining a personalized antioxidant supplement blend for a subject, the method comprising: i.obtaining or having obtained a measure of oxidative stress in an individual; ii.based on said measure, calculating an oxidative stress score; and iii.developing the personalized nutritional supplement blend based on the measure of oxidative stress, the calculated oxidative stress score, or both.

[0293] In some embodiments, the method comprises comparing the oxidative stress score with a reference score, and developing the personalized nutritional supplement blend based on the comparison.

[0294] In some embodiments, the measure of oxidative stress comprises antioxidant analysis, oxidative damage marker analysis, genetics analysis or combinations thereof.

[0295] In some embodiments, the antioxidant analysis comprises quantitative measure of an enzyme, a small molecule, a non-enzymatic protein or combinations thereof from a blood sample obtained from an individual for whom the personalized nutritional supplement blend is developed.Attorney Ref: VIB-029WO

[0296] In some embodiments, the blood sample comprises one or more of serum, erythrocytes, white blood cells or whole blood.

[0297] In some embodiments, the enzyme is selected from the group consisting of Superoxide dismutase, Catalase, Glutathione peroxidase and Glutathione reductase or combinations thereof.

[0298] In some embodiments, the small molecule is selected from the group consisting of Glutathione, Glutathione disulfide, Uric acid, Coenzyme Q10, Vitamin A, Vitamin C, Vitamin E and Selenium or combinations thereof.

[0299] In some embodiments, the non-enzymatic small molecule is Oxidized albumin or Ceruloplasmin or a combination thereof.

[0300] In some embodiments, the antioxidant analysis quantitative measure is obtained using mass spectroscopy.

[0301] In some embodiments, the oxidative damage marker analysis comprises quantitative measure of a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker or combinations thereof from a urine sample obtained from the individual for whom the personalized nutritional supplement blend is developed.

[0302] In some embodiments, the lipid peroxidation markers are selected from the group consisting of Malondialdehyde, 4-Hydroxynonenal, 8- Isoprostaglandin F-2α, 11β- Prostaglandin F-2α, 15(R)- Prostaglandin F-2α and 8-Iso-15(R)- Prostaglandin F-2α or combinations thereof.

[0303] In some embodiments, the nucleic acid damage marker is a DNA damage marker, an RNA damage marker or combinations thereof.

[0304] In some embodiments, the DNA damage marker is selected from the group consisting of 8-Hydroxy-2' -deoxyguanosine, 8-Hydroxyguanine and 8-Nitroguanine or combinations thereof.

[0305] In some embodiments, the RNA damage marker is selected from the group consisting of 8-Hydroxyguanosine and 8-Nitroguanosine or combinations thereof.

[0306] In some embodiments, the protein damage marker is selected from the group consisting of Allantoin, o, o'-Dityrosine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine and N-(1-Carboxymethyl)-L-lysine or combinations thereof.

[0307] In some embodiments, the oxidative damage marker analysis quantitative measure is obtained using mass spectrometry.

[0308] In some embodiments, the genetics analysis comprises determining the presence or absence of a polymorphism in an antioxidant gene or in a prooxidant gene from a sampleAttorney Ref: VIB-029WO obtained from the individual for whom the personalized nutritional supplement blend is being developed.

[0309] In some embodiments, the antioxidant gene polymorphism is selected from the group consisting of SOD1 (rs2234694), SOD2 (rs4880), SOD3 (rs1799895, rs8192287), GSTM1 (rs366631), GSTM5 (rs3754446), CAT (rs7943316, rs4756146, rs1001179), GPX1 (rs1050450, rs1987628), GPX2 (rs4902346, rs2071566), GPX4 (rs713041), GSR (rs8190955), GSS (rs121909307), GLUL (rs10911021), GSTP1 (rs1695), SELENOP (rs3877899), TXNRD1 (rs7310505), TXNRD2 (rs1548357), TrxR2 (rs4485648), HMOX1 (rs2071746) and PRKAA2 (rs2796498, rs10789038) or combinations thereof.

[0310] In some embodiments, the prooxidant gene polymorphism is selected from the group consisting of XDH (−337GA), CYB5R3 (rs916321), CYP1A1 (rs1048943), CYBA (rs4673, A-930G) and COX-2 (rs20417) or combinations thereof.

[0311] In some embodiments, the genetics analysis comprises RT PCR.

[0312] In some embodiments, the method further comprises determining a plurality of unified reference antioxidant scores, ΣAr, each associated with a distinct age range.

[0313] In some embodiments, the method further comprises determining a plurality of unified reference lipid peroxidation scores, ΣLPr, each associated with a distinct age range.

[0314] In some embodiments, the method further comprises determining a plurality of unified reference nucleic acid damage scores, ΣNAr, each associated with a distinct age range.

[0315] In some embodiments, the method further comprises determining a plurality of unified reference protein damage scores, ΣPDr, each associated with a distinct age range.

[0316] In some embodiments, the method further comprises determining a unified individual antioxidant score, ΣAi, for the individual for whom the personalized nutritional supplement blend is being developed.

[0317] In some embodiments, the method further comprises determining a unified individual lipid peroxidation score, ΣLPi, for the individual for whom the personalized nutritional supplement blend is being developed.

[0318] In some embodiments, the method further comprises determining a unified individual nucleic acid damage score, ΣNAi, for the individual for whom the personalized nutritional supplement blend is being developed.

[0319] In some embodiments, the method further comprises determining a unified individual protein damage score, ΣPDi, for the individual for whom the personalized nutritional supplement blend is being developed.Attorney Ref: VIB-029WO

[0320] In some embodiments, the method further comprises making a comparison selected from the group consisting of ΣAr vs ΣAi, ΣLPr vs ΣLPi, ΣNAr vs ΣNAi and ΣPDr vs ΣPDi or combinations thereof, and determining a recommended personalized intervention based on the comparison.

[0321] In some embodiments, the recommended personalized intervention comprises recommendations selected from the group consisting of diet, supplements, physical exercise and lifestyle changes and combinations thereof.

[0322] In some embodiments, a method for assessing oxidative stress in a subject, comprising: obtaining a urine sample from the subject; preparing three aliquots from the sample into aliquots and quantifying, using UPLC-MS / MS analysis, levels of 8- Isoprostaglandin F-2α, 11β-Prostaglandin F-2α, 15(R)-Prostaglandin F-2α, and 8-Iso-15(R)- Prostaglandin F-2α from the first aliquot; levels of 4-Hydroxynonenal-Glutathione, 8- Hydroxyguanine, 8-Hydroxyguanosine, o,o'-Dityrosine, 8-Nitroguanosine, 8-Nitroguanine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine, N-(1-Carboxymethyl)-L-lysine, and N-(1- Carboxyethyl)-L-lysine in the second aliquot; and incubating the third aliquot with DNPH to derivatize MDA present in the third aliquot and then quantifying the derivatized MDA in the third aliquot.

[0323] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0324] All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.Attorney Ref: VIB-029WO EXAMPLES

[0325] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed.

[0326] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992). Example 1-4: Approaches to Optimizing Antioxidant Levels

[0327] Below are examples demonstrating an ‘Oxidative Stress Profile’ test, which was conducted using Approach 1 (Defined Multiplication Factor) and Approach 2 (Exponential Multiplication Factor) to determine customized antioxidant supplements, thereby enhancing individual antioxidant defense system and relieving oxidant stress. The tables (e.g., Tables 23-28) provide the selected dosages for each antioxidant supplement. While the dosages may vary, the underlying formula used to achieve the CB remained consistent.

[0328] Example 1: 19-year-old female

[0329] A 19-year-old college student reported experiencing persistent fatigue, brain fog, and increased susceptibility to colds. She underwent the ‘Oxidative Stress Profile’ test, which indicated low antioxidant biomarker levels and suboptimal antioxidant genetics. However, her prooxidant biomarker levels were low, and she showed no genetic predispositions to oxidative stress via prooxidant genes.

[0330] Tables 23-1 through 23-6 demonstrate the test result using Approach 1. Table 23-1 showed this female’s biomarker levels and scores. For example, the measured serological antioxidant levels for GPX, CAT, SOD, and HO-1 were 33 μg / L, 1.2 U / mL, 2.1Attorney Ref: VIB-029WO U / mL, and 0.1 ng / mL, respectively. Each of these values fell below the reference lower limits (LL) of 46 μg / L, 4.0 U / mL, 3.5 U / mL, and 0.2 ng / mL, as listed in Table 19, and was therefore assigned an individual antioxidant biomarker score of 1 for each of the biomarkers. These individual antioxidant biomarker scores can then be combined to (e.g., by averaging) an antioxidant biomarker score using Equation 1, reflecting the 19-year-old college student’s overall antioxidant status. In this example, this antioxidant biomarker score was listed as an average score of 1 in Table 23-1.

[0331] Similarly, individual prooxidant biomarker scores were determined based on the measurements of urology prooxidants in Table 23-1 and reference ranges associated with each prooxidant in Table 20. For example, the measured Triclosan level was 15.1818 µg / g, which was below the LL of 358 µg / g and thus assigned an individual biomarker score of 1. The measurement of Bisphenol A (BPA) was 1.2616 µg / g, which fell below its LL of 5.09 µg / g and was also assigned an individual biomarker score of 1. Each individual biomarker scores was determined for each prooxidant biomarker listed in Table 23-1. These scores were then combined to a prooxidant biomarker score using Equation 2, reflecting the 19-year- old college student’s overall prooxidant level. In this example, the combined prooxidant level was reflected by an average score of 1 listed in Table 23-1.

[0332] Each individual antioxidant genetic score was also determined for each antioxidant genetic polymorphism listed in Table 23-1. For example, the result of GPX1 (RS1050450_OS) in Table 23-1 indicated C / T, which corresponded to a mutation and thus received an individual antioxidant genetic score of 1 based on the mapping in Table 21. These individual antioxidant genetic scores were then combined to an antioxidant genetics score using Equation 3, representing the 19-year-old college student’s genetic predisposition to antioxidant efficiency. In this example, the combined antioxidant genetic score was indicated by an average score of 1 listed in Table 23-1.

[0333] Next, individual prooxidant genetic scores were determined for each prooxidant genetic polymorphism listed in Table 23-1. For example, the result of XDH (rs206812_OS) in Table 23-1 indicated A / G, which corresponded to a mutation and thus received an individual prooxidant genetic score of 3 based on the mapping in Table 21. These individual prooxidant genetic scores were then combined to an prooxidant genetics score using Equation 4, representing the 19-year-old college student’s genetic predisposition to increased oxidative stress. In this example, the combined prooxidant genetic score was indicated by an average score of 3 listed in Table 23-1.Attorney Ref: VIB-029WO

[0334] Once the antioxidant biomarker score, prooxidant biomarker score, antioxidant genetic score, and prooxidant genetic scores were determined, the present system proceeded to calculate a multiplication factor, which was then applied to an RDA to derive a CB. As shown in Table 23-2, an antioxidant total score and a prooxidant total score were first calculated, according to Equations (5) and (6). In this example, given that both the antioxidant biomarker score and the antioxidant genetics score were 1, their product resulted in an antioxidant total score of 1. Because the prooxidant biomarker score was 1 and the prooxidant genetics score was 3, their product resulted in a prooxidant total score of 3. The resulting antioxidant total score and prooxidant total score were then normalized, using Equations (23) and (24). The normalized scores were then used to determine a redox ratio (RR) using Equation (7). Here, the redox ratio was 0.5, which derived a corresponding multiplication factor of 2 according to the pre-defined mapping (e.g., in Table 22). For example, if RR is no greater than 0.09, the MF of 1 is specified. If RR is between 0.1 and 0.49, the MF is set to be 1.5. If RR is no less than 0.5, the MF of 2 is determined.

[0335] Table 23-3 presented a personalized therapy plan for this 19-year-old college student, which was designed to address her redox status. Considering the conditions of poor antioxidant biomarker levels, weak antioxidant genetics, and other factors, the first three columns outlined a basic plan, specifying the types and dosages of supplements. Using this plan as a baseline, the multiplication factor of 2 doubled the dosage for this individual, with the customized dosage displayed in the fourth CB column.

[0336] The 19-year-old female took the CB for a specific period (e.g., 3-4 months), after which antioxidant nutrient values were retested. The follow-up tests, as shown in Tables 23- 4, 23-5, and 23-6, indicated that the CB was able to improve the individual’s nutrient levels, with their levels moving directed to the optimum range. For example, CAT levels increased from 1.2 U / mL (score = 1) to 5.8 U / mL (score = 5), and HO-1 levels rose from 0.1 ng / mL (score = 1) to 7.9 ng / mL (score = 10). This enhancement in antioxidant levels was accompanied by a marked reduction in fatigue, improved mental clarity, and fewer instances of illness. Additionally, the MF was calculated again. This factor decreased from 2 to 1.5, indicating a reduced CB dosage was followed for this individual.

[0337] Tables 24-1 through 24-6 presented a slightly different test result and supplement plan for this 19-year-old colleague student, using Approach 2. Unlike the multiplication factor of 2 in Table 23-2, a different multiplication factor of 1.5 was calculated as shown in Table 24-2. Consequently, the customized supplement plan for the individual was adjusted in Table 24-3 and further refined in Table 24-6. This adjustment was beneficial because theAttorney Ref: VIB-029WO antioxidant supplement blend was tailored to include both personalized supplements and lifestyle factors such as diet and exercise. The individual can select the plan that best aligns with her needs and habits.

[0338] Example 2: 77-year-old male

[0339] A 77-year-old male experienced chronic joint pain, reduced physical stamina, and episodes of mental fatigue. He underwent the ‘Oxidative Stress Profile’ test, which indicated low antioxidant biomarker levels, weak antioxidant genetics, and moderately high prooxidant biomarker levels. However, no genetic predispositions to oxidative stress through prooxidant genes were detected.

[0340] Tables 25-1 through 25-6 demonstrate the test result using Approach 1. The urology prooxidant tests in Table 25-1 revealed that the levels of certain biomarkers, such as Malondialdehyde, were at least 10% above the UL, and each was assigned a score of 20. This led to a relatively high prooxidant biomarker score of 2.055556. This prooxidant biomarker score contributed to a redox ratio 1.027778 in Table 25-2, which is higher than the 0.5 redox ratio determined for the 19-year-old female in Table 23-2.

[0341] Considering the test results that focused on lowering the level of urology prooxidants and other factors such as age, gender, a different base supplement plan was created, as shown in Table 25-3. Compared to the supplement plan for the 19-year-old colleague student shown in Table 23-3, the 77-year-old male was given copper and green tea extract instead of alpha-lipoic acid. Both individuals, due to their low antioxidant levels, were provided with common supplements, including vitamins D3, C, and E, CoQ10, selenium, etc. However, because of the difference in their conditions (e.g., age, gender), the supplement plan was first customized based on adjusting the dosages of these common supplements. The supplement plan in Table 25-3 was further refined using a different multiplication factor, ensuring that the CB best fits the 77-year-old male’s specific needs.

[0342] The CB was administered to the 77-year-old male for a specific period, typically 3-4 months, after which the antioxidant nutrient levels were retested. The follow-up tests, present in Tables 25-4, 25-5, and 25-6, demonstrated that his antioxidant biomarker levels showed significant improvement, and his prooxidant biomarker levels decreased to a healthier range. Specifically, GPX levels rose from 37 μg / L (score = 1) to 72 μg / L (score = 10), while CAT levels increased from 1.2 U / mL (score = 1) to 11.1 U / mL (score = 10). Additionally, triclosan levels dropped from 402.2 μg / g (score = 20) to 292 μg / g (score = 1), and malondialdehyde levels decreased from 189.83 μg / g (score = 20) to 145.2 μg / g (score =Attorney Ref: VIB-029WO 1). However, eight-nitroguanine levels showed only a slight reduction, from 124 μg / g (score = 20) to 120 μg / g (score = 20), indicating the need for further adjustments to the supplement formulation.

[0343] Further to quantify the change between pre- and post-supplementation, the multiplication factor was calculated again in Table 25-5. This factor value dropped from 2 (shown in Table 25-2) to 1.5, indicating that the CB dosage was reduced for this individual following the improvement in the antioxidant levels.

[0344] The test results and supplement plan using Approach 2 (“exponential multiplication factor) were presented in Tables 26-1 through 26-6, where the redox ratio (RR) was determined and increased by “1” to derive the MF. These adjustments offered an alternative supplement option that allowed the individual to tailor their plan alongside their diet and exercise routine, supporting the reduction of oxidative stress and improving overall health.

[0345] Example 3: 64-year-old female

[0346] A 64-year-old female experienced chronic muscle fatigue, frequent headaches, and occasional brain fog that disrupted her daily activities. She underwent the ‘Oxidative Stress Profile’ test, which revealed low antioxidant biomarker levels, suboptimal antioxidant genetic markers, and moderately elevated prooxidant biomarker levels. Additionally, multiple genetic predispositions to oxidative stress were identified through prooxidant genes, further exacerbating her condition.

[0347] The test results and supplement plans based on Approach 1 were shown in Tables 27-1 through 27-6. The multiple genetic predispositions to oxidative stress were reflected in individual and overall (average) prooxidant genetics scores shown in Table 27-1. These scores highlighted an increased expression or activity of prooxidant genes, suggesting a greater susceptibility to oxidative damage and potentially increasing the risk of inflammation, cellular dysfunction, and age-related diseases.

[0348] Her antioxidant and prooxidant biomarker scores, along with her genetic data, were analyzed to determine the appropriate multiplication factor (MF). This MF was applied to adjust the RDA or initial dosages of supplements, creating a customized blend CB for each supplement in Table 27-3. Here the CB dosages doubled the initial dosages using a multiple factor of 2 calculated in Table 27-2.

[0349] The CB was administered for a specific period, typically 3-4 months, after which the antioxidant nutrient levels were retested. The follow-up tests, present in Tables 27-4, 27-Attorney Ref: VIB-029WO 5, and 27-6, demonstrated that her antioxidant biomarker levels significantly increased, while her prooxidant biomarker levels declined to healthier ranges. Specifically, CAT levels rose from 2.7 U / mL (score = 1) to 6.4 U / mL (score = 5), SOD levels increased from 2.9 U / mL (score = 1) to 11.2 U / mL (score = 10), and HO-1 levels improved from 0.1 ng / mL (score = 1) to 3.4 ng / mL (score = 5).

[0350] Additionally, her prooxidant biomarker levels showed significant reductions: dityrosine levels dropped from 6.9 μg / g (score = 20) to 4.2 μg / g (score = 1), and Ne- carboxyethyllysine levels decreased from 107.2 μg / g (score = 20) to 89.7 μg / g (score = 1). However, triclosan levels showed only a slight reduction, from 482.3 μg / g (score = 20) to 479.8 μg / g (score = 20), indicating the need for further refinements to the supplement formulation.

[0351] Despite this, the overall improvements in her biomarkers were accompanied by a noticeable reduction in muscle fatigue, fewer headaches, and enhanced mental clarity, leading to a significant enhancement in her overall well-being and quality of life.

[0352] Tables 28-1 through 28-6, showed a different set of results based on the application of Approach 2, which offered some flexibility for enhancing the antioxidant defense system of the individual.

[0353] Example 4: 36-year-old male

[0354] A 36-year-old male athlete experienced persistent fatigue and difficulty recovering from physical activity, along with mild joint discomfort. He underwent the ‘Oxidative Stress Profile’ test, which showed optimal antioxidant biomarker levels and several genetic variations that supported antioxidant function. However, his prooxidant biomarker levels were moderately high, and he had significant genetic predispositions to oxidative stress due to prooxidant genes. Despite strong natural antioxidant defenses, these results indicated that his body was experiencing considerable oxidative stress from elevated prooxidant activity.

[0355] The test results and supplement plans for this individual were shown in Tables 29-1 through 29-6. As shown in Table 29-2, the individual exhibited both a high antioxidant level (6.375) and a high prooxidant level (12.33333). His antioxidant and prooxidant biomarkers, along with his redox genetics, were analyzed to determine the appropriate multiplication factor (MF). This MF was used to adjust the RDA or starting dosages of supplements, creating a customized blend (Table 29-3) tailored to address his redox imbalance. The formulation aimed to further optimize antioxidant function whileAttorney Ref: VIB-029WO counteracting the effects of his genetic predispositions to oxidative stress. The scores were calculated using the “Defined Multiplication Factor” of Approach 1, which generated the RR value and further derived the MF based on the pre-defined mapping.

[0356] Follow-up tests in Tables 29-4, 29-5, and 29-6 demonstrated improvements after three months of CB dosage administration. Specifically, his CAT levels increased from 1.2 U / mL (score = 5) to 11.3 U / mL (score = 10), and his HO-1 levels rose from 0.01 ng / mL (score = 1) to 5.5 ng / mL (score = 5). Simultaneously, prooxidant markers showed substantial reductions: bromotyrosine levels dropped from 396.1 μg / g (score = 20) to 271.8 μg / g (score = 1), eight-hydroxyguanine levels decreased from 62.3 μg / g (score = 20) to 47.8 μg / g (score = 1), and malondialdehyde (MDA) levels declined from 189.8 μg / g (score = 20) to 155.4 μg / g (score = 1).

[0357] Despite his genetic predisposition to oxidative stress, the supplement regimen effectively optimized his redox status. These biochemical improvements were reflected in his physical condition such as the reported enhanced energy levels, quicker recovery from exercise, and reduced joint discomfort, significantly improving his overall quality of life and athletic performance

[0358] Similarly, Tables 30-1 through 30-6 presented test results determined using Approach 2, reflecting the oxidative stress status and antioxidant defense system of a 36- year-old athlete.U,U es,esenirusuUsi sTsi, ,T e,mn do d uiroo streUlobleletseS,ue,adoelbelmual snioh oh reP,siTrUmsoallBW WS s,e,a ,eseP,,m,a,akranuisrsimsusdo ur msmsmtU,T al e, PsiolS alalnada ,T,bel,aP,P,dio olmsmd a uro olohmsmu mu xoitWa r rBlPeS BlPeSeSnarofselp ma)s0la1ciQ g o Colo )( n0i im B.A1 U(Q unebil2 krO amsela SG(GS)0 mt(es(eG(1 dimA C Emd albanaes aseQ cayznininiui eczipooTiBdiatudi axtc )difo C irnemoatimatimatineledi lu xrtn xo m)oru Hld Sus)( n0im OeCidtsiTe iU C V V V S a i n d AperG(d A1 unixo Aede e e eGUQbl3it iC(n n n n Smsx S(eA C E a aloesoiohitohitohih Gdic m ynininim udep eln b Are alaatat tat tat : a z ia pcn mamamanezidolu utaululululHSir eotititilixrT S C G G G G G U C V V VeS OeC O W92s0-nBiIVet:feorRPyenrottAa g mol r r sa eolvioh iu,au,aplap s ge srB,sm,emy rea niekmsmsu nlkmsroia ad nam A u e N gy g x a Rorm d a y dHd - i 8 ca c - ielc eg u a N ma dsr AeNkra'D m2-yx oax u o r u y o d gorgs-oy y do laH- I-β1R(5sy ytiI-H-H-N- x yrtiM 4 8 1 1 8α 288 8 H-o8edH- 8N- 8 yr soregnkneorαtoit2-acita a m aFtndi ex g diαnxo α2ia ddio a m rser 2- α 2 --Fnal5xre sop rea dpekFrlaniF nnidgaetlbordikrA diaednedinsn d a Ppia N nalorT L m DOpim y nalalgaPW Lh9eong2agats-)0-dlBIaiyxtstsorR(doVrororP5:4n d pfeeRloly o P -s)1-I -R osybeaaH- -β1(5I-nrT M 4 8 1 1 8 ottAe,eniu rsus,itd,o d olo oln enebe beoitirnliurolh ohce, wteau,a ,w,dmsmmu mreal spalreurk , p,se,as ra, m ene emme a tnirnirnirururnirmsms aU U UeSeS UalPalPdixo eorp nis ryolf- sL-elp e)nli y s hmasoetnan uis e elo nie emacis enisnisyx g gynaornisoororobolx u r gniyt orytytraoidyortiot iB naD'- ytoorC- .oormol15xoaddiaxheoalgng gat P-)g2-iso unigu H- 8N-ll8 A,tioo Nrh(-elB C Nbaor eo vredlaiyaxts atsa sorR(my g xnaynxaag u myx T6PitapdororporP-5 a 1d orugorg o a rd orselbdidino d l y o P s- ) -o d s Ay y d x ytid Ay rea xpkrT Oi aL MH- I4- β 81R(151I- 8αN 2 DH-o8edH- 8N- N 8 RH- 8 a meeg g a a m m a add nsireAetNokra RrP m O W920-BIV:feRyenrottAerocsksirrekram oibtnadixo sorre- P.krL-) 6alyelem ht banieso ae eT g n namieas eneornisisn m i y,x x409673 02090 9sr7 oso o o389 bit2873334)5009310999 1061( srugd niyor ryryran 2s4s1ssr( sr(9791s4s7s121srsrP(1 orntiietottinNaD'- yt totorC- e7Ar(r1(r2(15 3sr71r(r(r(8sr1sr( (O 1 D -ooormol1 ni el(1124(DD MMT0(L NR UP E N 8rllP A,tioo Nrh(- sB C Nylb DTT a 0 XXXRS T T O SO SOSSA1 P P P SSL SL S G G CsrG G G G G G GE SX T O W920-BIV:feRyenrottAcitteene snegarN elau St )gerG xotvdc naAin e=vi addrioc)7538451sr 82 ( 4s24sr(r( R.Dsr(12 A7eP R2 XAeln15 O NROKba e12331P M 11224 L N XxrMTG MTTT E T T HR P DDDDTTT XXXXXRSUL O SSSAAAP P P P P SSL SO SO SO S G G G C C C G G G G G G G GE S eesa emesrefssayzatn u ndixmeE marO xtsit- or tsSePysniW o n d 920-daede e ein n netoBI8eRdixxooiht es oioi rahthtpoV:efloreebitpatl a aRa nul att tT Au S GaululnelCeyeG G SnrottA3h scnao n oirtpod1 2 2 2 2 2 2 1 2 2 2 1odh n tAis7 ge1 1 1 3 1 1 1 1 1 1 1 3 xosani rn odfarebr snrT e 5786 8 054 8 3 3 5 49 0 A14 038657146 9 29 G7 14879 87 G38301 35407 0 7614734 7 r 1 r 4 r 2 r 2 r 1 3 r 9069- 0 ss s s s s3 −sr1sr4sr2 Asreltlebu9ellbu a Mba T M Ta12 2 2 T DD 1 A A 31 RR2 XA A R5 A1 A2- NNRO XxHB P B X MK K X T TrDYYY O T HR P R P X C C C C 3ee eism nsea anetcyzn 1to g u deersap or er0 2 5e-deedy 5b 4sasaOnWeta the eP edin9nig 2 x0- o yxvitnad e m o mxeg ooyBIdeocea- edixni rhrchcH x P oV: rfPeoimesMaohotnaototD olcRh T H Anikry y A yyeP X C C N CnrottAecnerefeR isrtea , .v msesse so gerny erpad n if icp y xbozm c n te drx iy tsex n oiue1sstczane ex vioo ssdeh HerrAerd 1tsen o,p h,lraotdi arceo G Zca cag tani ,.0trts1 neelm nxeievcaideC branieo mnipR,,nnihc- u yhtbt sul il eitcaeleco er aniec eta3-crrealu mnaT ppre eu uthw recioC, esxau u qapld A m Aeu Qp d EnaotsS Qr IetR A 3 C 4 A4 P 76 TG 9 3 + 20 84 5 43 29- 01 O NW S 3 −65 C Asr920-BIV 1 1 1:feR el eA AyHeb B 1nraneP D Y Y ottT G X C C Aalu Rκ- g Fneot,acaR eesenla ele .,ssaeersasn,ensi oi se rAv aiN acmrsiezil arrtbueseertcsni. rc atga raviDtsnvgs malehan ne e , sni stcOewossnitiselfvt rtmeo gnre ,e S vibitni elgnuemtsDvit oitkrDsa estac- xeβolre auimyz,lorpp p g pn mamamaneneucrneoPu oatititil eS C Me ru o Dnine .V V V S G C C g 1 mao1tincel0 yba8 V P T 8 4s4r96;5 57 4)0 11;98 6)2 82)3 P 32 D 4 9 7 D 929 D 7 4 SsO O71 O 1 N2 rS(5srS(1sr8srS(02 O Wsr920-BIV 2:fe2R-1eyeXelnrO baneD O o G SttC T AytpielDc -aniEnimCy n A,n mseDnmnA- h plmatimz i iuatinem minagui inmoati ati elena ele atiN A V V C V V S M S V )2 XP G 6(16497 0582 646 311;)6 3 46135 46510 0578 201 970 0 X 7 74 9 P 90 srsr1sr1sr1srG(4sr2srO W920-BIV:fe1RT XyeA Pnro C GttAC oui soninraor rrnimilnarpt a a, tamani ihtietntonealtcedoigeCkecuc ag gtcareloh rtemca parrtdedertvsV u LeS G BA- S m o PlB Gxeg g A Axe eR 596 1s1 1;)6;)7r;)1 ) 2 6 4 14551 0 36 4 3 1 01 47 31 6 MT45 M75 AP 19 17 7 63 S 7 T 3 S 9 TS TS 0 0 srsrG(srG(3srG(G(1sr2srO W920-BI1V:1fe4 M L XRX T U OyeP S L Mnro G G G HttAelvielree eldaldxrict s xhdin osHG dstcCsegnre eeoniA golbsyroorTud neot riarT .std xooit6 c 7 niesesa ec rht olecp esersoecnn ratnaeaesti nanitaalutsnitabdg e onah psygae , sSerprnaoitas ep n ufocC evilonigriv m auinioh ccs ntmx rtnt aaexlem at ccinimecro n oitile atiulilopga ati euelen E o S V G o FilM V Q SA.)2 21RelxrbaT T 9,9 1 88 93;)0 517;)2(8)8 0 D 5 D 4 A 7 23 4698 50 R 3 R 6 D 7 6 97 1 8 5 83 1 N 4 N 8 9 720Mr 1 3 r 7 X5 X4(srsrs s srT(1srT(4sr edyOtheW9d2ne l0- PBIO 3 2 1 3 maidV:R A D1 elfN pneE 5 A RelpolRayL B K N b uenE Y X arSMo S C R P T TttA]2 1- 1[,tnadixoitnatnetop asag nitcaybslevelA D MsesaerceD ,ninehd N neortaGle,,-atenaH-sliBair ga4(Mdesa,liesb, aEllw h diylniet s cA a oeue poma c ,gcirvairH, )tiS.n lGn e ut,iEV, de snip O, em N n usniesg acE ietcr eH- epd etrenoru n4(naaer almmaatcC i -,oi lyamhtac rn la la atneoG ht , aergni tcneVteee an nnioharnO,B W9,Nhulo d G n A,etuK,c to2 mset exeny0-uiC,tBIs nicana ,yxC L igmos enacseerni,en ni itolmn aentin oix orVe:nrt auifeg maxewned n ymaetel sacoencrelaui am gineg uhtd nnecratyRati ahslyeh-tiori rau ple aeruulHeM VetA S 4 Vac ab C Q E S M G C G - 4nrottA]5 1[dipilgnicu derdnaS Rg nig nevacsy b A M- E N H-4secu deRy , sl,tltafoos3)α neor- hya2 tgF ) p yeG Hylx m ooro P- Opd d y nosOae ta i-8 L( Tse,t )H,Lecna3(rtDα n 2 dineDetxe iFx m Lor emanoirelx e p oa(c- vtid ailovn p p 0 Lte-eyalOo us1 D Bcix gWr9cQ 20-CdyilreLe ,r ora t dttsBaEmIniH dg niyenisitiEniCni sa y ehiuanet orV:femadR tiipidemzgatinn eodirxamc- atimay dtid-e7sl2 di enzep- eosy,eV L A V C O L V V R 1ca a rH Gi- 8nrottA]0 4[gnicnahn ed S ot ofonss egi-odre rylln aca.OcssR af enieoierv o nitss rpnaht,pd it so hthtcts rn erd,Snsigrenysybslevelα2F G P- osi- 8sesaerceDepmseo sss retse s es etci es ;en ndiel ) ag toc aoag oitrpip Geac )L.p drucaemuedrmecr a aemo nc diS Hadaor e emax -aα 3 D d D p g D d o te2F1 O- B,Gel8ePn-b(a e,te1 T ni1scadort e ex Rni,ta )G p oc(neα acnierH y 2 uilmCu,tO- E L ni ,Fgyrd xacrca8maicnid di oeG,lu Cr(t enitiancO Vytatlad o gayttt e- g’r2e ,x0e-h 1en v au p Qil lgW9, a2C f3ts af n3 4eay mxoeo acm-eory tCx0-BIni-amor- morotci aorV:g uip- a1g eflelpddy -ayzremat renidyR teinmel β- eba pA h NnH pl e sa vsematiye1 meV O S 1 O T u S D- o 8 A Cey R VH- 8nrottAodfarytiAo tide r e riam N ytin viogdresr a apceilysNm zeonnife naDtlyzpi ppsnederesaesevevca ers,)s its ei es ittes ,siemsneerhecu Saeras aerfixaerasG- ale 2er alcelpecg u y ccihdOoroorciu p x D weRNci( eDticetn Deced DtiOced n N DarN.udSeRoid 4 )1el)GboaG- x T o ni2o- 8 m O(aN- 8e enci(d nistaeicieoemo nia tcsn yeaciraO nioc- gug ujt fW9 a p2 u L ayy0rneoe e- m gniil-ldimaxre5 m n oinisnBIuViormor:fenetiucdytcad orh 1 eltaryec cAdyctelpoo di s rynisiR leNy- uhia-ilNh raba p xdititieS 8 C D N o F R- 8 T T u S OcaD NnrottAenisorytidfqn o yer eo ysonoioitioi soici arbyscnis rpeyistctayron tatctafiaym oe s e edornditiliorudmtadmru xrdmro oesrni nidiyixobytorlinaoootetagaot rypadpo,tn )seAec egs ssneeatiosrnaeseadne sgns'seCenCn nit neevesuesit erniso aqa nenivi st ossiti- ntaeciterat et iti orGu dbicdcrper es ervnidHiuacppiliat naLP.( emRah dnIna eorDytmcInb IucsnIergrp AxdoeRylg ucSaf cal stIM C5 1el)baL T M )CC( ,AenetaNl(E ini slaeylgniemanir lynidicOtWs e92ynticis lv,etn h po toe itehcaaetci0- lnorortaCrdnidimyaxco n o itpilD6BIyto V:e itytfceo reniyhnigrx o ollaec ani1elR a-arti rtivs mat artcybrgireh pmatb N N Ne iAla ul iRe -p ayeV T L G C E Q A V TnrottAS R E K R A M T N A DIX OIT N Ane ee,Vmopma ,D,mel ,praetimapVyeztm neuiilmn -aatitim VV,uim unim unini ipu po,3neoer elh pl ,301el nel matietnelS C D C GeS A D QeSeu S V LeS )tT n A aedid C( e1 ne en xoriexesat eoisaoiitko rru)sahtdixhtaepmDlOat atoatn A mu SsidS( aulreulC G p GOtW n 92 a0-dBiIxyrseV:oofeitg m eRntyzAacnyeEnrottA.ydob ehtnisrekramtnadixoitnaner et,csp yloartniC a E Co mtnvt neaclfsiolanimninipermu aicl mamaelp u onbiti atitip n MocRo b V C V V A ) 3eR eGs(an oeC Edi ixhtsatcninidimcaoart ama ceulude titiirp GrV V U O W920-sBIVl e:felam yRmzyeSnenrottAg nipleh,rekramtnadixoitnanasatcanachcih w,dicasyni e,eniclhtCn m mon ou ytnani i iuihcrneecxtat maathtatul a- stiululCeS N A V G G eneoin toha) itHhetdaiutfllSulu GG(GsidO W920-BIV:feRyenrottAgnicnahnednaoitarGSS G / HS Gh gihag niniatniamyc, en l netytC oiE orCecnihA-mtniacniaattiulmati atematiN V G V B V eneoin ht / a)oi e )tHhtdaitflG u S ulSuS GG( lGsidG(O W920-BIV:feRyenrottA.egamad e vitadix o morfsall enritx dapoaeie athtru ge la iliaeolxoic e ep u kmak+ 2oluic scg 68 ecdicnnritrc sn Inib xemrtouercuritratnanIycys erfitSpcu maFniecnadertira eum V mFrs r(ecdenax tloeulsors lerU) C A N(enietsy Ae.PtenclC nasytreni6eotiecha- cpm 1eG C Nnipoati lZ C VbaT esni7 a 1 C msedeallb p a siniT dimolu xubrOla eCO W920-BsIVni:feetR oryePnrottAu 1 3 5 1,sred k nraa,smre ekgaramamtdenaviditaxodiitx no addeessaaeerrccneId dneataelirifpororpprep kr gatarn baitcn g o do itmedOaH- 5 S 0 AasigiTkcuter sw L ut0wN8f40 mseht oiti>o pneuit 1oo>BP5oib RiwtSsnd- o Lloes00sn.pNg -fni.cuaer0in 0ocreY2Lreo g wo 0vl0it5erffu Numd 00 wm leb 1ehtn u b 0 1 o 0 5 p 1,eyeK mso n ctndoeS o d BituitueeP,aiO v Otitn s)O O H Sernsb ( 2 2 b o HOaM A creeH f DefNh u NtR n B 2ideni8 1f1 et eL d e G Gelyla M YH- drab C NH- sa n 8 8 no T Aitaiv erbb 1A- m orfyltcerid Lu0001 nieytaltcicenoco 0cocl lclclclriswoneriswon0 5eriswonHMeriaiceai eriai eriai eriaid>L -peoesd >-peoesni d >-peO-Does8Ldv erid v edv edv edv e uln LlLlgu LhtLhtLhtLhtLht0ai lu0ainlg u0ainl0 u0 u u u u 0 v 01eit0 vitm0 vitm05 0 0 00 00 00 htn u 01ehtn u 01 01ehtn u5.2 0 0 1 5 01 01 01 l O olo Olololo SnanO S O OSn n nM htah 2 M 2 Ma a aDe tH D HhththtM E D E E E O 2W F F 9 G)2 G Gd Y L d - E E SyiGaG hP)B(F0-BIN-N- C C H NH P p O G D olV 8aR(1 G P:8 8 Hsi1fe8 51RyenrottA5.5 0 0 1 3 F GP A 5 D Y 1,M B 8 L m0 m / ogr5:f 0.y5 klcais0rov 5:otm1ltn rcoei tLsfm0ar5biflriu0o ornla9 LfaidL 0 yi c8 0 ult0 d v u es04 0c05na0.05eri4sU 0l1aidkvcotsrniL nio dfyltuc0 yltylo P n o O el0ceOh S riai0 5ri t :d v e nd .lne8 Luhtig Laivv 1e0 u 00m0 0 0ere lh dba ) )S 1 1 0tn 1 u T ) F H)α G 2P) )G- Gd F 5 F F E H G1,8 G G N P H O lolP-(P o) )( 8(sαR(la e )naO oi- 2 ht2na )8F B(1 51nenis(ni1( (n)Gd o o GH)G E HhtA E α d α α2 nna -:D 2 n yal2Fyx ugH-8(d e) )N-eM(FKenig F nioryx8(sd dantsni en Y Y8(o d d d n noalyedniisn o n)B(C( en n yal ralh- -a ayi enenisohegP- g ga42- u uD(isioOW Fitd9l at) ats ey gy gsna2 G Aaia0i s- PBI5 D YoB verR(ts5o orn oix x yxenoiroyrtytug r dnp-1- rP P-)htordordordso oororV1,M o 8 bblaosi os -β-R(atuly y yrytim orolti:feA M - 8i- 1 5H-H-H- hN-R8 1 1 G 8 8 8 D B C 8yenrottA09 ) L M C( )eL n E )isCGy(l-)en N8) lyis(Y h etyllniN( ey m h yteOnean xo y W9 uisb xo 20- goIoro yrabrBrVti torc( acfe- -:N-ti ε εR8 N N NyenrottAerocS stna dixoitn AirU a 1 L octst1 L Ld / s9C Te5.BfeR 1 ))R(≤ D xP)O R)SG((1- )eeG(O 0 ssaa eH 1 d tudisa(Qicxtc1)oAmsi )o u -ed TredssaeH CselS)(0sdciitepereAe eneu G(A1ni ccgcel eUQm nixitsay 9 1sediC(n n y on(exeoioixA C Essaloepxo elmoresal htathtomoidim at ellhtatcayzninininmmip T etol laenetnih byzpat u u maci ne a amaour nrp a n T E u Sa l l eul rotititiC G G Hm S G U C V V VrPeCeolorO 0 mhcolW2n oh920-elo nciBIbriv a gD-V a nr:feT E O4,2RyenrottA02 01 1 g / g u7.00.50.6.94.3.1.9. .3.5.30.0.4150.4. .1532 71 5 063313002672115 4 7 ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤3 ≤ 5 ≤8 ≤ 3 ≤ d)iP c)T)a )scP D) ) ) )BI ))eitA T BseDM)P T AAA HH H)PlA y diecP dEDa3icD(P H2 T E)M P M(O 2 M3 M4d GN(se ) ePtEaxleh ci) ( it ( ec et)D(( ( ( itcPeviayx bly di se aahD(M eDPe(EtaetdicdidiA(ntdieaM(hthor)renephpsthc c cictsvr ep d)Ah / hApcietpsoahetaD(epsarutA c A c A cirAycestally y h P Pseao hpphto pi i i yt c leax- H B(loo dirozh hs ahr r ru colnepspo ilyrht e5 H oio h hpsh oppaocrup up up bo yneP / hhl-lyE etAlnehiteth b oihtip o hsoihepipipisix y o hsPly hthtM(OaW9) ro n na2ol e splseyp asC- yx hptidl ihplhtlmhlhlhlxylp o4( )o odlyhtlyhplyhe eylreyheh y yorgly zite -2)e- P 2(eta0-D- h o nrhsiAnen yteyteyteninitBI4ehtehted ytcio - H-la,hcrepsilcoeirN-htp ylb- a 2,Dh P-grhteimihteimihtzeimi azrt ary tM-M-M-H-neecha-tsaln o o o noE nohtV:2f(eP B T 4 O G 2D(3 O D D D D D D A A 2342 P N P M mM(mh pRyenrottA02 01 1 g / g u4.32 56223. .49991 52 04 857. .4 647.32.37. .0542.0252.08.1.7.8. .0 ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤0 ≤0 ≤3 ≤0 ≤1 ≤ eenid)- n )lieetsiy)l cRP yts)lC ytA c A yhty)uirN(xeelClp b y)lyut en h o yohrx porpacieox)mateyx dtyre syeo- P b o 5 Hr n orhi )M Cta )G -lOay En) ahetb n c- E y dyD- B Dl ly y h ppsT(sla ebnene2(- AC-H2,4,Ahteorohen atOe-M(2erta abp ra ar baaS rN( (l2(l3(lN(y PlPlic em y a -l eyt )y)yex)yyylMmu mmn mW92(- a lolayplyplplyteni ecEtPtnorAtCececiedecneglyuillnileciuiduio uirm0-BIn h pytyc eHtsy M hylvy mknealmmituluiohtteaV -tsA- AA- AA- EA-piaer ulcis l d l smh p MoruhtycN(N(yH-H(gi e r a anni e e:feP B E N N N N C 2 N D T H B A N A P C A T T CRyenrottA0202 0101 1 1 g / gg / u g 9u5.5 54.03.09.06.11.14.05.20.00.04.68.65.06.03.13.12.1.2.0219.1.5.0704.≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤0 ≤6 ≤7 ≤1 ≤1 ≤1 ≤6 ≤8 ≤6 ≤1 ≤6 ≤2 ≤6 ≤ ) se)s neecne echteo hnthcdii oir cthcT 123lo A 1Asyc eir(ABsB B 1212ne cilmMnT(1s sB B G G laoOuinixW nnen nio xttmao nirB nininin n n vineuyrmuhtmmot ixotmnEelniacnitsinsinsi i i inininnix x x x n x h92 m0-uBiilosg nucdilu uiruinocot argIr i arduraio o o n nilototototyxotp ocVadaniutrea lamsB G TalP Mehioharyalfhc ra irren mmmirtL T B T U M Aet eo n u u uiutaalf alf alf alfoeoily:feO S Z R V E F F F C P A A A A D G MRyenrottA0202 0101 1 1 g / gg / n g 3n5.7 68.1132.32.41.01.01.06.78.62.92.22.6.3.9.1.1.3.7.≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤3 ≤ 1 ≤ 1 ≤2 ≤ 0 ≤0 ≤ 2 ≤1 ≤ ))s)s)sed) ) )) )AApci )Ao ocioAn) )s AicA NAd x HnaneDF )e e e ) )se eO F DFicHF Fxac DF P Snenecesesen neFAP PaP Pe eP(AcecehtD(onene ececeP(dcici(n n( co d din( (h d d di] ](d diclhtohtohccecehthtoicoiflfl ciacoflic c2 2 a C)Cicacieohchcirhtohto ohnAchca usuScia aciuscici3 1- A3)ax1- Acio o n)neirirT p)TT( hchcirirciT oe eniisVIr no n oeo on2,H2,Donacrier( ( F irirT t obN(csarG H niT(T( ( ( nana2-J tctc ) a annanatnaat1 Sxeoceuxepe[- F 1[Fna ed nP-2 - nP-2ceoOicol ly( ninx n o o h n d b h h- -d d oio W9org 2nx onix x xtaA H L in n nracoroorO o For )o Soroorooro)orooroorC o3orC o3orooro0- dyoteeBIhaltaecot otarotarrtaisdiirdiirdirurSu u P(u x u u u Su u u 1(u 1(u u r AlflfdilfHlflflfBlflflfd lfd lflfVihviai2-tatao o o oeFrerereFrerereFrerere ire irere:feD C N D T S SsIR R R V P P PcaPP(P P PP(P P PcaPcaP PRyenrottA02 01 1 g / g u450.26.2.9.1.9.7.9.7.36 ≤ 2 ≤ 1 ≤4 ≤ 0 ≤3 ≤3 ≤ 1 ≤ 2 ≤ 1 ≤ d)- i)c )A An(d a SneciOUDr eic eTtaa tato o F F) ao na ]P- P(d)FPetc44( tn a ocfilona eAena- x -l sCrsereo CCdiicA caB d n i ousnatp ornatPFoi3-9(krkara ] 3 21- 31( a ciF Pcfl e(aun pepph -) eh)P(d-o8roetaMmC4,dcio 33ona ecisoe antc l2- yxlSet,a4-ulnoegnol1,ic-na2, )2,cetaonaato yh 1a t oro y pfac op h 1icedancepeortHo Hc flait e adnoeuor en Mat3- eu ds- ma adyen [ A[- n d - O1- oflnrtatuet )ubdihr- u t1-lfm- r5- )lfp Aart orm- 5no5-P( eor a1 Dixheo p o n uxe-e ) eodlyOorForuororAororor ) epor etuor eor lf)hnaS vreaixW9 oP- oseo oDeo o o Spr )o OF -lf )otaoaAorn Nitapdnor20- ulf2 u r C3lfr naulfulfTu FlfulfulfHaSu FeOlfP-3,atXu b3,penelfno ucfeNolo llfdOhnaO3didio d layBIVe:1etcrereP rerereP niFreS 3,h G reu reoc- x F xpiH-feP(P o P P(P P P(L P P(2( (PsP DD(9 o P O L M 4RyenrottA02 011 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 o G o LrPeg / g / g / g / g g uug g .2.u u g / 5 6 24.2 2.g u.90.56u849. .011: -≤ 0 ≤0 ≤0 ≤ 4 ≤4 ≤1 ≤ 9 ≤2 ≤ 5 ≤2 ≤3 ≤9 ≤ 7 ≤9 ≤ 015.0 e -S)G Lsm y(lα a2sn- entcMre zk)neteF isuC( )n o deLra n E G a o αni sn α y α2- dnsnausreornix2-PsC mSSdiy(n 1 oG(2x orF 2-FF nialrdgegrakryexekr l eekrn a no)iln t yisitaezedloitib n dnyidnitsaoaism h yilfla A h- n d n nalormedni4alalgaPe-'na emoen n uni e auiesgeactellyituniT m o a nie enenylmy htUtsid u egnat gats-)ga2- gng a agnamaso ni isisGxoey neGblOostsorR(myx yx u myx ud nrysorordeb xo an o SSaWio9rorP5 aororg aorg 2htni itiorytyt cor brdixiGde0)p -aBtE o P -IulNs)1-dd dorI --βR(osAy ytiddoAyrtietotnIaD'- yto - NoHrmorn -H-N- NH-N-orllotiorolaah vc(acohd-ε-εittat :zinulHSdix V:feG H 811518 D 88 8 R 88 P A,o N B C A N N A G G ORyenrottAtu M 3 1 3 3 1 teH 2 1 1 2 1 dliW 1 3 1 1 3 ))13 ) 249)s / 6 e A 13 368 1471 neG 3904 g 7 7 33)0sr1 22( sr0 3(2 1sr−(18sr(R5 A(2H6H - B 1 02 P X DsDYY XrX C C C t u M 1 1 3 1 1 teH 2 2 3 2 2eldliW 3 3 1 3 3 3 3 3 1 3 ))9 ))9) )85)075) )688 93 )) ) )6)1)0 49 57 1344) ) )0)8)6)6) )7027750388474698 se64)9 088 92)646 2596516 349 175 1424615301814461 067325140599133 797 755070 2 ne3 g 2 8 2 8979166 137 ssr336158073 r 4s00 (sr45009901999sr101( sr1 r 1( sr822 ( 4srsr1 sr8srsr( sr2( el((1(9 577 s 40 s 11142712 ssrsrsrsrsr8 1(2(3(31s1srP ( O124 DDsr((122 b AA a P MMr(r(r( (1(1(2(2(4r( srL NRR2 X T DDDT(E AA D TTT U NNRO STT XXXXXRS LxKK O SSAAAP P P P P SSL XX S O SO SO S G G G C C C G G G G G G G GE S T TrM T HR P R P O W920-BIV:feRyenrottAerocSs 32.1.12 2 3 2 7 7 7 5 65 67 4 l 3 1 2.00-0- 060-8.45 3 91 47 06 e E E 1 E 71.00.19.02.09.3 12.1.0060 6 0 52 AP _ H _ elC B _ P AOOHP H P _ R _ N aOH HIS P S N b T _ EIP P H OOIOE T E E _ M A_ B H S o ATOOITIH H B D HP P A it_E _E L ORIH H L L TL _ A D P TYY L R aNININ TL L L YYA R 9 E P E YYYH H H N P xo94.Z Z L _ AAH Y_ H H H TE TE TE E L Y de0.0 - 5.XTD1- G R R P TATTT EEH H R0≤1.00P A OV TTS≥ G CO S H A A AIU DI IEIMIMIMIPIB B D D D D D D D D T E noit)tacn i a)tldna piOixdtiWlo x uito 9 n 20- M AorBI1-31e (P y(V:fe2lpde rg y o gR elmniotloolyebnra axfe car orT E DeottF S U A1 1 1 1 1 1 1 1 1 23 2 82 9841 3 62 107 - 0 E2.3 1 1 63045 002. -E 7.01 18.89 98.2 01 0 09.6 00.1.7 1 12.7 T T E E _ _ _ _ _ _ B P T D H E_ A H E _ N _ _ M _ _ P H E _ E ONITE E A M TT L _ E S A_ __ Y T H E _ C_ E TT P _ __ H A H L P L _ E _ A Y A _ H MT H L T _ U T_ E B M YH R X P E Y U _ _ T E _ _ AX O H L _ L O F_ YYP TAR _ XXE H D DIOE TY R H MHHC _ID O_ P E _ D A YX L _ _ T E TYR CI_ H O _ T_ 5 _ A 5 L XU R E _ _ E O U L _ A P O _ L L H F_ PIN _ YYHTL E E TN H H _ H H YE_ _ _ _ L H E W N Y_IPP _ E B T E T E P H R OON P _ Y _ T E O T_ E L XE TH E YYIHNINIS Y X YL _E A_ _ L E H TW TW TH R __ E X OB YONIE_CIXXL S S O O_ O H YTR OOY_ O__ __ __ P_ P_ S T AH _ AYR TN C E _ D_ OOYO R R R E TN AAWWH L L L R L E YN R R R H Y D E OS P T TW L L L A H L A D D TYTNIY M N OL _ T_ E TYTYTYTYTYTYOGP TL L L M_ P_ GS U OYYE TOS H _ _ H Y_ _ _ _ E E E L O F H H MOR O_ R R P H OOOO E E E H YYE E YL _ _ _ _ R T U U YTN N N N CCCCCCCN P E E A A A A A E R R LCIOOOOMO OL YH O L E OOOO_ _ _ _ _ A_ R OGF O F G M M M M M N N N N N N E P H P R P H TH TITR TW TW TW TWR HTIGT B C DIE O W920-BIV:feRyenrottAYY XXS S S _ OU U OO4 H M_E E TE S OO R R R GG P OOR R E Y D YXNIS S S S OS S S S S D D _ R R P P N _ _OIL XOS O O_ O O _ _ O 8 _ _ S S S 1 7 S 0 O_ O O O O O O O YYOTITIB_ R_ HAIOB B OR 97 05 3 S _ _ _ _ _ _ _ O 0203975 5 866648 _ H HSIN N N TD R R Y 1 49 O92 641 991 _ _ _ _ _ N N T 1 0811 03 _ 865 7 3 643 TTTTTE E A H H H H H OAAO 985 97 1 1 3 466 VE T II I I IE TU L C L _ C 0 E _ R G 050709012 45 9697 8970707032 97 66 GG G G G FA ETIV 1S 1S 1S 1S 1S 1S 1S 1S 1S 2S 2S 2S 2S 2S 3S E E E E E L EIF G M N N N A R R R R R R R R R R R R R R R )tna dix O o Wit92 n0-AB(IVs:fecitReyennerottG A&g G nitntneaGtToim = BrtoioS S S S S S S S S SnaBttcaO O S S SdinaF _ O O O O O O O OS x 6 _9 _8 _6 S _ O_ _ _ _ _ OS O odin 449 484 7 64 5 1 O6 6 _ 4 _ 5 65 7 3 O_ _ 03 1 2 40 05 1 03 5 8 4 _ 2 O1itx 3 9022 97 1 _ 2 n ooiorta5 7 85 803 1 499 8414863 3A zi73 8 S 3 4 S 47 S 48 S 49 S 41 S 7 3 S 7 9 S 7 1 S 81 S 8 G 0 S V 1 0 S 2 07 S 2 66 S 41 S 9 G = S VlP=lalR R R R R R R R R R R A R R R R R Aatoatmro T o T N 2tnt t)t -3an2 dinanaddiaexix x di lx b o aito o no itnO oWorT ArP A 920-PB(IVs:fecitReyennerottG A1 s 48.l 55.29.7 76661 0.50.02r otcaFn oin taoiztil alaucmrlaFpar ococ Mex hSNtertoA1 &081 / lato Ttnadixo orP =rlaD R05 02 05 58.5 otmr4 2 1 7 5 1 2 caF o N d ntoin ic0 taadzi r ta1 ilx o3 neciQ o 3e eaotoc -a 3 mpilD EmCmsenimrroP F 2 el-=nelpaniniyo b hmzniuinam a ppl atimatinemoatineg u lnacrT1- G u X D NtoiitT u S A V V C VeP S M C AOOV n G C S H A ataacdiR ilx x o opitOordleu)tnaW P R M4-9 31ydi2el0-2p gBIeloxo b mla oitV:fea xren AR TE S(yenrottAP _ _ _ _ _ A E O P H A A E P O _ H L _ _ C H L _ _ AP _ H T AS P H O H H _PN _ YY T TYE _ _ L YYO C B _ P OOIP P PS _IE E N E H H H H E R OON P W R _ NOIHP H H S ON H H _ B TT E E P_ TH W E O T T E E _ E S P _ M A_ B H OOITIOOIE L P _ W H H H A_ _ L E T T TH R __ P B YL E OO _ _ _ _ P P S _ _ L ATIH H D P T_ AH YTR Y T A H O_ _ _ _ _ _ E E OR D P TL L L L R E N AS P W TWTWL L L L L L NINN ATL L L YYYYA O L _ T_ E TYYYYYY ZIP Z E L E_ YYYH H H N P M N OY_ _ _ _ TTTTTT A Y TT L _ _ H E E E E E E A H _ H H H TE P H OOOO R R P TATTTE E E H YR R TN N N N CCCCCC TTSIU DEIEIEIMIMIMIPIH U U Y T L E OOOO A_ A_ A_ A_ A_ A_ A A B B D D D D D D D D E O F O F G M M M M M N N N N N N )tO n W a 92 y0- gdixBIolo V:ofrorePRU(yenrottA1 65 9.3 .I_TCEI_ E _PIB T_ OH B U O_ _ 2 U U G OG L S L TOP _ E _ GGAN N AAYD YT O _ L N H Y_ H ESIPIE YYYTAATT H YH E _ _ YE L XE T YYNINIS XXXS U U S S _4 H TME E X TOB Y AYAH ONIECIXXH S S O OGGOOE E E YNC_ D L OO_ OOO R R R R OOR R P N D YXIS R L R TN OGAE E _ Y _ OOY R R R E P_ R R P_ _ L XOO P MH P L N R R H A Y U D D TYNE TTID D D S YYYO STITIB ROI_ _ HAIOB R D B O L L L _ _ G H YYE E L S OOYY O F H H MOR O H_ H_ H_I_ N_ N_ N N T R R YT R TTTT E E AN AA CN P E E YL _ _ _ _ L MO TT YH H H H VE TO C CO R E OR RCIOOOOOL H H ETIE TU L R A_ _TG H HGP H P RIR WWWWR HGIGIGIGIGIGIL P T T T T T T T T B C D E E E E E E EFIL E EIV F G M N N N A O W920-BIV:feRyenrottA1 C / C / S S S S S O O O_ S S S S S S S S S S S S S S S S S S S S O_ O_ _8 _1 70 O_ O_ O_ O_ O_ O_ O_ O O O O O O O O O O O 903 2 3 7 S 5 86 _ O_ _ _ _ S _ O_ _ _ _ _ 7 5 0095 O 6648 _ 6986 6 _ 5 65 7 3 1 491 92 641 991 4944 O41 01 5 8 4 1 081 0938 _5 8967 51 71 33 6446364487 65 16 _032 405033 902 9 05 7 91 49987 7 7 3 965 7 85 80 2 8 00002 5 67 90002 7 67 84 3 1 499 4 1 1 1 1 1 1 1 1 1 2 2S 2S 2S 2 7 891 3 91 1 G 0 S S S S S S S S S S S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8S V 1S R R R R R R R R R R R R R R R R R R R R R R R R R R A R )tn O W9sa 20-cidiBItxseociitteV:nfenneAeRG(GyenrottA3C / G / C G / C A / C GirnaGtNtitA ocssdixnoandaalD 70 i 0diucR1 & noitx 3 08 xla=gnin / lB itset1elp max E:ma4a :-oim = 3 BrP=zil 5- 2toioelnaBt r a3 A 0 tcaotmr2D000 badinFcaoelR 5 4 xad F n NbaS S T oiixointn T S O O Otn otaoi a rd _ _ S 2 O _1A orPzitladziix otcic71 1 48 _3 23 =l=a06 2 076 61at llmoat r ao orataci3 omrP Fn6-neopDS 2S 4S 9 G S V T o o T N N=o 3 i2milniR R R R A5t-3na t tnana toniattaacelelb p -ap h pma2didiR ila ulti)telx b odixdixpaitxiT S A V o o no itxo otlno deu O n T Ar rW a P A P R M 92d0i- xBIo V:ofrePR(yenrottAev 1.e0 0.1. . .1 2 0 2 60 0 0 3 6 L.1.12.15.15.1a_ C B _ P OOP 2 0 0 x R _ NOH HIS P 2 01 57 558.1 52E6- T _ EIP P H E E AB H SO3 _ M_O TIOIH 2 _ ATOID HP T elE _E L ORIH H L L L bNININ AP TD P TYYY E L L L H 0aT Z Z E L _ YYY H H AAH Y_ H H H TTT 11- G P ATTTE E E Q XTD R R TE E E M MEeCes P enA OV TTSI I I I IMIyi iG CO S H A A AIU D B B D D D D D D D nimnm uinam mzatinemoatineg u lnacr r)tV C Veu S M C o n)ttca adina F xdiO o Witxo 92lno n0- aitorBI1-V 41:elitancA(Pfeily(ye2p npR el ig olg b motloolyenra ax pxureorottT E E M SUA1 1 1 1 1 1 1 1 1 7042 2 8941 3 2.6 1.310- 2 2 83 15 1060 0 5 70 E 7 0.1 4901 .18.82 61.98.09.00.1 1 T E___P H T E H _ E __ M_ P _ H E O TE A M L _ A_ T E E HTT _ H A _ L _ P_ A A _ H H L T M YH T R X P E_ U E __ _ T O H L _ E F YYP _ _ T _ _ XXE _DIOE M P R H _ P C D O_ D AT YXE _ _ E T _ ECI_ H OA T R _ T_ E 5 _ 5 L T L _ _ _ A A H E UP O _ L L _ H P _ S _PINE T YY N H H T_ _ _ __ ON H H E E L P _ E TTH P H R OON P W T_ N _ YE L Y H EIP_ B E XE T YINNI_ E_ _ T E H WWE O H R _ E XB YONIECIYH XXLIS S H B YL E A L _ T T T _ TOAH _ D O P R OOY _ _ _ P P S N C_ _ OOYO _ AH YT O_ _ _ _ _ _ AYR TE R R L R TN AAWWH L L R L E YN R R R H Y YAE OS P T TTW L L L L YYYYYYOGAP MH P L GAU D D TY E TT N P M N OL _ _ E T E L _ _ H Y_ _ _ _ TTTTTTL L L _ _ S L OOO E E E E E E H YYE E OOYY O F H H MOR H YR R P H OCCC E E YL _ _ _ _ MO PIH U U YTN N N N CCCCN P L T L E OOOO A_ A_ A_ A_ A_ A_ R E OR RCIOOOOOL N N N N N P P P H THGTITR R H D E O F O F G M M M M M N E H R TW TW TW TW T B C O W920-BIV:feRyenrottA_ YYYS S S _ H M_ S OXXXOU U O4 T E S _ OOOR GGO R R E E E Y D YXNIS S S O E R R R P OO P P N L X S S O O_ S S S S S S S NID D D _ R R _ _ OT TB ROIAO I OB O O_ O_ _8 _1 70 O_ O O O O O O S _ _ _ _ _ _ S YYYI I_ _ H B OR 903 2 3 7 5 86664 H H HSIN N N TD Y 7 5 0095 O92 641 9 O_ _ _ _ _ _ N N R R T 1 491 03 _ 865 7 3 6 R TTTTTTE E A AA 1 081 985 97 1 1 3 4 YH H H H H H VETTO II I I I IU L C_ CO 0 _ R G 050709012 45 9697 8970707032 TIG G G G G GE LFIL AE ETIV 1S 1S 1S 1S 1S 1S 1S 1S 1S 2S 2S 2S 2S D E E E E E E E F G M N N N A R R R R R R R R R R R R R )tna dix O o Wit92 n0-AB(IVs:fecitReyennerottG Airnoc sx 1 oa1 s noi itdin xx E:oim B 1toiS S S S -4naBtOS S S _ O O_ O_ O_ O_ OS S S S S S S S _ O O_ O_ O_ O_ O_ S O O2e dinxa8 _ 6986 S 6 _ 5 65 7 3 O_ S _lodi91 4944 O41 01 5 8 4 _ 2 Obaitx 43 4861 _ 3 45 3 92 97 1 _ 12 T n o 696647 5 602 003 02 81 83 3A or7 657 7885 803 1 499 4467 6 =P2 3 3 3 47 891 3 91 1 G 00061 Gl= S S S S 4S 4S 4S 4S 7S 7S 7S 8S 8S V 1S 2S 2S 4S 9S VlR R R R R R R R R R R R R A R R R R R AatoatTto T 2nt)t -4ann2 di aa xdidielb oitxo nO xo a TorWorA P920-PB(IVs:fecitReyennerottG AL 33 7 3 6 3 6 3 6 0.1 00.50.50.1 r otcah Fcnaoiortap zipala tn mreroefNfitdnaag yp=sit21 0 a Bu se1 3 / l08din xisrC y T at1 o / loituen hpareTtnadixoitn A =r =zita1-4 ot rlot aR eld2caFcamrxo pic0elF obNdema ta1an oi txciQ T nREn3 taoina=:3e ezit 2-4eo mpi D EmCmseniladi ro-42 el lazilx- niniy niuinam otc2 elpahmzaman maneg u mr aoraelba ppltiti eotilenacru omrP F baT u S A V V C V S M C N o n t N=o T na toiitta XT P dina a cdiR ilA G C xoitx xpio otl)no deutnO Ar4-1aW P R M 9 4 2ely0-2gdixBIelp molo oitV:b afea xren ART E S(yenrottA1 5.2.R _ __ _ H _ S _ H ECI__ T_ 5 _ 5 L X N U _ P _ A E P R E _ E OAD T_ T S H OTS T L _ _ A F Y P A E OETP H AOAT E UP O _ L L _ YYH H L _ Y C H AP __ H AS P O H H HP __PIN T E E TN H H YE _ _ C B POIP P S E E H H OO R _ N H H S N H H _ TT P TR TE _ EOIPS P H OOIOE L P _ B E_ E_ _ L E H WW E AB HTIH B YL A T T T _ M_ OOIH H E OO _ _ _ _ _ _ L A RTIH H DL P T P_ AH YTR Y T AWWH O_ _ _ E E N O INZIN A D P T L L Z E P T YYYL R N A L L L AE OS P T TTWY L E L L L _ YYYH H H YP M N OL _ _ E TTYTYT TTTN E L _ _ H Y_ _ _ _ OOOOE E E 1 AAHP Y_ HTHTHTE E E H YR R P H N N N N CCC D - G R RSTAEIE E M M M PH U U YT E OOOO A A A OO V TTIU DI I I I I ITOOL _ _ _ S H A A A B B D D D D D D D D E F F G M M M M M N N N )tO n W a 92 yd0i- gBIolxo V:ofrorePRU(yenrottA1 1 1 1 1 1 1 442 6 9.0- 5 6 65 9 9.66 1 94 2 70 0 E7 463 21 690 0.50.29.61.2 67.1 T E___E A N__E NIT E E T _ S _ Y _ T C A T H E E _ _ _ _ M _ _ L E _ _ P R Y E H T R AP N AT E H E _ T _ N _ _ L __ _ Y O _ E _ E O GDNINIM PIC E A _ E _ A TTBD_ S YS RICIYA C RZ _ _ _ C C C ATU _ OL U S D L E S L L R _ Y _ L _ L _ _ E N G R Y R S O AANOTCI_ P EIGD E L H _PIB T_ OH B OUP O_ _ _ 2 U U G OG L _ AN N AAYD YT YY E L _ L TSE E GGTAATT H Y E N P W_ N H Y H EIPINYYYS S S _ H E O T H R _ _ YE L _ E XB YXE T ONIE_CIYYHNXXLI IS S S XXXOU U O OOOOR GGOO4 H R E E TM E Y P P S TOAH C D O _ R R R OOR N D YX _ _ _ AY TN _ _ OOY R E P R P P L XO L L L R L R AE E Y H L N R R R H R YYNID D D _ R _ _ OTITB ROIAIOB YYYOGP AU D D T T YYYI_ _ H B O TTTL L L M_ P_ GS L OYYE T OOS O H_ H_ H_SI_ N_ N_ N N TD N R R E E E CCCH YYE CN P E E O F H H M R E YL _ _ _ _ MOR TTTTTTE E A E TOAA A_ A_ A_ R E OR R L GICIOOOOOL YH H H H H H V R HTL C C IGE TU A_ _ T T T T T T B C DIGEIGEIGEIGEIGE E EFL E E N N N E P H P R P H TH T R WWWWILIF G M N N O W920-BIV:feRyenrottA1 821 9.531S O_E NIS S S S S S O OS S S S S S S S S S S S S S S S S O O R _ O O_ S S _ _8 _1 70 O_ O O O O O O O O O O O O O O O O S _ _ _ _ _ _ _ O_ _ _ _ S _ O_ _ _ _ Y 97 0 1 5 3 402 903 1 97 053 O5 _ 98 82 6 666 5 46 7 1 4 3 98 69 _ 41 6 3 49 498 846 641 O64 _1 5061 55 78 T 1 081 985 97 1 1 3 4664 _ 3 45 3 92 O R 05 7 91 49987 7 7 7 5 602 003 02 G 01 01 0 S 1 0 S 1 2 S 1 5 S 1 67 900032 97 6657 788457 880931 13 4991 91 TIV S S 1S 1S 1S 2S 2S 2S 2S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8S N A R R R R R R R R R R R R R R R R R R R R R R R R R R )tn O a W9sd20-ci it xoBI enitV: enfeARG(yenrottA1e 7 7 6 6 7 7 6 4 4emit61 6 6 1 7 67mitsualA oratg u o / liatisy t nupa D R nclxerPxTto TAnore=tBorl s1t iBot aRc otx1elpna t acamroelA mdinaF a x F odep D0 odin NtR maR 5 xitxooin ona=x S E O S S:ntA or a izitadi rE x o:dic_ S 3 O O_ S O_4-4 =P lazilotc5-4ta4 _ 2 O1l=aoran ci987 1 _ 224148637 36elat labotmromrP F 2el6-4eop T o N o=nob 2me ilG 01 0061 Ga tTt tNtoiit aTel lp -aV S 2S 2S 4S 9S V T5-nA R R R R R A 4an nataacb p h p2 di and di adR ila T ulS A elxoix xoix xpi)tbitoito o dtluO n a n T Aorn Por eWsa A P R M 920-cidixBIteo V:nfeorePRG(yenrottAL.1.12.15.1 yad / UI00001 53288 5.0744 yad / UIUIm m m m m _ htP AA E O P _ TS 01C B _ H N P A H O 0 0 0elR __OIP H 02 05 58.5 p T E P 4 2 1 7 5 1 2 E E A S ma_ M_ B H ATOOIx _ _ 0 E E E L RI1:D H H P 6-NINO I N ATL L TL E P E YYY 3 Qe4 Z Z L __ H H H DEeC seni2T1- G AAH R P YTATTT ninim ymznim uinamea ulX b P AD R O V TSG CO TIU DEIEIEIS H A A A B timatinemoatineg lenaB D D D D acru T V V C V S M C n O oi )tn)tW921-2ta0- 5el ca n iBlydia yI2 diV:eflpdepi rgx ooloig olxoeb manifRa xetlutco artnororyeT E D M FeSA(UP(nrottA1 1 1 1 1 1 1 1 6951 67 42 2 8 2.09.47 0 3 12.6 1.310- 2 2.6 0 5 7 E 5.0 17.01 18.9 T E_ T _ E _ _ A __ T H P E_ M T _ R D _ M P U T O D E TT F _ _ M E_ _ _ _ _ _ D _ E _ _ TP _ PDIAME P C H D T D AT P _ A__ _ S _E HCE_ P EIR _ O H TS TTU L _ _ _ P AOA H E_ P O_ N _ YY _ T E C_ H_ L OTCI__PIB _ O L O OIHP HP P _PIE T E N H H H YE OOYYP W E_ L N H Y_ T H ESIH S S ON H H _ E B TT E E P H R N _ TH WWE O T_ YE L XE TCIYY TIOOIH H H E L P _ B YL E A_ _ L E OO _ T_ T_ T_ H P R _ P _ E X S TOB Y AH ONIE N C_ XX _ D D P T P AH YTR Y _ _ _ AY T _ OO L L L _ YYYL R TN AAWWH OL L L _L _L _L R L R AE E Y H L N R R R D HTHTH YAE OS P T TTW TN P OL _ _ E TYYYYYYOGP M P GAS U D YY L M_ N_ H Y_ _ _ _ TE TE TE TE TE TL L L _ _ L OO F H H E E E E YR R P H OOOO E CCCCCCH YYE E N P E E YL _ _ _ MM MH P H U U YTN N N N C E OOOO A A A A A AR E OR R LCIOOO II I IT L _ _ _ _ _ _ H HGM N N N N N N P P P T TIR W D D E O F O WW D D F G M M M M E H R T T T T T O W920-BIV:feRyenrottA1 74843 8.2 T E___ A H M O W T__ DIC A_ CIR UP _ _ _ PIE E _ GGATN N AAYD T T H YYE O HINYYY AATS _ H _ NIS S OXXXS OU U S GGOO4 HE TME E Y S L S O OOOR R ENIS S O YOR _ R R R P OOR P P N D L YXS S S O O_ S S S S H R E D D D _ R R _ _OIXOO O_ O_ _8 _ 7 O O O O TYYNIOTITIB RAIOB R 903 12 0 _ S _ _ _ E TT OS YYYS_ _ H B O 7 5 003975 O5982 66 MO _ R O H_ H_ H_I_ N_ N_ N N TD R R YT 1 491 03 _ 865 MOR TTTTTTE E AN AA 1 081 985 97 1 VE TO C CO 0050709012 49987 OOL YH H H H H H TU L _ _ R G 1 1 1 1 1 51 67 90 R HTIGIGIGIGIGIGEFL AE ETIV 1 1 1 2 WILIS S S S S S S S S S T B C D E E E E E E E F G M N N N A R R R R R R R R R R O)tW n 9 a 20- sdiBIcitx eoV:ifentnReyeGA(nrottA1 A / Ax Ecler:ao1- CcSBtnaS S S S O O O OS S S S S S S S S S Sdix O O O S S S o _ O O O O O O OSi6 _6 _ _ O_ _ _ _ S _ O_ _ _ _ _ OS Otn 41 4989 _ 6986 6 _ 5 65 7 3 O_ _ 7 3 641 4944 O41 01 5 8 4 _ 2 O1A1 3 4 3 4861 _ 3 45 3 92 97 1 _ 2 = 707 3 6647 5 602 003 02 81 83 3l2 02 97 6657 788457 880931 13 4991 91 4467 6 G 00061 GatS 2S 2S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8S V 1S 2S 2S 4S 9S V o R R R R R R R R R R R R R R R R A R R R R R A T 2t-5na2dielx b oitnO)taW n T A920- sa dBiIcitxV: eofenReoryeGP(nrottA7 3 6 3 6 3 6 3 6 311.0.60 0.00.12 y yayya ay yayaad / d / Ud / agd / yayad / d / gd / g r otcaerFn ocsoistacizitelanemro GtN ntand0aix 3 0dio / ol8 x rat1 o P o / lixTattnoAax U mUIUIm2etm m m m m rnaTt / ro Eelt :bam oi r=zi .Bot rlR 92 6 9 5 2 3 1 2 ot atcac mr tnaFadiF ocNa0 trt1 x n ointnn3exeQ o ortaoiPzita3ad- ezi r5 mE D Cmseaeemniix ot 2 elrenininiuinat yzm =lallatmr ao ocaelp pmamamanegnenmrb p peuco orP Fa u otititilenaeroru N o=no T S C V V V S M G C C Tt tNoniitana tndataacididiR ilx xo x xopio orito nordetlu OW P A P R M 920-4-BI52V2 elp:feelRb mya axenrT EottA5 27_ AP _ H C B _ P A H H H _PH OOIP P PS _IN _ E TN H H TYE H E E TTH H R TR __ NOIP HP H S E E E AB H STIOOION L H _ B E E P_ TH H E P YL _ A_ _ L E T _ M_ ATOOIH H P B E AH YTR OOY_ _ _ _ L RIH H DL PL TL _ R TN AAWWH O_ E E N O D P T L INZIN E P TWL A Z E P T L E L L L YYY A OS T T Y _ YYYH H H YP M N OL _ TTTN _ _ E TT E L _ _ H Y _ _ _ O E 1 AAH Y_ HTHTHTE E E YR R P H OOOC XT P D - G AOO V RTR P TA TSIU DEIEIEH IMIMIMIPIH U U YTN N N N E OOOO A A A A B B D D D D D D D D T L _ G C S H E O F O F G M M M M M N )tna dix )to O Wo9 nr2 a P0- ydi(BIgx y V:ofloeoig tolR rye enornrSA(U ottA1 1 1 1 1 1 1 1 1 342942 66964 0.3 4069. -5 E 65 9.61 92 70 2 607 46 3 2 60 5.00.50.1 29.9 61.2 67.1 T E_ T _ E _ T_ E E _ A _ _ N _ P _ _ H _ E CA E A N T _NIE N _ E _ E T _ S _ _NIY _ E NIE C A TTT_ H E S E E_ _ M TS Y_ C_ _ _ _ L E R Y E Y_ H T R C_ P P L AAT E_ H _ N E _ T _ P N L _ L O__ _ _ _ Y O _ YRP E ODH E GITYNINE XEIM P_ C A TE A _ TB _ OODN R S S RICIAD Y YY CYA C A R _ C C _ C T _ _ E UP _ H_ L L YYOTCEI_ L _PI_ _ OON P W T_ N H _ YE L Y_ H EIPXE T YYINNIS YYY XX S U U S S _4 H W TWE O TH R __ E XB YONIECIH XXLIS S O X OOOO R GGOO R E E _ _ P P S TOAH C_ D OO_ R OOR N D _ _ _ _ _ AY L L L L L R L R TNE _ YN _ OOY R E R R P P P L R R R H R Y D D D _ R R _ _OIYYYY OGAE P H L AU D D TYTNIYYYOTITIB_ R_ HAITTTTYTL L L M_ P_ GS L OYYE T OOS O H_ H_ H_SI_ N_ N_ N N TD E E E E E CCCCH YYE E O F H H M R E E AN C CN P E E YL _ _ _ _ MOR TTTTTT E TO A_ A_ A_ A_ A_ R E OR R L OOOO YH H H H H H V L GCIOLTIE TU A T TIR HGT T T T T T B C DIGEIGEIGEIGEIGE E EFL N N N N N E P H P R P H H R WWWWILIF G M O W920-BIV:feRyenrottA1 6.91 S _ LE _E NIS L L H_ TME E Y S YXNIS S S S S O O OS S S S S S S S S S S S S S O _ _ 8 _ _ 1 70 O_ O_ O_ O_ O_ O_ O_ OS S XO O O_ _ O O_ O S _ O_ O_ O O O OB R 903 2 3 7 S 5 866648 _ 6 S _ O_ _ B O 7 5 0095 O92 641 991 986 6 _ 5 6 R R Y 1 491 03 _ 865 7 3 4944 O41 01 T 1 081 985 97 1 1 643 4861 _ 3 45 3 AAO 05 7 91 499 3 46647 5 602 003 C C 00002 5 87 7 7 3 965 7 85 803 1 4 _E _ R G E V 1S 1 67 90002 7 67 847 891 3 9 TIS 1S 1S 1S 1S 1S 1S 1S 2S 2S 2S 2S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S N N N A R R R R R R R R R R R R R R R R R R R R R R R R O)tW9 n 20-BsaIVcidix:tfe eoR n itnyeenrGA(ottA1 / 2.5 4 21.54 0.41.00.00.1elpS o drc inaeleSxcodi ap m xF m4- m =zi5 Bo2t i r5o- n Bt rla5 tcaotmr2S S Sel aFcaoelO_ O S S _ O_ S O Obadinxad F Nba5 7 3 O S T oin ntT 598 4 _ _itxoin 602 9 _7 21 O_ 12 n o 929 84148637 36A ortaoizitaadr -5 zix o 2 181 G 00061 G =P=la ilS 8S V 1S 2S 2S 4S 9S Vlalmr aotocraelb R R A R R R R R AtoatT o omroP Fa = n T )tn5tT N -na t tN na toioittaaa 5 di2 dinaxdidina cixdiRlp xelo x o x xoio bitoitod tluOora n Tornor eW A P A P R M 92P0(-BsIVci:tfe eR nyeenrG ottAyyayay yayyaad / d / d / ad / yayada / d / d / U ggg UI I0mcd / d / g g g gm meypareh TA0e02 0lU D 0053.00 0005baT R 92 6 9 5 2 3 1 2 T P A C t R ne3 ED CeT seE E n _ M mn nmeaemi_ _ elre i iniuinagttyzmu E E pp pmamamanenecanu potititil naerrt eo 01crNINZIZ S C V V VeS M Gxeu C Q C1- G AA XT AD R R P O V TT G CO S H A A A l no)t)O aitntnW91-2 ita2ca d a06 -BI2 elelpneilyirgx ygdimnopitooloitolxoV:fbea ax plxutco arRenororyT E E M F SA(UP(enrottA1 1 1 1 1 1 1 302 7 7475 53 6 60-8.1 0 99 1 E 7.0.1.2.60 0 0 2.15.1 T T E_ E _ _ _ __ TP P E T T _ D D __ M E D TP D_ _ E T _ E _ _ E E __ D T P __ A T TE E E A _ H D THP _ P _ AS_ _ T S _ A E E H O P TS T L ATU _ _ _ _ L L AH F_ YY C_ C_ C_ _ E UP P _ O H TS HP AOH E_ P O H N _ YYTL E C_ H_ L L OTCI__PIB _ P AOOIHP HP P _PIE T E N H H H YE OOYYP W E_ L N H __ NEOIHP H H S S ON H H _ E B TT E E P H R N Y _ TH WWE O T_ E L AB H S PTIOOIH E L P _ B YL A_ _ L E T T TH R __ E X TOB Y _ L ATOOID HP H E T P AH YTR OOY_ __ __ __ P_ P S AYAH T ORID H H _ P TL L L L R TN AAP WWH OL L L L _L _L R L R AE N AP TL L L YYYYAE P OS T TTW OL _ _ E TYYYYYYOGL P M E L E_ YYYH H H N L M_ N_ H Y_ _ _ _ TE TE TE TE TE TL L E _ HP _ H H H TTTE H OOOO H YYE Y SITATTTE E E YR R P CCCCCCCN P E U DEIEIEIMIMIMH IPIH U U YTN N N N T L E OOOO A_ A_ A_ A_ A_ A_ R E OR D D D D D D D D E O F O H B B F G M M M M M N N N N N N E P H P R P T O W920-BIV:feRyenrottA1 72 6.0 T E___ A BP EE R H T__ DIC A_ CIO ZN _ G R YU R S D AAN_ L E B O _ U U GIOGGD E L H S B T_ OH U O_ 2 L TOP _ E _ GGATN N AAYD T T YE O Y_ ESIPE Y AAT H YH _ XE HINIYYS U S S _ H TME ONT I ECIYY XXHNLIS S S N O OXXX OOOO U R GGOO4 R R E E E YNIS S C_ D O _ OO N D YXS S S O O E _ Y _ OOY R R R E R R R P_ R R P_ P_ L XOO O O_ _ H L N R R HTYYNID D D OTITB ROIAIOB R _ _ 81 P_ GAU D D E TTS YYY L S OYY OOO H_ H_ H_SI I_ _ H D B OY 97 05 3020 _ N_ N_ N N T R R T 1 491 E YOL F_ H_ H_ M_ R R TTTTTTE E AN AAO 1 081 E R L OOOOMOYH H H H H H VE TOL C CR 00507090 GCIOLTIG G G G G GE T C D E E E E E E EFU _ _ G L AETI1 1 1 1 HIR WWWWR HI I I I I IL E V S S S S T T T T T T T BIF G M N N N A R R R R )tO nW0sa92di-cBiItxoVe:fen itenRyGA(enrottA1 C / CS O_ S S S S S S S S S S S S S S S O O O O O OS S S S 7 O O O O O O OS O S S 0 _ _ _ _ _ _ _ _ O_ _ _ _ _ O_ O O O OS 3 7 S 5 866648 _ 6986 S _ _ _ _ OS O 95 O92 641 991 4 6 _ 5 65 7 3 O_ _ 03 _ 865 7 3 944 O41 01 5 8 4 _ 2 O1 985 97 1 1 3 6446364487 65 16 _032 405033 9022 9871 18 _3 2 1 49987 7 7 3 965 7 85 803 1 49 3 2 5 67 90002 7 67 847 89 9 4467 6 1 1 1 1 1 2 2S 2S 2S 2S 3 1 3 91 1 G 00061 S S S S S S S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8S V 1S 2S 2S 4S 9S R R R R R R R R R R R R R R R R R R R R R R A R R R R R )OtnW920sa-cBidItixoVe:feneorRGPy(enrottAhcaorp patnereffidaegniecitelaag 5 1 75.89 n s Gn mrni2811 662 77 88 us1 1 87 gniroc ss noi&tgaln u itcslea t C 2elp maxE m m m m m : Bo1- t i r= Bot rzilaE 6n2a tcao:t aRmx2- Fca ro o 6 A D002 00053.eldinxadiFdn Nt e2elR 92 6 9 5 2 baoitxoinn R=bT n oaotaoitadrT ArlP zi aziix ott=lala=aoc3-ne3et lmoat roomra rP F6 2 mE D C snein nmnG T Vto o T NtN=n oioitelelri ib pep pui ag pmat mat mat nel naA2-na tnna tntaaca T u oi i iS Ce6di adailV V V S M 2elxdi ix xdiRxpib oito o no itxo otln O arordeu W T A P A P R M 920-BIV:feRyenrottAS 271.9.1.2 2 302 7 7475 53 6951 64704623_ 2 A E OTS P OH E P 0elAP _ H C B _ P AOOIHP HP P __PI00005baR __ NOIHP HP H S S ON H 3 1 2 T T E E E _ M A_ B H S ATOOITIOOIH E L B Y D H H P H 0 _ _ LIH H P T_ A 1 E E OR T ATDL PL TL L L L R L YYYYAE Q eNINZIN P Z E L E_ YYYH H H N P L M aetntmnecayiAAH Y_ H H H TTT E E E E _ YR z m XTD1- G R R P TATTT neucrP A O V TTS E EH H U G COIU DI IEIMIMIMIPIT S H A A A B B D D D D O errto D D D D E F xeu G C C )tO n)tn W94-62a ydia 20-BI2 elelp g olx y oigdioxoV m:fb a otea nloorRyTxrEeSA( rUP(enrottA1 1 1 1 1 1 1 1 2 08 - 2 9841 11 3662 E20.3 5 0030- 1 49012.0 E 8.82 61.7 98.09.00.1 12.7 T T E E _ _ _ _ _ _P B H T D E_ A HE _ N _ _ MP _ _ E _ H E ONITE E A M TT L _ E S A_ __ Y H E _ C_ TT A P _ H L H E L P A Y __ H MT L T _ U YH T_ E B X P E Y E _ _ TX H _ _ A L _ O YYP L R X TA XE H D OE Y R H MT _ H PHID O_ _ D T YXE L _ E TYR _ H _ T_ O_ A U L E 5 5 L X O _ _ _ E O _ L L A H H F N TL __ _ _ _ _ _ _ YY E C H L OCIO E TN H H H YE _ _ YY T _PIB _ W E L H E N H Y_ L TOP _ E _ G ESIPE YY P _ E B TT E E P H R OON P _ T E O T__ YE L XE TH CYYIHNINIS S XX L _ H WW _ E X E A_ _ L E T T TH R _ TOB Y H ONIE_ID XXL S O O_ OO YTR OOY_ O__ __ __ P_ P_ S A _ AYR TN C E _ OOYO R R Y _ R R R R E N AAWWH L L L L L L R L E N R H Y D D OS PL T_ T_ T E W TYYYYYYOGAP MH P L GAS U D D TY E TTNIS YY N O _ _ TTTTTTL L L _ _ OYY O H H _ H Y _ _ E E E E E L O F H H MOR O_ _ R P H OOOO E H YYE E YL _ _ _ _ R TT U YTN N N N CCCCCCCN P E E A A A A A E OR R LCIOOOOMO OL YH H OL E OOOO_ _ _ _ _ A_ R H HGN N N N N N P P P T TIR WWWWR HTIG GF G M M M M M E H R T T T T T T B C DIEIE O W920-BIV:feRyenrottA1 2 0- E 3 S O_E NIS O N A UGAN N AAYD T YTAATT H YY H E O_ XS OU U S S _ GGOO4 H TME E E E YNS S S O R R P OOR R P P N D D _ R R _ _ L YXIS S OS S XOS O O O_ O S S S S S S S _ _ S YOIO _ _ 81 70 O_ O_ O O O O O O O OTITIB R _ _ HAIOB B OR 97 05 30203 S _ _ _ _ _ _ O_ 975 O5982 666648 _ 6 HSIN N N TD Y 1 491 03 _ 865 47 13 991 4 _ _ _ _ N N R R T 1 081 985 97 1 1 3 6443 4 TTTTE E A AAO 05 7 91 49987 7 7 3 664 H H H H VE TO G T IGIGIGIE U L C_ C_ R G 01 01 01 01 21 51 61 71 91 02 02 02 2 9 2 7 6 2 65 3 73 LFIL AE ETIV S S S S S S S S S S S S S S S S E E E E E F G M N N N A R R R R R R R R R R R R R R R R )tO nW920sa-cBidixItVeoit:fenenR AyG(enrottA1 T / CtnneciteerGtneset oim = 2 Br= etoiot rlpnaBtcaotc S S S S S S O O O OS O O O O S Sm dinFaS S SaxaF odin n _9 _8 _6 S _ OS xi6 O_ _5 _6 _5 _ _ OS O Etx n ooitaoi9844 O41 01 5 78 34 O_ _2 O_:orta7 61 _ 3 45 3 92 97 1 _ 124-A P zizi7 58602 003 02 81 83 3 6 =l=lala83 45 S 47 8 S 480 S 493 S 41 1 499 4467 62S 7 3 91 1 G 00061 G S 7S 7S 8S 8S V 1S 2S 2S 4S 9S Velat loatmro omro R R R R R R R R R R A R R R R R AbaT T5tT NtN -6na tnt2dina adinaelxodix xdix ) Otbaito o no ito oW T Arn n P ArP 920sa-cBidiItxVeo:feneorRGPy(enrottA.2 sl13 1 5 4 1 0 40e22 95 9mit0.10.5 1c0.1ificepsarreottfcaaF &n h oictaaozrip lapamtrnoerM3 9 Ntefx 1.843 2 9 2 40& &92 1 747 1 06h g 34.3.57.9.7.cn fi aniadA4 a D04.1 5 5 2 94 607.6 1 366.7 2 45 3 1 9 1 82or tpse53 T 1zila aU m m m m m m mpR samrx2 reo oelhtNdtep m A20 0 000elnaRa=x D02 0053.005 p di rE R 92 6 9 5 2 3 1 2max o:5 x otoc -ra6 01 E PF 2etln3eQ:6- = n oib 6- eE D C seaeni6 oitt a6 m aacT2 neilelr ninmnem2pe ipui agtntcyzmuelXT Rilb p pmat mamanena eeartnecrbaP A xopia oititiltlT u S C V V Ve ro u T G C S M GxeC C d Oeu n W R M oi )t920-1B-I73tn elaca ydiV:2pdfeeRlb meilnipitrgx l ooloityea axfeutco arnenrT E D M F SAo(ttA_ _ R E_ H D TP _ _ _ S _ H ECI_ T_ _ AL XU N R U T_ P A E R _ E 5 5 E OAD _ S _ H OTP T L _ _ _ A F Y P T A E OETP H AS OAT E UP O _ L L H H L _ Y C H AP _ S P _ H A H O H H P _PIN _ T YY N H H TYEE _ _ C B_ N P H HOIPS P S _ E N H H E H _ E TT P H R OO TRE _ EOIPS P H OOIOE L P _ B E_ E_ _ TH WW E AB HTIH L A L E T T T _ OOIH H B Y E OO _ _ _ _ _ M_ _L ATIH H D P T P_ AH YTR Y T AWWH O_ _ _ E E N OR INZIN A D P TL L L Z E P T YYYL R E N A L L L OS P T TTW L E L L L _ YYYH H H YAP OL _ _ E TYTYTYT TTTN M N E L _ _ H Y_ _ _ _ OO E E E 1 AAH Y_ HTHTHTE E E H YR R P H OO N N N N CCC D - G R R P S TAE E E M M M PH U U YT E OOOO A A A OO V TTIU DI I I I I I ITOOL _ _ _ S H A A A B B D D D D D D D D E F F G M M M M M N N NO W9)t20- naBIy V:gdifxeoRlo oyeor rnrPoU (ttA1 1 1 1 1 1 442 9.066 - 565 9669 0 E7 49.12 26 0.63 0 1 99 5.2.61.6.T E___E A N__E NIETS Y TT C_ E E _ _ _ _ _ L _ _ Y P RP H T A T E A _ N N EL _ __ _ _ Y O E _ E O GINIM P ENIE A __ TS TB S RDI I_ _ Y CYA C A R Z _ _ _ OL TCIS E N N A_ _ C L EIAAL R OYY L _ C L _ _ T E UP N G R YU B R S O D_ AA OTCI_PE T OH U O_ 2 U U GNIS L _ O L GGD E AYD L H T YY _IB _ L TOP _ E _ GGAN N A YE N P W E_ L E O T YN H H _ _ E L Y_E H ESIPIENIYYYTS AATT H YH U S S _ H TM E XB YX T ONP R P _ S TOAHIECIYYHNIS XXX U S S O OGGOO4 E E E Y N C_ XXL _ D OOYOO_ OOO R R R R OOR R P N D YX _ _ _ AY L R T _ R E P_ R R P_ _ L XO L L R L E E YN R R R H R Y D D DOIOB YYYOGAP MH P L AU D D TYNE TIS YYYOTITIB_ R_ HAIB O TTTL L L _ _ GS L OOYY TO H H HSIN N F H O O_ _ _ _ _ _ N N TD N R R E E E CCCH YYE E H M R P E E YL _ _ _ _ MOR TTTTTTE E A E TOAA CN A_ A_ A_ R E OR R L GICIOOOOOL YH H H H H H V R HTIG GE TU L C C A_ _ T T T T T B C DIEIGEIGEIGEIGEIE EFL E E N N N E P H P R P H TH T TR WWWW LIF G M N NO W920-BIV:feRyenrottAS O_E NIS S S S S S O O O_ S S S S S S S S S S S S S S S S O O_ O_ _8 _1 70 O_ O_ O_ O S S _ O O O O O O O O O O O O R 903 2 3 7 S _ _ _ _ O_ _ _ _ S _ O_ _ _ Y 71 540095 O5982 666461 4989 _1 64998464 O64 _1 5061 55 T 1 09811 0938 _5 8967 51 71 33 6446364487 65 16 _032 45 3 9 O R 05 7 91 49987 7 7 3 965 7 003 0 G 01 01 01 01 21 5 S 1 6 S 1 7 S 1 9 S 1 0002 7 67 88457 880931 13 4991 TIV S S S S S 2S 2S 2S 2S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S N A R R R R R R R R R R R R R R R R R R R R R R R R RO W)t92 n0- aBI sdiV:cixfeteoiRyentennrGAo(ttA3 3.33 8 5 0 6 5 1 2 1.00.00.22: a 1- Cocern7S oadt rnot :a 2rerc iS xadica -7 hToim = Btoi r=ziorlanaBttcaotmrdinFcao xaF N otdiix n ointn S S n otaoiO S S _ OA orzitaadi ro 7 _ S OS O = 8 3 2 4 O_ _2 O_1lPa=lazilx a otca tl2 9a mromrrP F9 871 18 _3 23 oto T o N o=no 1 4467 6 8 G 00061tTt tNtoiitS V 1S 2S 2S 4S 9 G S V2-nan nan taacR A R R R R R A 7 2di adi aR il3elx b odiitx xdix xpi -7 o o oto ito odleu2O a n W T Arn Prelb9)tA P R M 20- n a TBI sa V:cidifxeteoRyeneornrGPo(ttAL T U F MxA D R=B C syyy yay y7 A A T taind / yaya agd / d / da / gd / d / aggcda / gd / 2R E_ H D_ A gelU _ PS _ H U mUIUIm m m m mbaT_ P T A E OE P T AP _ TS C B _ H AO R __ N P OIHP H A 0 TE E S P D0002 005 58.0 E 5 _ M A_ B H ATIOOIR 5 42 1 7 5 1 2 _E _E L H H N OR INATD P T L L L d ZIN Z E PL E YYY i _ c 0 AAH Y_ H H H T1- G R P TATTT ta1 X D RS Enecio 3 Q eeP AIEIEIG COO V TT S H A A AIU D B B D D D D mp elilD E C sneinimnmn ni) O p -ayhmmz iun minag mutn)ta nW p 9 upl ati ati eoati el nacr4-320- S A V V C Veu S M C 7da 2elygix ydiBIelpoloV:b ma oig t xo noloofrea xreART E S( rUP(yenrottA1 1 1 1 1 1 1 6951 6470462 2 2.972 1310- 0.3 1.6 0.5 7 E 5.0 17.0 18.9 T E_ T _ E _ _ A __ T H P E T _ M _ R D _ U MTP T O D E T _ _ M E F _ _ _ _ _ _ E _ D_ _ TP _ PDIAME P C H D T D P _ A_ A _ _ T E S _ OE HP ECI_ T R __ _ L E _ _ E OAD C C C ATU Z _ _ _ OL U H T AS AT E U O _ A _ L L H H F YY_ L _ L _ _ _ E N _ P E G R Y T OH B P H O H H _ P PIN _ T YY N TYE C H L E _ _ YYOTCEIL _PIB _ L TO OIP P _ E H H H S P S N H H E E TT P H R OON P W T_ YN H L Y_E H ESIH OOIOE L P __ B E_ E_ _ T E H WWE O_ _ E E XB YX T ONIECIYY TID H H H B YL E A P T P AH YTR OOL Y_ T_ T _ _ T _ _ H _ P R _ P _ _ S TOAH _ AY TN C_ XX _ D_ OO L L L _ TN AAWWH O L R E YN R R R YYYL R AE OS P T TTWL L L L L L R YYYYYYOGAE P MH L AU D D H H H Y TTTN PL M_ N OL _ _ E T _ H Y_ _ _ _ TTTTTTL L L _ P_ GS E E E E E E H YYE E L OOYY F H H E E E E YR R P H OOOO E E YL _ _ _ MM MH P H U U YTN N N N CCCCCCCN P A A A A A AR E OR R LCIOOO II I ID D D D T L E OOOO_ _ _ _ _ _ E O F O F G M M M M M N N N N N N E P H P R P H THGTITR TW TW TW T O W920-BIV:feRyenrottA1 74843.8.2 T E___ A H M O W T__ DIC A_ CI_ R S S U O O D _ _ AAL E S L L R _ 2 U U GNIO L Y GGD E L H AN N AAYD TS P _ PIE E _ GG NIYYYTS AATT S S H_ YY H E O_ HNIS XXX U U 4 H TME S L S S O O O _ OOOR GGOO R R E E E Y D YXNIS S S O YO H R R E R R R P OO P P N L XOS S O O O_ O_ _ S S S S 7 TYY D D D _ R R _ _OE TTNIYYYOTITIBIOS H H HSIN N _ R_ HAIOB O B OR _9 _083 12 0 O 3 _ O 7 S _ O 5 _ O 8 _6 N TD R R Y 7 5 0095 O92 6 MOR O_ _ _ _ _ _ N N T 11 409811 0938 _5 865 _ M R TTTTTTE E A E OAAO 05 7 91 49997817 O O OL YH H H H H H VTT U L C CR G 00002 5 67 90 RTIG G G G G GEFL A_E _ETIV 1 1 1 1 1 1 1 1 1 2 W H T BI I I I I ILIS S S S S S S S S S C D E E E E E E E F G M N N N A R R R R R R R R R R )tn O a W9s20-cidit x eoBIitV:nfeneARG(yenrottA1 A / A / tcle3arelCocS-7 B 2telnabadiT xo S S S S S S S S S SitS S S S S S n O O O O O O O O O S S _ _ _ _ O_ _ _ _ _ O O_ O_ O_ O_ OSA6648 _ 6986 S 6 _ 5 65 7 _3 OS O = 41 991 4944 O41 01 5 8 4 O_ _ _l71 33 6446364487 65 16 _032 405033 9022 9 2 O1 871 1 _ 2at7 7 3 965 7 85 803 1 499 4483 3 o 002 7 67 847 891 3 91 1 0067 6 T 2 2 2 2 3 3 3 44447S 7S 7S 8S 8 G 061 GtS S S S S S S S S S S S V 1S 2S 2S 4S 9S V5-nR R R R R R R R R R R R R R R R A R R R R R A 7a2dix )telb oitn a nO Wsa T A920-cidBItiexoV:n ofe rePRG (yenrottA111 5 1 52.1 7 1.55 1.80 0.02.0 .1erocssciteneGtnadi0 x 3 0 o / ol8 rat1 / Polatx T etornaTt / rs1yp= elocdinaotcela B p S xotdi axFpreh Cmax aoi r=zi5orla -t7ind / gd / d / d / gd / ggcd / gd / g2BtoU mUIUIm m m meltcna taFcamr2em lbadiF o NbaA 0 T 0 0 0 x n oointn T D R 05 0422 01 57 558.1 52 ortaoitaPzi=ladazi rix otc tci3ellatmr ao ora6-n7eoempD EmCmsenio omrP FN o=n2oelelilp-aniniytmmzniuminnag mu TtNib ha ane0a ecrnana toniattaaca pupldititio1tilenau i T S AcaV V C Q V S M C dididiRlx xo x xpio orito otlno deu OW P ArP R M 920-BI1-V 8:fe2R elyebnra ottT A_ AT AE E H D _ _ E H O R E D TP __ A_CI_ _ _ U _ H T_ P _ AS E H E _ T E 55 _ S _ H OTP T R L _ _ _ P T A E OE AP _ H TPS H S ATU P AO O _ L L H E P _ YY C B _ P AOOIHP HP P __PINE T E NE H H R _ NOH H S S N H H _ TT T _ EIP P HOO L P B E E E E _ M AB H S OOITIOIH H H E B YL _E A_ _ OO _E _ _ E L A RTIH H DL PL T P AH YTR L _ TN AWW N O INATD P T L R L L L YYYYAE A OS P L T_ T_ ZIN Z E PL E_ YYYH H H N PL M_ N O _ Y_ _ XT1AAH Y_ HTHTH TTTE H TE E E H YR R P H OO N P D - G R R P TA A O V TTIU DI I I I I IU YT N SEIE E M M M PH U L E OO G CO S H A A A B B D D D D D D D D T E O F O F G M M MO W n 92lo0- ait)tn)tIia nB 3tacV:elnfeilygdia x ydiep npi roolo gxRmyea optltoitolo onrx xucarenooAr rttE E M F S( UP(A1 1 1 1 1 1 366232 03 20- 4 094 34 1.1.0 E.9.7 26 0 12.6 75.0.T E___ B D A N__ T E E NIT_ E _ E _ _P TT_ S _ H E_ YE CA _ CA N _ _ P _ H _ N _ E E L _ Y_ M ENIT E _NITT T_ U B E S E E E _ TYTS Y_ C_ __ AXY_ _ L O _ P P R CL A TA __ P N E H D L O_ MTYYR _E _ H _ PHIH P YNE _ D TIEITL _ E XT AYR OO L XU ON R S SR C O_ P _ Y_ O O _ D YYA R Z _ OL TCIE N N AENIAA AE F A C C C A_ TU _ U R S S D AAL S L L H H _ YY_ _ _ E P N G R YB O _ U GNIOGG TL YE C H L L E _ _ YYOTCI__PIE B T_ OL H U O_ TOP _ E 2 U _ GGAN N AA H O W E L N H Y_ ESIPIE YYYTAATT P H R ON P T__ YE L E THN NIS S U U S S _ TH WWE O_ X XCIYYHIS XXXO OO L E_ T_ T_ T_ H P R P _ E B YONS TOAHIE XXL S OOOO GG C_ D O_ R OOR R Y _ _ _ _ _ AY TN _ _ OOYOR E R R R P P P H O _ TW L R E E YN R R R H R Y D D D _ R R _ _ L L L L L L R A H L D D TYNIOTE_ TYITIB R _ TYTYTYTYTYOGP TL L L M_ P_ GAS U L OYYE TT OS YYY H H HSIN N _ _ N OOE E E E E E H YYE E O YL F H H MOR O R _T_T_T_T_T_ N TE E N N CCCCCCCN P E E OO A_ A_ A_ A_ A_ A_ R E OR R L _ _ _ _ GCIOOOOMO OL YH H H H H H VET M M N N N N N N E P H P R P H TH TITR TW TW TW TWR HTIGT B C DIGEIGEIGEIGEIGEIE E L EFIFO W920-BIV:feRyenrottAOS S O L R _ Y D E L Y H YD L TS H_ YYE O_ 4 H H E E TME E Y N D YXNIS S S S S OS S S OIL S S S S S S S S S S S AXOS I OB O O R _ O O 9 _ _ O 08 _ _ S S 3 17 20 O 3 _ O S _ O_ O_ O_ O_ O_ O_ O O_ O_ O_ O_ O O S _ O_ H B O 7500975 5866648 _ 6986 6 _ 5 TD A R R Y 149 O92641991 4944 O410 N T OAAO 1008110938 _5896751713364463644876516 _0324050 T C C 57 91499877739657858031 U L _ _ R G 010101 012151617191020202227263 738344748494173 L AE ETIV S S S S S S S S S S S S S S S S S S S S S S 7S G M N N N A R R R R R R R R R R R R R R R R R R R R R R RO W9)t20- naBIVsdi:fxecitoReyen itennroAttG(A1 1 1 1 1 1 1 1 75 53 695 67 42 0.9.2.1 9.47 0 2.6 1.31 1 00 3 160 5 7 5.0 17.1 T E_ T _ E _ _ A __ T H TP E_ M E T _ R _ _ _ D _ MTP U E TT O E F TP D T_ _ M_ _ E _ _ _ _ _ E _ E _ D P _ _DI_ D_ T _ PP C P _ AME E E H D T D A _ _ _ D TP A_ __ AS _E H ECIR E H O P H TPS T ATU_ _ _ _ _ T AO E P _ YY E C H L OTCI_PO AS P OOH H _ P H P _PIN T E TN H H H YE _ _ YYW E L _IB _ N H _ L HIP S E E TT H R OON P _ Y YE H P H H S N H H _ B P T E O T_ E L X T S PTOOIOE L P _ E E _ H WW A_ _ L E T T TH R __ E XB YONIECIOOI IH H H P B YL E H H D P T H YTR OOY_ _ _ _ P P S TO AYAH N C__ D_ P L L L _ A R TN AAWWH O_L _L _L _L _L _L L R TE E YN R L TL YYYL YAE OS PL T TTW R YYYYYYOGAP MH P L GAS U YYH H H N P O _ _ E T H H TTT L M_ N_ H Y_ _ _ _ TE TTTTTL L L _ _ L OO F E E E E YR R P H OOOO E E E E E CCCC H YYE E P E E YL _ TT EE M M MH P H U U YTN N N N CCCN E O A A A A A AR E OR R LCIO II I I I IT L OOO_ _ _ _ _ _GD D D D D E O H H M M M M N N N N N N P P P T TIR W D F O F G M E H R T T T O W920-BIV:feRyenrottA1 1 482 03 40 2 0 4.8.099 T E___ A ME T E H _ _ _ _ _ DIBICH AO _ CIW T R _ U _ TPDIAC C A_ R ECIMR _ Y L T YU H BTOP _ _ _ _ GGAN N AAYD YT ESIPYYIE E HNINIS YYYT XXXS AATT U U S S H_ Y H H E O M_ E S S O OGGOO4 T E E E YNIS S S XXL OOYOO_ OOO R R R R OOR R P N D YXS S S O O O_ S S R R H R R E P P D D D _ R R _ _ D DOL XOO O O_ _ 7 O O TYYTNIOTITIB RIAIOB R _9 _083 12 03 _ S _ OS YYY H H H N N _ _ H B O 7 7 5 YYE TSID Y 5 0095 O9 H H O O_ _ _ _ _ _ N N TN R R T 1 491 03 _ 8 _ _ M_ R R TTTTTTE E A AAO 1005 87 1991 85 9 MO OL VE TO C C 0000 499 OOO YH H H H H H T L R 2 5 67 IG G G G G GE T F U _ _ G L AETI1 1 1 1 1 1 1 1 WWWR HI I I I I ILIE V S S S S S S S S T T T B C D E E E E E E E F G M N N N A R R R R R R R R )tnOsa cidixW92t0eo -n itnBI eV:GA(feRyenrottA1 1 T / G / C Agnitelp maS S S S S S S S S S S S S S S S x O O S S S S E _ _ O_ O_ O_ O_ O O O O O O O O O OS:82 66646 O_ _ _ _ S _ O_ _ _ _ _ OS O 1 498 _ 6986 6 _ 5 65 7 3 O_ _4- 65 7 91 4944 O41 01 5 8 4 _ 2 O1 8 7 1 1 33 6446364487 65 16 _032 405033 9022 9871 18 _3 2328970707032 97 6657 788457 880931 13 4991 91 40467 6el1S 2S 2S 2S 2S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8 G 0061 GbS V 1S 2S 2S 4S 9S VaT R R R R R R R R R R R R R R R R R R A R R R R R A 5-8 )t2nealbOscdiaWitx T920eo -n oBe rIV:GP(feRyenrottA111 5 1 2.1 51.8pseay mrayd ya aydayaya itre / ottfgd / / U gd / gd / ygad / cd / gcifierocSerso cictse snecitGetnneaG dts ixnn oaodi0 ititn x 3 o / l08 alat1 / uA orolactlxe PTto arCo xcernT Soarcdtine xa auctid / d / d / d / dkSr reodiiktxlgd / d / ggc / isn oFn1ac n U mUIUIg g g m m m m mutoiot rsoaR 3R 5 4 2 1 7 51 2tnaB dtca tinaFcamrx o oedl3e pelxdF n Nmdip oiitx n oointRat xcaoina= r Eta01mcai3 Q x Aor=lP zitadziix ot:5-6-n8eopD EeCesenE i:=lalao oca82melil- ninim ynim uinam6- at lmor rF 2 elpammzg u 8 atomrP elha an manec 2Tto o n b p T N N=oi baa upltiti eotilena ruelnta tna toitta T T S A V V C V S M CbaT dinana a cixlodidiitx x o odiRitx xpio otlnornordeu OW A P A P R M 920-1-BI9 V2:feelRbyaenrT ottAnircnits_ _ _ U _ HP _ AS _E H E _ E T_ P _ T S _ H OTP T R L _ OE P H S ATU O _ AA E P _ H T C B _ P AS P A OOH O H H E P P _PIN _ TN R _ NOH HIPS P S _ E N H H E_ E T _ EIP P H E E AB STOOIO L H E P B L _ A __ M_ _ H ATE E LIOOI ID HP H B Y E T P AH YTR N OR D H H P TL L L _ L R T INIE N AA S P N AP T E L L L YYY H H H YAP O M N OL Z Z E L _ YYY N L _ Y AAH Y_ H H H TTTE _ H TTTE E E YR R P H XT1- G R R P TA H YT P AD O V TTSIU DEIEIEIMIMIMIPIH U U T L E G CO S H A A A B B D D D D D D D D E O F O F G M n O o)tW)t9itn 20-4 aca n d aBIelV pdeily:pfi rgiydoxo gixemRanif tlotlcoitnolo ooryxeueareAnrE D M F S( rUP(ottA1 1592 9.0 E P E E L P L E 5__ L L A F C C U _ U R D AA YYH H _ YY_ _ _ _ E N TL E C_ H L L OTCI_ P E G R YB S _PIU B T_ OH OP O O _ _ _ 2 U U GNI_ GGAN H H TTH YE _ OOYYW E_ L N H Y_ L TESIPIE E YYYTA E P H TR N P E T_ YE L XE TH YYHN_ E_ _L E H WW O_ E XB YONIECIXXLINIS XXXS U S S OOOOOG OOY_ T W O_ T _ _ T _ _ H _ P R _ P _ _ S TOAH _ AYR TN C_ D OO_ R R R R O E _ YN _ OOY R R R R E P D D D _ R TWH _ T _ _ T L L L L L L R L AE H L R H D D TYYNIYYYOT_ E W _ TYYYYYYOGP M P _ TTTTTTL L L _ _ GA L S U TIYYE T S H HSOO O HIN F H H O O_ _ _ _ _ OOOOE E E E E E H YYE E M R E E YL _ _ _ _ M R TTTTT N N N N CCCCCCCN P R R LCIOOOO O OL YH H H H H OOOO A_ A_ A_ A_ A_ A_ R E OGIR HTIGIGIG G GM M N N N N N N E H H R WWWW M M P H P R P T T T T T T T T B C D E EIEIEIE O W920-BIV:feRyenrottA1 05 9.7 E I S_ OGGD E L L H N AAYD TS ATTS H YE O _ YH _ U S GOO4 HE TME E Y S OR R E R P_ P N D _OIL YXNIS S S S OS S S S S S S S S S S XOS O O_ O S S O_ O_ _8 _1 70 O_ O_ O_ O_ O_ O_ O_ O_ O O_ O O O TIB RAIOB R 903 2 3 7 S 5 866648 _ _ _ _ _ H B O 7 5 0095 O92 641 99 _1 64986 N N TD Y 1 491 03 _ 865 7 3 643 498464 _ N N R R T 1 081 985 97 1 1 3 46647 5 1 TE E A AAO 05 7 91 49987 7 7 3 965 7 86 H VE TO TU L C_ C_ R G 01 01 01 01 21 51 61 71 91 02 02 02 22 72 63 73 83 45 47 GIEFL AE ETIV S S S S S S S S S S S S S 4 L S S S S S S E EIF G M N N N A R R R R R R R R R R R R R R R R R R R O)tW9 n 2 a0-BsIVcidix:tfe eoR n itnyeenrGA(ottA2 / oFgcSern nisooiBtoiot rlaoan Bctmrdt ainaFcaF o xdin N o xointS S S S S SitOS O O O O O oo naS _ S S S norta iztadi ro O6 O 4 _ _ 1 5 _ 06 _ _ _ OS OA1 55 78 34 O_ _2 O_1 =Pilazilxotc_03 45 3 92 97 1 _ 2l82003 01 3 02 81 83 3a= tlmoat r aora omrP F891 3 4991 91 4040607661 o o n 4S 4S 7S 7S 7S 8S 8 G S V 1S 2S 2S 4S 9 G T S V2tT N 9nt tN=ointoittR R R R R R R A R R R R R A- an2 di a anaacddi aR ilelxix xdix xpib o aito o norito otlnOordeuW)tT A P A P R M92 n0- saBIcidiVtfe ex:oR nyeorenrGP(ottA5.1 yyayaad d / / d / / U U gI I00 L Tm000 1 00U 1 1 1 02 41 5 1 8 05 33 0055.5 005 g F 31 931 284.5 5 7 3 4 1 3 y ninroitaluclacerocselp ax E:2-92 R 9 2 695 2 3 1 2 elba0 Tt1 3-ne3 ED CeQ seT 9 m meaemniE 2nininin t_ elelrpeui agntcyzmu _ b p ppmamamanene anecrE a T u otititilS C V V Ve aerrto uNS M GxeC CIZ XT1- G A R P AD OO V T G C S H A A )tO W4-4na 9 9 2elydiy0-2p gBIelmolxo g oitolV:bfea axrnorR TEeSA( UyenrottA1 1 1 1 1 1 1 2 03 - 02 7 7475 53 E 6001 -8E.710.00.19.0 2.6 12.15.1 T E___ T P E T _ D __ T E E TP T _ D E E _ __ _ E E __ D_ T P _ T T A E E R E A U _ H D T T_ P _ A S _ H_ _ _ P _ T A E OE P H T AS AT E UP O _ L L H H YY L _ _ C H L _ _ _ E_ AP _ H T AS P H O H H _PIN _ YY TN TYE L OTCE _ _ YY EIL _ C B _ _ N P H O HOIP P _ E H H H S P S H E E TT P H R OON P W_ YN ROIP H N H _ B E E _ T E O T_ E E _ E P M AB H STOOIO H E L PL _ H WW A_ _ L E T T TH R __ E XB _ _ OOI IH H B Y E _ _ _ _ P P S TOA L ATIH H D P T P_ AH YTR OOY T AW H O_ _ _ _ _ _ AYR E OR L L L R N A W L L L L L L R L A D P TYYYL AE OS P T TTW GA NIN P T Z E L E L L L _ YYYH H H Y N P OL _ _ E TYYYYYYO P L M_ N_ Y_ _ _ _ TTTTTTL L L AH Y_ H H H TTT E E E E H YR R P H OOOOE E E E E E CCC H YYP R P TATTT H YTN N N N CCCCN TSIU DEIEIEIMIMIMIPIH U U T L E OOOO A_ A A A A AR E O D D D D D E O F O _ _ _ _ _ A B B D D D F G M M M M M N N N N N N E P H P R P )tO n W a 92d0i- xBIo V:ofrePR(yenrottA1 4700.2 7.1 T E___ A H M EE R H T__ DI IC A_ CI IR U N_ G R Y SN_ P PIE B O _ U U GIOGGD E L H S B T_ OH U O_ 2 L TOP _ E _ GGAN N AAYD YT O H Y_ E H ESIPIENIYYYTS AATT S S H_ YH E M_ L X T YYNS XX U U 4 H T E YONIECIXXH LIS S O X OOOOGGOOE E E YNIS H _ D O_ R OOR R N D YX S S TN C_ _ OOYOR E R R R P_ R R P_ P S _ L XO O O O O_ E E Y L N R R R H R YNID D D OT TB ROIAIOB R _ _ 8 MH _ P AU D D TY _ G E TTS YYY L S OYY OO H_ H_ H_SI I I_ _ H D B O 97 05 30 _ N_ N N N T R R YT 1 49 E E YOL F_ H_ H MOR _ R TTTTTTE E AN AAO 1 08 E E _ _ R R L OOO MOYH H H H H H VE TOL C CR 005070 GCIOOLTIG G G G G GE T B C D E E E E E E EFU _ _ G L AETI1 1 1 H HIR WWWWR HI I I I I IL E V S S S T T T T T T T TIF G M N N N A R R R )tnO W9sa di20-citxoBI eV:n itfeneARG (yenrottA1 C / C / S S O OS S S S S S S S S S S S S S S S S S _ _7 O O O O O O O OS O O O S S 1 0 _ _ _ _ _ _ _ _ O_ _ _ O O O O O O OS 2 3 7 S 5 866648 _ _ S _ O_ _ _ _ _ OS 095 O92 641 6986 6 _ 5 65 7 3 O_ 1 03 _ 8 991 4944 O41 01 5 8 4 _ 2 O 1 985 967 51 71 33 6446364487 65 16 _032 405033 9022 987 1 _ 91 49987 7 7 3 965 7 85 803 1 83 02 5 67 90002 7 67 84 1 499 4467 1 1 1 1 1 1S 2S 2S 2S 2 7 891 3 91 1 G 0006 S S S S S S 2S 3S 3S 3S 4S 4S 4S 4S 7S 7S 7S 8S 8S V 1S 2S 2S 4S R R R R R R R R R R R R R R R R R R R R R R R A R R R R )tO nW9sa20-cidBItiexoV:n ofe rePRG (yenrottA3 6 G / G e mitcificepsaretfneci atfU 1 1 1 2 4 atg Genn mra02 005 it eo n rnaG o 0 2 09 5 t NtitF 9 6 ocs&gnitset4elp max E:4-9 Bor -2t iorlaU mI Im m n Btcot9 m2el a t acbadinxaFa rdiF oelA n NtbaD0 0 R02 005 T oixoin T 9 2 69 5 StO n otaointa r_A orzi adzix o 12 =P la il3l6a= tlmr aotocratn 3 1a9 G otT o omrN oP F 6=n - o 9emE D Cm S VtTtN R A5-9na tna toiitt2 elrenininiuiaa elp pmamamn2 dinaxdidina cixdiRlba p potiti ati elT ueelx x xpiS C V V V S b oito oito otla norn O T Aordeu W P A P R M 920-BIV:feRyenrottA1 2 0- E0 8.9 T E__ L N EH E_E TT P H TR N _ _ E O T_YE L XE T YYHNINISXXXS P _B E E _ HWW _E XB YONIECIXX SS O O L E A__L E_ T T THR_TO H _ D L O_OOOR YTROOY ___ P P S A NC__OOYORE RRR P NAAWWHO_L _L _L _L _L _AY L RL RTE YNRRRHR DDD_ OSP T TTWYYYYYYOGAE P NOL __ E T MH P L DDTYYNIYY O GAU E TTS YS_HY____TE TE TE TE TE TL L L __L S OOYY O H H HIF H H MORO____ RP HOOOO E HYYE E E YL ____M RTTTT UYTNNNNCCCCCCCNP E LCOOOO OYHHHH OL E OOOO A_ A_ A_ A_ A_ A_RE ORR F G M M M M M N N N N N NE P H HHGP R P T TI IOL RWWWWRHTIGT T T T T T B C DIGEIGEIGEIE O W920-BIV:feRyenrottA1 8738 7.21 S _ E NIN A_ UUSS_HT E GGOO4E E E OONSSS RR DYSIS OS SSSS RR P_ P N _OIL X OS _O O O SSS SSSS S _ _ O 8 __ 170 O S _ O_ O O O O O O O O O O O TITIB RAIO0 R 9 S ______ O____S_ __H B 5 7 3020397 5866648 _6986 6 N N NTD 4Y 1 91 5 O926419914944 O4 __N NR0 T 1 8 03 _865736434861 _3 TTE E A A HH 5 O 198597113466475602 VE TO C GIGIE TUL 0 R 0 7914998777396578580 LFIL A_ E 1STIG0 V1 0 S 10 S12 S15 S16 S17 S19 S10 S20 S20 S22 S27 S26 S37 S38 S34 S47 S48 S49 S4S E E E F G M N R N A R R R R R R R R R R R R R R R R R R R R )tna dixo Oitn W92A0(-BsIVci:tfe eR nyeenrG ottA1 T / Chchc4S oelrc aeSxodicap kreitxF 4n1 elp mraak x mrn o aA oroi+ ma=P taoitx E:oim Bor=zilaE:SSSSS O O O O S S S1- t i0naBtot rcaot aRcamrxo2-0 O__ 15 _6_5 _ OS 7 _ O OnF o 3 O_S_3 d 3e40ldixadiF n Nt eel051 3035 398 02 4 _ 2 9721 O_12 81833baoitxoinR b113499191 440607661 T n o ortaoinzita= adi r ao T 7S7S7S8S8 G0 GASV12249 SSSSSV =P=lazilxotcR R R R R A R R R R R Alat lmaora oat romrP FT )t to T N o t N=n o oitn2- a 0na tnda t it adinadina a cili3xdixdiRxpixelo o baitxo o xo otlno itno deuOorT Ar rW P A P R M 92P0(-BsIVci:tfe eR nyeenrG ottAyyayaad / d / yayd / ad / y yad / U ggadd / g U LI I000mc / 0mg g mm0m0cTm0000m0 00aU01 11 01 02 0411 05 21 08orgt3T __ E 3-elE E _ M AB n 3e0eE D C seae_ A mniba_E _E L R 3 mr nininimna ettym T OAT elelpepuign czuNININ E P E b pmamamane e ane0crZ Z L _ a ptititil naerrt1 AAH Y_ T u o S C V V VeS M Gxeo u C Q C XT P D1- G R R P TA AOOV TTSIU D G C S H A A A B B D )tna)tdina xodiitxoO nW Aor9 P24-0- 04el(y(g yBI3p gV:efloleb ma oolRa xr orTeyeE S UnrottA1 1 1 1 1 1 1 1 1 1 747 . 553695164704622 100.19.02.09.7 310- 312.6 01.57 E 5.0 17.0 18.9 T E_ T _ E _ T _ A E _ _ _ T H _ P E_ M _ T P E T _ R T _ _ U _ D P D _ MT E TP D E TT O E F _ _ M_ _ D E T E _ __ D _ _ __ __ D ETP _ _ _ PDIE _ _ P C TP _ AME D A AE E H D T T _ _ _ E H D TP _ A_ P _ AS E H ECI_ R _ S _ H OTPS T L OETP H A AT E U O P AS O P H P H OOH H P __PINE OIHP HIP P S P H S S OOION H HE L P __ B E_ E_ _ T L E H TW TW O H R _ _ _ E XB YONIECH TIOOITI IH H B YL E A _ T TO D HP T P AH YTR OOY AH _ D O__ __ __ P_ P_ S_ AYR TN C_ _ D H H P TL L L _L R TN AAP WWHTWL L L L L L R L AE E Y H L N AR L L L YYYYAE OS T T YYYH H H N P OL _ _ E TY H L M_ N_ TYTYYYYOG L P M P GS U O H Y_ _ _ _ TTTTL L _ _ E E E E E E Y E E L O F THTH TTTE TE E E YR R P H OOOOCCCCCCH Y CN P E E YL _ E H IE E M M M PH U U YTN N N N E OOOO A A A A A AR E OR R LCIO II I I I ID D D D D D D T L _ _ _ _ _ _ E O F O F G M M M M M N N N N N N E P H P R P H THGTITR TW T O W920-BIV:feRyenrottA1 48042 4.0 T E___ A M E H__ DIC A_ CIR U TP A C RE M_L Y HT E Y_ S O OO E S XXL S O O_ OOOR GGR R E E Y D YXNIS S O OOYOR E R R R P OO P P N L X S S S O O_ S S S R R H R D D Y D D D _ R R _ _OTIOO O O_ _ 7 O O O TYNIO S YYYTITIB_ R_ HAIOB B OR _9 _ 810 _ S _ _ 7 0530203975 O58 YYE TO H H HSIN N N TD R R Y 1 49103 92 H H MOR O_ _ _ _ _ _ N N T 1 08198 _586 _ _ _ R TTTTTTE E AOAAO 057914997 OOOMO OL YH H H H H H VE T C CR 00002569789 TIGE TU L A_ _TG 1 11111111 WWWR HIGEIGEIGEIGEIGEIE EFIL E EIV S S S S S S S S S T T T B C D L F G M N N N A R R R R R R R R R )tna dixoitO n W9A2(0- sBIciV:tefenReyeGnrottA1 G / Agnircla ocC sseS S S S S S S S S S S StO O O S S S S S S S4_ _ _ O_ O_ O O O O O O O O O O OSel66648 _ _ _ _ _ S _ O_ _ _ _ _ OS O p 64199164986 6 _ 5657 3 O_ _ 51713364434984641 O_ 431405135982 49 _721 O_ 12max 7077 6647560200302 81833 E 20203 229 276 265 377 388 345 47 8 480 493 411 734 799 719 81 44676 8 G 0 S 10 S 20 S 2 61 G:S S S S S S S S S S S S S S S S V S 4S 9S V4- R R R R R R R R R R R R R R R R R A R R R R R A0 3el)tban T a5-0 dix3oelOob r aW9P2(T0- sBIciV:tefenReyeGnrottA5 2.1 160 0 0 1cepsareerocSerso cictse snecitGetnneaG di txnoaitdi0 n x 3 o / lAo atxrP o eroxT cetrnaSo dinaotalarB Cdrcexd cauc eakSrareoiiktxFn o1 lah T gn mr on roi+ c yay yaisoaiAm =P tazoiertoc stid / yayda ay / d / d / d / ayday / day / da / d / uy Btoi r=iorla aRsngcggcg g g g U mU pnaBt IUIm m m m m madtcaotmrx4 roel eh inaFcaF odep A0 0 0txodiin NtmaD02005 t x nRR 9 2 6 9 53.0042030152eln ooitaoina=x r E p Aorzitadlzix o:5tcma=Pa=la ilaotc -0at lmro r01 x E mra F3t t3 x Q:oatorPT nel6-ne etos ee6- T N o ntN=oitba0E D Cat3mneininimn aetmni0 3dinana toxdiniataaRcT ilelelrb pepummmi agn yzmuela p poati ati atinel na eernecrbaodidiueo u itx x o oix xpio otlT S C V V V S M G C C T nor tno deu O A PrW A P R M 920-BIV:feRyenrottA

Claims

Attorney Ref: VIB-029WO CLAIMS 1. A method for determining a personalized antioxidant supplement blend for an individual, the method comprising: (a) obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for the individual; (b) determining an antioxidant score from the antioxidant biomarker values and a first set of genetic information; (c) determining a prooxidant score from the prooxidant biomarker values and a second set of genetic information; (d) determining a personalized factor for the individual using the antioxidant score and the prooxidant score; and (e) identifying the personalized antioxidant supplement blend comprising dosages of one or more nutrients that are determined using the personalized factor.

2. The method of claim 1, further comprising repeating steps (a)-(e) every three or four months.

3. The method of claims 1 or 2, wherein an antioxidant biomarker value comprises a quantitative measurement of an enzyme, a small molecule, a non-enzymatic protein or combinations thereof from a sample obtained from the individual.

4. The method of claim 3, wherein the sample comprises one or more of serum, plasma, erythrocytes, white blood cells, whole blood, tissues, or urine.

5. The method of claim 4, wherein the enzyme is selected from the group consisting of Superoxide dismutase, Catalase, Glutathione peroxidase and Glutathione reductase or combinations thereof.

6. The method of any one of claims 3 - 5, wherein the small molecule is selected from the group consisting of Glutathione, Glutathione disulfide, Glutathione:Glutathione disulfide, Uric acid, Coenzyme Q10, Vitamin A, Vitamin C, Vitamin E and Selenium or combinations thereof.

7. The method of any one of claims 3 - 6, wherein the non-enzymatic protein is Oxidized albumin or Ceruloplasmin or a combination thereof.Attorney Ref: VIB-029WO 8. The method of any one of claims 1- 7, wherein the antioxidant biomarker value is obtained using mass spectroscopy.

9. The method of any one of claims 1 - 8, wherein a prooxidative marker value comprises a quantitative measurement of a lipid peroxidation marker, a nucleic acid damage marker, or a protein damage marker or combinations thereof from a sample obtained from the individual.

10. The method of claim 9, wherein the sample comprises one or more of serum, plasma, erythrocytes, saliva, Peripheral lymphocyte, cerebrospinal fluid (CSF), whole blood, tissue, or urine.

11. The method of claims 9 or 10, wherein the lipid peroxidation markers are selected from the group consisting of Malondialdehyde, 4-Hydroxynonenal, 8- Isoprostaglandin F-2α, 11β- Prostaglandin F-2α, 15(R)- Prostaglandin F-2α and 8-Iso-15(R)- Prostaglandin F-2α or combinations thereof.

12. The method of claim 9 - 11, wherein the nucleic acid damage marker is a DNA damage marker, an RNA damage marker or combinations thereof.

13. The method of claim 12, wherein the DNA damage marker is selected from the group consisting of 8-Hydroxy-2' -deoxyguanosine, 8-Hydroxyguanine and 8- Nitroguanine or combinations thereof.

14. The method of claim 12 or 13, wherein the RNA damage marker is selected from the group consisting of 8-Hydroxyguanosine and 8-Nitroguanosine or combinations thereof.

15. The method of any one of claims 9 - 14, wherein the protein damage marker is selected from the group consisting of Allantoin, o, o'-Dityrosine, Nitrotyrosine, Bromotyrosine, Chlorotyrosine and N-(1-Carboxymethyl)-L-lysine or combinations thereof.

16. The method of any one of claims 9 - 15, wherein the prooxidative biomarker value is obtained using mass spectrometry.Attorney Ref: VIB-029WO 17. The method of any one of claims 1 - 16, wherein the genetic information is determined based on a presence or absence of a polymorphism in an antioxidant gene or in a prooxidant gene from a sample obtained from the individual.

18. The method of claim 17, wherein an antioxidant gene polymorphism is selected from the group consisting of SOD1 (rs2234694), SOD2 (rs4880), SOD3 (rs1799895, rs8192287), GSTM1 (rs366631), GSTM5 (rs3754446), CAT (rs7943316, rs4756146, rs1001179), GPX1 (rs1050450, rs1987628), GPX2 (rs4902346, rs2071566), GPX4 (rs713041), GSR (rs8190955), GSS (rs121909307), GLUL (rs10911021), GSTP1 (rs1695), SELENOP (rs3877899), TXNRD1 (rs7310505), TXNRD2 (rs1548357), TrxR2 (rs4485648), HMOX1 (rs2071746) and PRKAA2 (rs2796498, rs10789038) or combinations thereof.

19. The method of claim 17 or 18, wherein a prooxidant gene polymorphism is selected from the group consisting of XDH (−337GA), CYB5R3 (rs916321), CYP1A1 (rs1048943), CYBA (rs4673, A-930G) and COX-2 (rs20417) or combinations thereof.

20. The method of any one of claims 1 - 19, wherein the genetic information is obtained from a polymerase chain reaction (PCR) analysis.

21. The method of claim 20, wherein the PCR analysis is a reverse transcription (RT) PCR analysis.

22. The method of any one of claims 1 - 21, further comprising: determining a plurality of individual antioxidant biomarker scores based on the antioxidant biomarker values; and calculating an antioxidant biomarker score by combining the plurality of individual antioxidant biomarker scores.

23. The method of claim 22, wherein determining the plurality of individual antioxidant biomarker scores comprises: for each of one or more of the antioxidant biomarkers, assigning an individual antioxidant biomarker score for the antioxidant biomarker based on whether the measurement value of the antioxidant biomarker falls below a lower limit (LL), between the LL and an upper limit (UL), or above the UL of a range defined for the antioxidant biomarker.Attorney Ref: VIB-029WO 24. The method of any one of claims 1 - 21, further comprising: determining a plurality of individual antioxidant single nucleotide polymorphisms (SNP) scores based on the first subset of genetic information; and calculating an antioxidant genetic score by combining the plurality of individual antioxidant SNP scores.

25. The method of claim 24, wherein determining the plurality of individual antioxidant SNP scores comprises: categorizing each individual antioxidant SNP into a group based on the obtained genetic information; and assigning a value as an individual antioxidant SNP score based on the group.

26. The method of claims 24 or 25, wherein the group includes a poor function group, a moderately affected group, and an optimal function group.

27. The method of claims 22 - 26, further comprising determining an antioxidant score by combining the antioxidant biomarker score and the antioxidant genetic score.

28. The method of any one of claims 1 - 26, further comprising: determining a plurality of individual prooxidant biomarker scores based on the prooxidant biomarker values; and calculating a prooxidant biomarker score by combining the plurality of prooxidant biomarker scores.

29. The method of 28, wherein determining the plurality of individual prooxidant biomarker scores comprises: for each of one or more of the prooxidant biomarkers, assigning an individual value as an individual prooxidant biomarker score for the prooxidant biomarker based on whether the measurement value of the prooxidant biomarker falls below a upper limit (UL), above the UL and within a pre-defined range, or above the UL and beyond the pre-defined range.

30. The method of any one of claims 1 - 29, further comprising: determining a plurality of individual prooxidant SNP scores based on the second subset of genetic information; andAttorney Ref: VIB-029WO calculating a prooxidant genetic score by combining the plurality of prooxidant antioxidant SNP scores.

31. The method of claim 30, wherein determining the plurality of individual prooxidant SNP scores comprises: categorizing each individual prooxidant SNP into a group based on the obtained genetic information; and assigning a value as an individual prooxidant SNP score based on the group.

32. The method of claims 30 or 31, wherein the group includes an optimal function group, a moderately affected group, and an altered function group.

33. The method of claims 28 - 32, further comprising determining a prooxidant score by combining the prooxidant biomarker score and the prooxidant genetic score.

34. The method of any of claims 1 - 33, further comprising determining a redox ratio representing a measure of prooxidant to antioxidant activity in the individual.

35. The method of claim 34, wherein the redox ratio is a ratio of the prooxidant score and the antioxidant score.

36. The method of claims 34 or 35, wherein prior to determining the redox ratio, the prooxidant score and the antioxidant score are normalized.

37. The method of any one of claims 1 - 33, further comprising: determining an antioxidant biomarker score based on values of antioxidant biomarkers; determining an antioxidant genetic score based on the first set of genetic information; and calculating an antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

38. The method of claim 37, further comprising: determining a lipid peroxidation biomarker score based on values of lipid peroxidation biomarkers;Attorney Ref: VIB-029WO determining a lipid peroxidation genetic score based on lipid peroxidation genetic information included in the second set of genetic information; and calculating an individual lipid peroxidation score based on the lipid peroxidation biomarker score and the lipid peroxidation genetic score.

39. The method of claims 37 or 38, further comprising: determining a nucleic acid biomarker score based on values of nucleic acid biomarkers; determining a nucleic acid genetic score based on nucleic acid genetic information included in the second set of genetic information; and calculating an individual nucleic acid score based on the nucleic acid biomarker score and the nucleic acid genetic score.

40. The method of any one of claims 37 - 39, further comprising: determining a protein damage biomarker score based on values of protein damage biomarkers; determining a protein damage genetic score based on protein damage genetic information included in the second set of genetic information; and calculating an individual protein damage score based on the protein damage biomarker score and the protein damage genetic score.

41. The method of any one of claims 37 – 40, further comprising: identifying a reference range for each of the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score; and determining an actual marker zone (AMZ) based on the respective individual score and respective reference range.

42. The method of any one of claims 37 – 41, further comprising: identifying a target marker zone (TMZ) for each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score; and determining the personalized factor respectively for each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score,Attorney Ref: VIB-029WO individual nucleic acid score, and individual protein damage score, based on a number of zone transitions from the AMZ to TMZ.

43. The method of any one of claims 37 – 42, further comprising identifying the dosages of one or more nutrients on each category of biomarkers associated with the individual antioxidant score, individual lipid peroxidation score, individual nucleic acid score, and individual protein damage score using the respective personalized factor.

44. The method of any one of claims 1 - 43, further comprising: obtaining or having obtained antioxidant biomarker values, prooxidant biomarker values, and genetic information for a population including the individual; determining a reference antioxidant score from the antioxidant biomarker values and a third set of genetic information for the population including the individual; and determining a reference prooxidant score from the prooxidant biomarker values and a fourth set of genetic information.

45. The method of claim 44, further comprising: determining an antioxidant biomarker score based on the values of antioxidant biomarkers associated with the population; determining an antioxidant genetic score based on the third set of genetic information associated with the population; and calculating the reference antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

46. The method of claims 44 or 45, further comprising: determining a prooxidant biomarker score based on the values of prooxidant biomarkers associated with the population; determining a prooxidant genetic score based on the fourth set of genetic information associated with the population; and calculating the reference prooxidant score based on the prooxidant biomarker score and the prooxidant genetic score.

47. The method of claims 44 – 46, further comprising:Attorney Ref: VIB-029WO determining an antioxidant biomarker score based on values of antioxidant biomarkers for the individual; determining an antioxidant genetic score based on the first set of genetic information for the individual; and calculating an antioxidant score based on the antioxidant biomarker score and the antioxidant genetic score.

48. The method of any of claims 44 – 47, further comprising: determining a prooxidant biomarker score based on values of prooxidant biomarkers for the individual; determining a prooxidant genetic score based on the first set of genetic information for the individual; and calculating a prooxidant score based on the prooxidant biomarker score and the prooxidant genetic score.

49. The method of any of claims 44 – 48, further comprising: identifying a first percentile ranking of the individual antioxidant score relative to the reference antioxidant score; identifying a second percentile ranking of the individual prooxidant score relative to the reference prooxidant score; and determining the personalized factor based on one or more of the first and second percentile rankings.

50. The method of any of claims 1 – 49, wherein identifying the personalized antioxidant supplement blend comprises determining a personalized intervention.

51. The method of claim 50, wherein the personalized intervention comprises recommendations selected from the group consisting of diet, supplements, physical exercise and lifestyle changes and combinations thereof.

52. The method of any of claims 1 – 51, wherein the supplements for improving a level of Prooxidant enzyme SNPs comprises one or more of Quercetin, Aqueous extract of Carica papaya mature leaves, Alpha lipoic acid, Dealcoholized red wine, red grape juice,Attorney Ref: VIB-029WO Catechins, Myricetin, Epicatechin, Indole-3-carbinol, Soybean, Green tea, Curcumin, Garlic, Fish oil, Rosemary Astaxanthin, Vitamin D, Pycnogenol, and β-carotene.

53. The method of any of claims 1 – 52, wherein the supplements for improving a level of SOD comprises one or more of Copper, Manganese, Vitamin E, Vitamin D3, Vitamin C, Selenium, Green tea extract, Curcumin, Coenzyme Q10, and N-Acetyl Cysteine.

54. The method of any of claims 1 – 53, wherein the supplements for improving a level of CAT comprises one or more of Alpha-lipoic acid, Vitamin D3, Vitamin E, Coenzyme Q10, Vitamin C, Vitamin A, Selenium, and Manganese.

55. The method of any of claims 1 – 54, wherein the supplements for improving a level of GPX comprises one or more of Selenium, Vitamin C, Vitamin D, Lutein, Selenium, and Glutathione.

56. The method of any of claims 1 – 55, wherein the supplements for improving a level of GSTM comprises one or more of broccoli, S-Adenosyl methionine, pomegranate- Black carrot juice, and grape pomace extract.

57. The method of any of claims 1 – 56, wherein the supplements for improving a level of GLUL comprises aged garlic extract.

58. The method of any of claims 1 – 57, wherein the supplements for improving a level of HMOX1 comprises one or more of aged garlic extract and resveratrol extra virgin olive oil.

59. The method of any of claims 1 – 58, wherein the supplements for improving a level of SELENOP comprises Selenium.

60. The method of any of claims 1 – 59, wherein the supplements for improving a level of CYB5R3 comprises one or more of Vitamin C and Glutathione.

61. The method of any of claims 1 – 60, wherein the supplements for improving a level of PRKAA2 comprises one or more of folic acid, Alpha lipoic acid, Magnesium, and Vitamin C.Attorney Ref: VIB-029WO 62. The method of any of claims 1 – 61, wherein the supplements for improving a level of TXNRD1 comprises one or more of Quercetin, Seleno, and methionine.

63. The method of any of claims 1 – 62, wherein the supplements for reducing a level of Malondialdehyde (MDA) in improving lipid peroxidation effect comprises one or more of Magnesium, Vitamin E, Olive oil, Melatonin, Vitamin C, Beta-carotene, grape seeds, green tea extract, Neem, Curcumin, Holy basil, Ashwagandha, Selenium, and Glutathione.

64. The method of any of claims 1 – 63, wherein the supplements for reducing a level of 4-hydroxynonenal (4-HNE) in improving lipid peroxidation effect comprises one or more of Vitamin C, Anthocyanins, Vitamin E, Beta-carotene, Lutein, grape seed. Scutellaria baicalensis, Korean red ginseng, Ashwagandha, Carnosine, Quercetin, Epigallocatechin gallate, Selenium, Manganese, Green tea extract, Curcumin, and Glutathione.

65. The method of any of claims 1 – 64, wherein the supplements for reducing a level of 4-Hydroxynonenalmercapturic acid (4-HNE-MA) in improving lipid peroxidation effect comprises Vitamin C.

66. The method of any of claims 1 – 65, wherein the supplements for reducing a level of Lipid Hydroperoxides (LOOH) in improving lipid peroxidation effect comprises one or more of Aged garlic supplement, Tea polyphenols, Vitamin E, and Coenzyme Q10.

67. The method of any of claims 1 – 66, wherein the supplements for reducing a level of Oxidised LDL (oxLDL) in improving lipid peroxidation effect comprises one or more of L-carnitine, Vitamin E, Beta-carotene, Hydroxytyrosol, Vitamin C, 1,27-dihydroxy vitamin D3 and omega-3 fatty acids, Hazelnut, and green tea.

68. The method of any of claims 1 – 67, wherein the supplements for reducing a level of 8-iso-prostaglandin F2α (8-iso-PGF2α) in improving lipid peroxidation effect comprises one or more of Vitamin C, Vitamin E, Omega-3 fatty acid, Lycopene, Beta- carotene, and Selenium.Attorney Ref: VIB-029WO 69. The method of any of claims 1 – 68, wherein the supplements for reducing a level of 11-β-prostaglandin F2α (11-PGF2α) in improving lipid peroxidation effect comprises Omega-3 fatty acid.

70. The method of any of claims 1 – 69, wherein the supplements for reducing a level of 8-Hydroxy-2’-deoxyguanosine (8-OHdG) in improving DNA damage comprises one or more of Alpha-tocopherol, Garlic extract, Coenzyme Q10, Curcumin, Red yeast rice-olive extract, Creatine, Resveratrol, and Vitamin C.

71. The method of any of claims 1 – 70, wherein the supplements for reducing a level of 8-Hydroxyguanine (8-OHG) in improving DNA damage comprises Selenium.

72. The method of any of claims 1 – 71, wherein the supplements for reducing a level of 8-Nitroguanine (8-NO2-G) in improving DNA damage comprises one or more of Curcumin, Dihydrolipoic acid, N-acetyl-L-cysteine, and folic acid.

73. The method of any of claims 1 – 72, wherein the supplements for reducing a level of 8-hydroxyguanosine (8-oxoG) in improving DNA damage comprises Tart cherry juice.

74. The method of any of claims 1 – 73, wherein the supplements for reducing a level of Dityrosine in improving protein damage comprises one or more of Nitisinone and N- acetyl cysteine (NAC).

75. The method of any of claims 1 – 74, wherein the supplements for reducing a level of Nitrotyrosine in improving protein damage comprises one or more of Resveratrol, Vitamin C, Vitamin E, Tetrahydropterin, L-Arginine, and Glycoxidation.

76. The method of any of claims 1 – 75, wherein the supplements for reducing a level of Carboxymethyl lysine (CML) in improving protein damage comprises one or more of Epigallocatechin gallate, Quercetin, Alpha lipoic acid, and Vitamin D.

77. The method of any of claims 1 – 76, wherein the supplements for improving small enzymes of antioxidant markers comprises one or more of Vitamin C, Vitamin E, Calcium ascorbate, Apple polyphenols, Curcumin, Selenium, N-acetylcysteine (NAC), Astaxanthin, Glutathione, Glycine, Lutein, and Beta carotene.Attorney Ref: VIB-029WO 78. The method of any of claims 1 – 77, wherein the supplements for improving proteins of antioxidant markers comprises one or more of Chitosan, N-acetylcysteine (NAC), Zinc, Copper, and Vitamin C.

79. The method of any one of claims 1 – 78, further comprising administering or having administered the personalized antioxidant supplement blend to the individual.

Images