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Nature Wisdom Science™ Synthetic vs. Natural Vitamin Forms INTRODUCTION Our Commitment to Excellence Pharmanex has always maintained a single goal when developing new products and improving existing products: to provide the highest quality products that are proven by science to be safe and effective. Pharmanex has always used a pharmaceutical approach to research and development activities. All of Pharmanex’s products are supported by credible, scientific research and, when necessary, are re-substantiated through in-house trials and clinical studies. These criteria, which form the foundation of our 6S process, are what guide our decisions as to which raw materials and ingredients to use, as well as what products to research and develop. We have employed these same criteria when determining which sources of vitamins and minerals provide the best benefits and highest quality to customers. Whenever scientific findings show that one vitamin form is preferable over another, we will always formulate our products to conform to those findings in order to provide the highest quality and most effective products possible. When formulating LifePak, Pharmanex reviewed the available literature and research regarding vitamin, forms, bioavailability, and efficacy. The remainder of this document provides a summary of those findings along with the corresponding references. Use of Multi-vitamin and Mineral Supplements Large nutrition surveys consistently show that inadequate intakes of essential vitamins and minerals are common in the U.S. and other industrialized countries (Benton et al 1997, Block et al 1993, Pennington et al 1982, Pennington et al 1996). The Continuing Survey of Food Intakes by Individuals (CSFII), conducted in 1994-96 by the US Department of Agriculture (USDA), showed that most people do not meet the Recommended Dietary Allowances (RDAs) for essential vitamins and minerals (USDA 1996). It is a well-established fact that multi-vitamin and mineral supplements (MVMS) are beneficial in those suffering from nutrient deficiencies. A recent study in healthy adults, however, showed that use of MVMSs is safe and beneficial to healthy individuals as well (Kiely et al 2001). A recent article published in the Journal of American Medical Association (JAMA) states that healthy individuals can derive benefit from regular use of multi-vitamin and mineral supplements and even encourages everyone to use some sort of MVMS daily (Fletcher and Fairfield 2002). Yet another study concluded that, Nature Wisdom Science™ “Supplementation with a multivitamin supplement can improve micronutrient status in healthy, older Americans to levels above those obtained with a fortified diet” (McKay et al 2000, italics added). Natural, Synthetic, and Nature-identical “Natural” has come to be associated with substances in their native, unaltered state derived directly from a wide variety of plants, animals, or other organisms. “Synthetic” substances are produced from basic chemical building blocks by means of chemical synthesis processes. “Nature-identical” refers to synthetic substances that have the same chemical structure as its natural counterpart. There is a proliferating belief that natural substances are inherently superior in function, efficacy, and safety to synthetic substances. Except for certain specific instances, however, this belief is not substantiated by scientific research. In addition to the exorbitant costs associated with natural substances, they are typically less stable and less conducive to a single-dosage delivery form. Vitamins with the same structure are recognized and utilized in the same way by the human body, regardless of their origin. This was reiterated in a recent study performed by the International Union of Pure and Applied Chemistry (IUPAC). The study states that the actions of individual substances are determined by their individual chemical structures and dose, not whether they are of natural or synthetic origin (Topliss et al 2002). Supplement Bioavailability A common concern with MVMS use is bioavailability of vitamins and minerals in supplement form compared to those from foods. A study performed on healthy individuals showed that increases in serum nutrient levels after taking a supplement are higher than after eating a comparable meal (Navarro 2003). This indicates that the bioavailability of nutrients in supplement form is at least equal to, and may even be greater than, that of nutrients in actual foods. It is also important to point out that the forms of vitamins and minerals used by the food industry to enrich and fortify foods in the United States are the same synthetic forms used in many dietary supplements. WATER-SOLUBLE VITAMINS Vitamin C: Studies have shown that there is no difference in bioavailability between synthetic and natural forms of L-ascorbic acid, or vitamin C (Gregory 1993, Chalmers 1993). Studies have shown that vitamin C from supplement forms are more readily absorbed and Nature Wisdom Science™ produce a greater increase in serum ascorbate levels than that from a variety of fruits and vegetables (Gregory 1993, Mangels et al 1993). Available literature provides no evidence that one form of vitamin C is better than another. It has been shown, however, that certain vitamin C forms which are less acidic help alleviate gastrointestinal distress that may arise from supplementation. Mineral salts of ascorbic acid are buffered and therefore less acidic than ascorbic acid. Consequently, some people find them less irritating to the gastrointestinal tract than ascorbic acid. Sodium and calcium ascorbates are the most common forms. Both are readily absorbed and bioavailable to the body. Bioflavonoids are a class of water-soluble plant pigments that are often found in vitamin C-rich fruits and vegetables, especially citrus fruits. Despite overwhelming evidence of the antioxidant functions and properties of bioflavonoids, there is little evidence that the bioflavonoids in most commercial preparations of vitamin C increase the bioavailability or efficacy of vitamin C (Johnston and Luo 1994). Ester-C®, a common vitamin C supplement, contains mainly calcium ascorbate. It also contains small amounts of the vitamin C metabolites dehydroascorbate and calcium threonate, as well as trace levels of xylonate and lyxonate. Despite the belief that these metabolites supposedly increase the bioavailability of vitamin C, the only published study in humans found no difference between Ester-C® and commercially available ascorbic acid tablets with respect to the absorption and urinary excretion of vitamin C (Johnston and Luo 1994). Ascorbyl palmitate, a fat-soluble esterified form of ascorbate, is sold and labelled as a “vitamin C ester”, but has not been shown to have any increase in bioavailability. It is most likely hydrolyzed to ascorbic acid and palmitic acid in the GI tract prior to absorption (Austria et al 1997, DeRitter 1951). LifePak utilizes calcium ascorbate as it is as bioavailable and efficient as other forms of vitamin C. Additionally, since it is a buffered form, the reduced acidity allows individuals to ingest it without gastrointestinal irritation that is occasionally experienced. Vitamin B6: Natural vitamin B6 in many plant foods is in the form of pyridoxine glucoside. The bioavailability of pyridoxine glucoside is only about half that of other forms of vitamin B6. Vitamin B6 in supplements is in the form of pyridoxine hydrochloride (Hendler and Rorvik 2001). Studies have shown that there is no difference in bioavailability of synthetic and natural vitamin B6 (Nelson et al 1976, Institute of Medicine 1998). LifePak uses a nature-identical pyridoxine hydrochloride as its B6 source. Vitamin B12: In 1988 the Food and Nutrition Board (FNB) of the Institute of Medicine revised the Recommended Daily Allowance (RDA) for vitamin B12. Because of the increased risk of Nature Wisdom Science™ food-bound vitamin B12 malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B12-containing supplements (Institute of Medicine 1998) Methylcobalamin and 5-deoxyadenosyl cobalamin are the forms of vitamin B12 used in the human body. The form of cobalamin used in most supplements, cyanocobalamin, is readily converted to 5-deoxyadenosyl and methylcobalamin (Brody 1999). Because the chemical structure of B12 is so complex, chemically synthesizing it is not feasible. As such, a bacterial fermentation process has been found to be efficient in producing bioavailable and safe B12 in large enough quantities to meet world demand. Studies revealed that bacterially fermented vitamin B12 supplements are just as bioavailable as both naturally sourced B12 supplements, as well as B12 ingested from a typical mixed diet (Navarro 2003, Institute of Medicine 1998). LifePak uses a natural B12 (cyanocobalamin) which is derived through this bacterial fermentation process. Additionally, we use a unique, stabilized form that provides even greater bioavailability. Folate: Efforts to ensure optimal folate intake are a relatively recent development. In 1992 the US Public Health Service (PHS) first recommended that pregnant women increase folate intake by 400 mcg. In 1996, in accordance with the PHS and FDA Food Advisory Committee’s suggestions, the FDA required that specific flours, breads, and other grains be fortified with folic acid (Suitor et al 2000, Insitute of Medicine 1998). This was due, in part, to the discovery that folate from foods is significantly less bioavailable than that in supplement form. It is a well-established fact that the bioavailability of folate in a typical mixed diet is incomplete. A long-term controlled study in humans showed that bioavailability of folate in a typical mixed diet is no more than 50% of that in a formula diet (Sauberlich et al 1987). Another study in free-living subjects confirmed these results. It found that folic acid from supplements or folate-fortified foods was significantly more bioavailable than that in a diet of high-folate foods (Cuskelly et al 1996). The role of folic acid supplementation in preventing neural-tube defects is well established. Recently, however, it was shown that folate from food sources readily absorbed by younger individuals is not absorbed by the elderly. It has been found that supplementation with folic acid is important in preventing deficiencies in elderly individuals (Baker et al 1978). Additionally, it was found in another study that synthetic and natural forms of folic acid have the same bioavailability and are absorbed equally well by healthy individuals (Nelson et al 1975). Pharmanex uses synthetic folic acid derived from amino acid building blocks. This form of folic acid is stable, bioavailable, and chemically identical to natural folic acid. Nature Wisdom Science™ Thiamin (B1): Thiamin mononitrate is the form used by the food industry to enrich and fortify foods. Human supplementation studies have used thiamin mononitrate as a thiamin source and have found it to be readily absorbed and utilized by the human body (Levy et al 1994, van der Beek et al 1994, Moss et al 1994, Baker et al 1975, Suzuki and Itokawa 1996). In one animal study, thiamin mononitrate was found to have the same bioavailability as other water-soluble forms of thiamin (Geyer et al 2000). In Mexico, a government study to determine the best vitamin forms for fortifying grains based on bioavailability, stability, and cost showed that thiamin mononitrate was preferable over other vitamin B1 forms (Rosado et al 1999). Another study showed that the relative biological values of thiamin in white and whole wheat breads compared to thiamin mononitrate in supplement form were 88% and 91% respectively. This indicates superior bioavailability of thiamin mononitrate in supplement form compared to that in foods (Ranhotra et al 1985). LifePak uses thiamin mononitrate which is synthetically produced from the natural thiothiamine. Riboflavin (B2): Only two forms of riboflavin are commonly used in dietary supplements, riboflavin and riboflavin 5’-monophosphate, riboflavin being the most common form (Hendler et al 2001, Institute of Medicine 1998). This is the form found in LifePak. There have been no studies to suggest that riboflavin 5’-monophosphate is more bioavailable or preferable over riboflavin, which has substantial evidence validating its easy absorption by humans. Niacin (B3): Though niacin is common in many foods, that found in plants, especially mature cereal grains like corn and wheat, may be bound to sugar molecules in the form of glycosides, which significantly decrease niacin bioavailability (Gregory 1998). Despite its relative abundance in different foods, average niacin intake by both men and women in the United States was found to be significantly lower than the RDA (15% and 25% respectively) (Institute of Medicine 1998). Niacin supplements are available as niacinamide or nicotinic acid. Niacinamide is the form of niacin typically used in nutritional supplements and in food fortification. Nicotinic acid is available over the counter and with a prescription as a cholesterollowering agent (Hendler and Rorvik 2001, Knopp 2000). Niacinamide has been shown to be more easily tolerated as a supplement and is utilized as well as any other form of niacin. Synthetic niacinamide and nicotinic acid have been shown to have no difference in bioavailability in low doses (20-40 mg). However, high doses of nicotinic acid (2002000 mg), used primarily by doctors to treat high-cholesterol, may produce serious side effects and, as such, is available by prescription only (Institute of Medicine 1998, Knopp Nature Wisdom Science™ 2000, Schuna 1997, Sikand et al 1998). In order to mimic niacin content of a normal diet, Pharmanex uses a blend of nicotinic acid and niacinamide in doses found to be safe and effective. Pantothenic Acid: Many foods contain pantothenic acid. Refining of grains and the freezing and processing of various food sources, however, can reduce pantothenic acid content by as much as 3575% (Institute of Medicine 1998). Few studies have been devoted to the research of pantothenic acid and its various forms. Supplements commonly contain either pantothenol or calcium or sodium D-pantothenate. Pantothenol, an alcohol derivative, is converted by the human body to pantothenic acid. Calcium and sodium D-pantothenate, the calcium and sodium salts of pantothenic acid, are available as supplements and are readily bioavailable to and utilized by the body (Plesofsky 1999). A recent study showed that pantothenic acid supplementation in the form of D-calcium pantothenate was readily absorbed and effective preventing nutrient deficiencies in children (Rivera et al 2001). LifePak provides pantothenic acid in the form of D-calcium pantothenate. FAT-SOLUBLE VITAMINS Vitamin A: The principal forms of preformed vitamin A (retinol) in supplements are retinyl palmitate and retinyl acetate. Beta-carotene is one of the most common sources of vitamin A in supplements, and many supplements provide a combination of retinol and beta-carotene (Hendler and Rorvik 2001). Beta-carotene is one of the few vitamin forms that have significant research indicating a preference of natural over synthetic. Studies have shown that a natural beta-carotene mix was significantly more bioavailable than the synthetic all-trans form (Ben-Amotz and Levy 1996). Later studies supported these findings and also revealed higher anti-oxidant activity in natural beta-carotene versus synthetic forms (Ben-Amotz and Fishler 1998, Levin and Mokady 1994). Vitamin A palmitate (retinyl palmitate) has been shown to be beneficial in those who cannot convert beta-carotene, a vitamin A precursor, to vitamin A. Retinyl palmitate is the preformed vitamin A that is found commonly in foods. In accordance with these findings, LifePak provides a blend of all-natural beta-carotene and vitamin A palmitate to provide individuals with safe, bioavailable vitamin A source. Vitamin E: Vitamin E is another of the few vitamins with substantial research verifying that the natural form is preferable to the synthetic form. LifePak provides vitamin E derived entirely from natural soy. The bioavailability of the natural d--tocopheryl acetate and d-tocopherol used in LifePak is approximately twice that of synthetic dl--tocopherol Nature Wisdom Science™ used in other leading brand multivitamins (Hendler and Rorvik 2001, Acuff et al 1994, Burton et al 1998, Ferslew et al 1993, Horwitt et al 1984, Kiyose et al 1997). In addition to d--tocopherol, LifePak also provides mixed natural tocopherols and tocotrienols. The level of 300 IU of vitamin E in LifePak is supported by numerous human studies that show significant health benefits at daily vitamin E intakes between 100 and 400 IU (Acuff et al 1994, Spencer et al 1999, Stampfer and Rimm 1995, Stephens et al 1996). Vitamin D: Ultraviolet radiation from the sun is our main source of vitamin D. Ultraviolet B radiation at 290-320 nm hits our skin and converts 7-dehydrocholesterol into precholecalciferol. Precholecalciferol is converted to cholecalciferol via thermal isomerization. However, many groups are at risk for vitamin D deficiency due to restricted sun exposure. The US Bureau of the Census estimated 5% of individuals in the US over the age of 65 (approximately 1 million people) and more than 20% of those over the age of 85 are in retirement homes with little exposure to the sun. One study at a Boston hospital showed that 57% of patients admitted for a variety of reasons were deficient in vitamin D (Thomas 1998). Additionally, restriction of sun exposure stemming from studies correlating ultraviolet radiation with several skin and cancer conditions has made vitamin D status in healthy humans more of a concern (Neale et al 2003, Veierod et al 2003, Livingston et al 2003). Currently, ergocalciferol (D2), a form of vitamin D that is can be either naturally derived or synthesized, and cholecalciferol (D3) are used in supplements. The body uses and metabolizes ergocalciferol, which is derived from the plant ester ergosterol, similar to the natural cholecalciferol (Specker 1994). However, ergocalciferol has been shown to be less active than cholecalciferol, and it has been shown to lead to severe toxicity problems when taken in large doses (Takahashi 1993, Albert et al 1988). For these reasons, Pharmanex uses a nature-identical form of cholecalciferol, the natural form of vitamin D in our bodies, which has the exact same chemical structure as cholecalciferol derived from natural sources. Vitamin K: The natural form of vitamin K found in nature is phylloqiuinone (K1), or phytonadione. A synthetic phytonadione is the form used in most dietary supplements and MVMS’s (Hendler and Rorvik 2001, Institute of Medicine 1998). This form has been shown to be safe and is even used in infant injections to prevent deficiencies and subsequent bloodclotting abnormalities (Institute of Medicine 1998). Menaquinone (vitamin K2), an active form of vitamin K, is synthesized by bacteria that normally colonize the large intestine. Until recently it was thought that up to 50% of the human vitamin K requirement might be met by bacterial synthesis. Based on recent research, the contribution of bacterial Nature Wisdom Science™ synthesis is much lower than previously thought, although the exact contribution has not been quantified (Suttie 1995). In some studies, it was shown that the bioavailability and absorption of synthetic vitamin K in supplement form was superior to that of vitamin K in a variety of foods and green vegetables (Booth et al 1998, 1999). LifePak uses the nature-identical vitamin K1 (phytonadione). CONCLUSION Pharmanex has always placed emphasis on science as the foundation and guideline for everything that we do. Pharmanex makes every effort to keep consumers informed concerning the science and research that forms the foundation of Pharmanex’s products through, among others, our web site, product support teams, and printed materials. This compilation of studies and references is by no means comprehensive. We encourage all consumers to be proactive and seek credible sources of information through free, publicaccess resources, focusing on those that cite and make reference to credible scientific studies. Nature Wisdom Science™ References 1. Acuff, R. V., Thedford, S. S., Hidiroglou, N. N., Papas, A. M., and Odom Jr, T. A. Relative bioavailability of RRR- and all-rac-a-tocopheryl acetate in humans: studies using deuterated compounds. Am.J.Clin.Nutr. 60, 397-402. 1994. 2. Albert DM, Saulenas AM, Cohen SM. Verhoeff's query: is vitamin D effective against retinoblastoma? Arch Ophthalmol. 1988 Apr;106(4):536-40. 3. Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal. 1997;15(6):795-801. 4. Baker H, Frank O, Zetterman RK, Rajan KS, ten Hove W, Leevy CM. Inability of chronic alcoholics with liver disease to use food as a source of folates, thiamin and vitamin B6.Am J Clin Nutr. 1975 Dec;28(12):1377-80. 5. Baker H, Jaslow SP, Frank O. Severe impairment of dietary folate utilization in the elderly. J Am Geriatr Soc. 1978 May;26(5):218-21. 6. Bendich A, Langseth L. The health effects of vitamin C supplementation: A review. J.Am.Coll.Nutr. 1995;14:124-36. 7. Ben-Amotz A, Fishler R. Analysis of carotenoids with emphasis on 9-cis b-carotene in vegetables and fruits commonly consumed in Israel. Food Chem. 1998;62:515-20. 8. Ben-Amotz A, Levy Y. Bioavailability of a natural isomer mixture compared with synthetic all- trans beta-carotene in human serum. Am J Clin Nutr 1996;63:729-34. 9. Benton D, Haller J, Fordy J. The vitamin status of young British adults. Int J Vitam.Nutr Res 1997;67:34-40. 10. Block G, Abrams B. Vitamin and mineral status of women of childbearing potential. Ann.N.Y.Acad.Sci. 1993;678:244-54. 11. Booth, Sarah L; Maueen E O’Brien-Morse; Gerard E Dallal; Kenneth W Davidson; and Caren M Gundberg. Response of vitamin K to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults. Am J Nutr 1999;70:368-77 12. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998;128(5):785-788. 13. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999. 14. Burton, G. W., Traber, M. G., Acuff, R. V., Walters, D. N., Kayden, H., Hughes, L., and Ingold, K. U. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 67(4), 669-684. 1998. 15. Chalmers AH. Ascorbic acid bioavailability in foods and supplements (Nutr Rev 1993;51:301-3) Nutr Rev. 1994 Mar;52(3):110-1. 16. Cuskelly G. J., McNulty H., Scott J. M. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. Lancet 1996;347:657-659 Nature Wisdom Science™ 17. Dawson EB, Evans DR, Conway ME, and McGanity WJ. Vitamin B12 and folate bioavailability from two prenatal multivitamin/multimineral supplements. Am J Perinatol. 2000; 17(4):193-9 18. DeRitter E. Physiologic availability of dehydro-L-ascorbic acid and palmitoyl-L-ascorbic acid. Science. 1951;113:628-631. 19. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology 1992;3:194-202. 20. Ferslew KE, Acuff RV, Daigneault EA, Woolley TW, Stanton PEJ. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol. 1993;33:84-8. 21. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002 Jun 19;287(23):3127-9. 22. Food and Nutrition Board, Institute of Medicine. Biotin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:374-389. 23. Food and Nutrition Board, Institute of Medicine. Folic Acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:193-305. 24. Food and Nutrition Board, Institute of Medicine, National Research Council. Dietary reference intakes: folate, other B-vitamins and choline. Washington D.C.: National Academy Press, 1998. 25. Food and Nutrition Board, Institute of Medicine. Niacin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:123-149. 26. Food and Nutrition Board, Institute of Medicine. Pantothenic acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:357-373. 27. Food and Nutrition Board, Institute of Medicine. Riboflavin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:87-122. 28. Food and Nutrition Board, Institute of Medicine. Thiamin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:58-86. 29. Food and Nutrition Board, Institute of Medicine. Vitamin B 6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:150-195. 30. Food and Nutrition Board, Institute of Medicine. Vitamin B 12. 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Montvale: Medical Economics Company, Inc; 2001. 36. Horwitt, M. K., Elliott, W. H., Kanjananggulpan, P., and Fitch, C. D. Serum concentrations of alphatocopherol after ingestion of various vitamin E preparations. Am J Clin Nutr 40(2), 240-245. 1984. 37. Hunt C, Chakravorty NK, Annan G, Habibzadeh N, Schorah CJ. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Int J Vitam.Nutr Res 1994;64:212-9. 38. Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc. 1994;94(7):779-781. 39. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001 40. Kiely M, Flynn A, Harrington KE, Robson PJ, O'Connor N, Hannon EM, O'Brien MM, Bell S, Strain JJ. The efficacy and safety of nutritional supplement use in a representative sample of adults in the North/South Ireland Food Consumption Survey. 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