Cosmeceuticals vitamins

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Clinics in Dermatology (2009) 27, 469–474

Cosmeceuticals vitamins Mônica Manela-Azulay, MD, PhD a,⁎, Ediléia Bagatin, MD, PhD b a

Department of Medical Clinics (Dermatology), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil


Abstract The term cosmeceutical was created over 25 years ago to define products with active substances that cannot be considered cosmetics or drugs. Cosmeceuticals are increasingly popular, with sales representing one of the largest growing segments of the skin care market. These products are found in many forms, including vitamins, peptides, growth factors, and botanical extracts. Cosmeceuticals that contain topically applied vitamins have an increasing role in skin care. © 2009 Elsevier Inc. All rights reserved.

Introduction The term cosmeceutical was created over 25 years ago by Albert Kligman of the University of Pennsylvania to define products with active substances that cannot be considered cosmetics or drugs. A cosmeceutical is a logical evolutionary concept, given the advances in skin anatomy and physiology. Contemporary belief is that almost all compounds applied to skin have the ability to penetrate and exert changes to skin structure.1 Currently, cosmeceuticals are very popular, with sales representing one of the largest growing segments of the skin care market, especially for products that are designed to help in the prevention and the treatment of aging skin. The demand for products that reduce the cosmetic effects of aging continues to grow because people wish to remain looking youthful as long as possible. These products are found in many presentations and are represented by vitamins, peptides, growth factors, and botanical extracts.2 There are still many controversial points about the drugs presented in cosmeceutical products; among them, mechanisms of action, optimal concentration, biologically active form, formulation ⁎ Corresponding author. E-mail address: [email protected] (M. Manela-Azulay). 0738-081X/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.05.010

stability, penetration, and retention within the skin. Although tests are available to answer some of these questions, we can speculate that at times there is little interest in such data, given that cosmeceutical products are not regulated and are usually well-accepted by consumers.3 For these reasons, dermatologists should be aware of cosmeceutical products and have access to accurate scientific theory with validated data—if any exists—to support cosmeceutical claims. For some products, in vitro evidence shows that these ingredients do have antiaging activity. The question remains whether it is possible to deliver adequate doses to the skin in vivo and to produce clinical or histologic effects. It is important to evaluate these new products with a critical and careful methodology, giving consideration to intended product use and the design of available studies supporting product use. Then, one can decide if the product is useful as a main or adjuvant treatment for aging skin.2 Vitamins are essential compounds for many functions of the human organism. Some vitamins can be synthesized, but others need to be obtained by an adequate diet. The most important are vitamins A, B, C, D, E, and K, as well as folic acid. Scientific evidence shows that, in addition to their specific functions, certain vitamins are useful for prevention, as well as for topical and systemic treatment of photoaging and chronologic skin aging. They are also effective in the

470 management of acne vulgaris. Various vitamins are used as drugs or cosmeceutical products are also of great interest for topical treatment. It is postulated that molecular mechanisms of photoaging are the same for chronologic skin aging, which also occurs in all others organs.4 The difference is that skin is in direct contact with the environment and undergoes the influence of other factors, such as the cumulative effect of ultraviolet (UV) A and B irradiation. Skin damage related to sun exposure may accelerate its intrinsic aging process; therefore, photoaging represents the superposition of the biologic effects of sun irradiation over the intrinsic aging that occurs. Two important pathways are related to chronologic aging. One is the progressive telomere shortening and finally its disruption that is caused by low-grade oxidative damage. This also affects other cellular structures and is a consequence of aerobic cellular mitochondrial metabolism.5 Damage is initiated by the generation of reactive oxygen species (ROS), also called free radicals. This reaction is an inherent part of the cellular metabolism related to energy production. Cells have enzyme processes that keep the oxidative damage at a minimum; nevertheless, it is progressive. Over time, the consequences are damage to DNA, resulting in mutations, reduction in protein functions, and peroxidation of membrane lipids affecting the transport and transmembrane signaling.6 In skin, these mechanisms are accelerated by UV irradiation that activates protein kinases, up-regulating expression and activation of the nuclear transcription factor AP-1, which then stimulates genes for matrix-degrading enzymes such as matrix metalloproteinases 1, 3, and 9. These matrix metalloproteinases degrade skin collagen and thereby impair the structure of the dermis. The AP-1 also interferes with types I and III collagen gene expression in human dermal fibroblasts, down-regulating its synthesis. Elevated levels of degraded type I collagen within the dermis, especially the larger fragments, may also negatively regulate its synthesis.4 The knowledge of these mechanisms provides the basis for the three most important approaches for prevention and treatment of aging skin, mainly the photoaging process. Although primarily an aesthetic problem, photoaging constitutes the background for the development of precancerous and cancerous skin lesions. Clinical and histologic evidence indicates that certain structural changes induced by excessive sun exposure can be reversed, to some extent, by an adequate treatment regimen. The most important measure to prevent photodamage lies in the daily and continuous use of sunscreen that blocks both UVB and UVA.7 Another approach is the potential effect of topical and systemic antioxidants that enhance ROS neutralization.6 The last is the use of compounds that help to repair DNA and collagen damage, as well as stimulate collagen synthesis. Topical vitamins, α-hydroxy acids, and growth factors can provide some of these effects. The results are better when these products are used before and maintained after the execution of procedures available in cosmetic dermatology.

M. Manela-Azulay, E. Bagatin There are substances with benefits documented with sufficient scientific background, and many more that lack such data.8 Many products are being introduced in daily skin care antiaging cosmeceuticals or cosmetic products based on hypothetical in vitro mechanisms of action, without confirmation by controlled clinical trials. It is accepted that cosmeceutical products must be as safe as a cosmetic and should not act as a drug. They have performance characteristics that suggest pharmaceutical action, but they are registered (where necessary) and sold as a cosmetic.8,9 The skin care industry is marketing a huge number of new agents promising results that have not yet been proven. In our opinion, this is one of the serious side effects of these antiaging products: They sell the fantasy of the eternal beauty, they have minimal or no effects, and usually, they are very expensive. On the other hand, the treatment of acne vulgaris with topical vitamins, mainly vitamin A, is very well supported by evidence. Vitamin A is more frequently used in pharmaceutical than in cosmeceutical products. Vitamin B3, commonly known as nicotinamide or niacinamide, is available in cosmetic and cosmeceutical products and can be used as a complementary agent for some types of acne, as well as aging skin. Acne is a multifactorial disease involving excessive sebum production by the sebaceous glands related to an increase in the androgen levels in the onset of puberty, ductal hypercornification of the follicles, and proliferation of Propionibacterium acnes and other bacteria that activate the tolllike receptors, resulting in attraction of lymphocytes, neutrophils, and macrophages. Other factors are production of proinflammatory cytokines such as interleukin (IL)-1, IL8, IL-12, and tumor necrosis factor-α. This is the base for the inflammation and immune response, which is extremely variable in different sites of the affected skin and individuals, perhaps on an inherited basis. P acnes can also induce follicular keratinocytes to release IL-1α, which causes keratinocytes proliferation and contributes to the formation of the preclinical lesion of acne, which is the microcomedo. Activation of toll-like receptors may also be involved in the scarring process by activating the metalloproteinases.10-12 The retinoids are vitamin A derivatives constituting the most effective comedolytic agents. They function by normalizing desquamation of the follicular epithelium, preventing the formation of new microcomedo, and minimizing the formation of comedones and inflammatory lesions.10-12 Nicotinamide is useful as a complementary drug because of its mild anti-inflammatory activity and its possible action in the reduction of sebum production and improvement of the skin barrier.13-15

Vitamin A The human epidermis contains significant amounts of vitamin A (all-trans-retinol), enzymes responsible for its

Cosmeceuticals vitamins metabolism, binding proteins for its protection and transport, and the nuclear receptors involved in the respective induced gene activity modulation. Data have shown that this complex system can be a direct target for UVB and UVA, as part of the adaptive response to UV irradiation. This mechanism may lead to a vitamin A deficiency in the skin.16 Vitamin A cannot be synthesized; it must be obtained through dietary means. The ingestion of vitamin A depends on the presence of retinoids (animal sources) and carotenoids (vegetable sources) in the diet. In the body, a small percentage of retinol is converted to its biologically active form, all-trans retinoic acid (tretinoin), through an intermediary, retinaldehyde. Most of retinol is converted to retinyl ester, its storage form. Topical retinoids have successfully been used to treat acne for nearly 4 decades. Initially, a retinoid was a compound of similar structure and action to retinol. Variations of this molecule have resulted in three generations of topical and systemic retinoids: the nonaromatics (retinol, tretinoin, and isotretinoin), the monoaromatics (etretinate and acitretin), and the polyaromatics (arotinoid, adapalene, and tazarotene).17 The efficacy of topical use of tretinoin in the treatment of photoaged and intrinsically aged skin is sufficiently evidence based. The effects are believed to be mediated through its binding to the nuclear retinoid acid receptors (RARs), RAR and RXR that exist as three distinct gene products: alpha, beta, and gamma. It induces type I and type III procollagen gene expression in human skin, resulting in increased deposition of collagen fibrils in the dermis. It also reduces collagen breakdown by inhibiting the metalloproteinases. An overall thickening is observed in the epidermis, a compaction of the stratum corneum, and deposition of a mucinous material (glycosaminoglycans) in the stratum corneum and intercellular spaces. The effects result in an improvement in the clinical and histologic skin appearance. It is still the gold standard topical treatment for this purpose.18-21 A few benefits have been reported for two other topical retinoid compounds, isotretinoin and tazarotene, but a lower level of evidence is available.21 Tretinoin cream in the appropriated concentrations of 0.025%, 0.05%, and 0.1%, as well as 0.1% isotretinoin and 0.1% tazarotene, frequently produce a moderate to severe skin irritation. Also, because they remain as prescription drugs, there is an increased interest in achieving the same effects with other retinoids (retinol, retinaldehyde, retinyl propionate, and retinyl palmitate), permitted allowed as components of cosmeceutical products.21,22 Retinaldehyde (0.05%) is another useful topical agent for the treatment of photoaged skin. It has a lower frequency of irritation but less efficacy than tretinoin. Unfortunately, few clinical trials have studied this interesting compound.23,24 There has been considerable confusion and doubt about the benefits of retinol and retinyl cosmeceutical products marketed as “antiaging” formulations. They have varying low concentrations, and usually there are few clinical trials

471 demonstrating efficacy. It seems that the useful concentration of topical retinol should range from 0.3% to 1%. Most of the over-the-counter products available usually contain lower levels of retinol (about 0.08% or less), compared with the concentration used in the few clinical studies available.2,25 These forms are not biologically active until enzymatic conversion to the active metabolite, retinoic acid, occurs in vivo. It has not been proven yet, if the skin has adequate levels of these enzymes to make a clinical difference. Most of the studies are in vitro and do not explain these aspects. Retinal is speculated to be 20-fold less effective than tretinoin, and the cutaneous concentration of tretinoin is 1000-fold less with topically applied retinol than with the proper drug. A small quantity of retinol appears to be converted into tretinoin in human skin.25 It is possible that a much higher concentration would be required, increasing risk of irritation that could be similar to what is observed with the use of tretinoin and other retinoids.22 Another problem with retinol compounds is that they are easily degraded by oxygen and light exposure. A new synthesized retinol derivative with higher photostability, named retinyl N-formyl aspartamate, was described as effective in a recent very small, uncontrolled study.26 For treating acne, topical retinoids are useful in all cases, because they interfere with the precursor lesion, the microcomedo. They can reverse the abnormal desquamation process, and in addition, they have anti-inflammatory properties, including suppression of toll-like receptor expression. The main retinoids used in treatment of acne are pharmaceutical products. Most of the studies are related to tretinoin in older formulations as well as in newer vehicles that provide less irritation. Other studies have investigated isotretinoin, adapalene, and tazarotene. 12 Only in vitro studies have addressed the comedolytic and antibacterial effects of retinaldehyde.27,28 Retinol or retinyl cosmeceuticals are not indicated in the treatment of acne. Current research on receptor selectivity holds the promise of the development of new retinoid molecules with improved benefits and safety.29,30

Vitamin E Vitamin E, like vitamin A, is present in mammalian skin. The probable physiologic function of epidermal vitamin E is to contribute to the antioxidant defense of the skin. Owing to its physical properties, vitamin E absorbs UV light in the solar spectrum region that is responsible for most of the deleterious biologic effects of the sun.31 Although human skin possesses various intrinsic defense systems that help to minimize the oxidative damage, excessive and long-term exposure to free radicals can deplete the body's own endogenous antioxidants, with the consequence of disruption of normal biomolecules such as lipids, proteins, and nucleic acids.22 The available literature concerning the efficacy of systemic and topical antioxidant substances such as

472 carotenoids and vitamins, specifically C and E, is very extensive, but the results are often contradictory. Positive as well as strongly negative results have been reported by different investigators. Skin treatment with these topical products for cosmetic purposes in these studies resulted in a range of observations from improvement in appearance to no effect at all. Almost no adverse reactions have been reported in most studies. 32 Vitamin E is the body's major lipid-soluble antioxidant represented, by 8 molecular forms, 4 tocopherols, and 4 tocotrienols. Alpha-tocopherol is the most active and is important in protecting cellular membranes from lipid peroxidation by free radicals. Once oxidized, vitamin E can be regenerated back to its reduced form by vitamin C or L-ascorbic acid. Vitamin E is available in dietary sources, and its concentration is highest at the lower levels of the stratum corneum, where it is released by sebum. Vitamin E as alphatocopherol or tocopherol acetate is used in topical over-thecounter products in concentrations ranging from 1% to 5%. In vitro studies have demonstrated the effects of alphatocopherol in reducing minimal erythema dose and the number of epidermal sunburn cells, which are markers of skin damage related to oxidative stress caused by UVB.5 Some human studies, however, have showed no evidence of conversion of tocopherol acetate or succinate to the biologically active form, alpha-tocopherol, despite its adequate absorption by the skin. Further, the metabolism of tocopherol acetate was highly dependent on the delivery system, emphasizing the importance of formulation of cosmetic preparations.22 Vitamin E can reduce UV-induced erythema and edema when it is applied before UV exposure. Use of vitamin E after sun exposure seems to have no benefit.31 Topical application of vitamin E may increase stratum corneum hydration and enhance water-binding capacity. Alpha-tocopherol also acts synergistically with vitamins A (retinol) and C (ascorbic acid) in combined products, providing an appreciable photoprotection and antioxidant action that suggests a potential effect in the protection against photoaging and skin cancer.33,34 A recent study35 analyzed an interesting new formulation with the association of vitamin E (tocopheryl acetate), vitamin A (retinyl palmitate), vitamin C (ascorbyl tetraisopalmitate), and bioflavonoids from Ginkgo biloba. The authors presented it as a “biological filter” against UV damage. They demonstrated that this formulation possesses a higher in vitro antioxidant activity, due to its free radical scavenging properties (almost 100% of inhibition of free radical production) compared with the separate use of the components. When they tested it in vivo, using hairless mice skin, the photoprotective effect (reduction in UV-induced erythema) was not observed. The authors concluded that this result was possibly related to the formulation vehicle, which influences the cutaneous penetration, as well as to the concentration of vitamins. They further hypothesized that these substances together may act on the epidermis by

M. Manela-Azulay, E. Bagatin different mechanisms and can be a promising new concept in antiaging and photoprotection cosmeceuticals. These combinations are very unstable, and it is important to achieve an ideal way to avoid chemical instability. One recent published proposal was the incorporation of ferulic acid into a solution of 15% ascorbic acid and 1% alpha-tocopherol, which doubles the photoprotective effect of the formulation.36 Although topical application of vitamin E demonstrates promising photoprotective effects, specifically when it is combined with other antioxidants, controlled studies in humans are needed before it can be recommended as an effective cosmeceutical agent for the treatment of both intrinsic and extrinsic aging.2,31

Vitamin B3 (niacinamide or nicotinamide) Vitamin B3, or nicotinamide or niacinamide, is a derivative of niacin obtained through diet from meat, fish, milk, egg, and nuts. Its deficiency is one of the causing factors of pellagra. Niacin has been used in medicine, most commonly to lower cholesterol. Nicotinamide is part of the coenzymes nicotinamide adenine dinucleotide (NAD), NAD phosphate (NADP), and its reduced forms are NADH and NADPH. These molecules are important in many cellular metabolic enzyme reactions.2,22 The reduced forms may act as antioxidants. Nicotinamide is one of the newest vitamin-based components of cosmeceutical products. Most of the studies available have focused on its anti-inflammatory and antiacne actions.13 It is also believed that its anti-inflammatory effect may improve skin appearance by reducing leucocyte peroxidase systems that may lead to localized tissue damage as well as by ameliorating the cutaneous barrier.12 In a comparative study, the anti-inflammatory effect of 4% nicotinamide gel in the management of acne vulgaris was as good as the benefits of 1% clindamycin gel.37 This antiinflammatory effect is also useful to reduce cutaneous erythema in various disordes.15 The possible utility of topical nicotinamide in the improvement of skin appearance may be related to its action in the synthesis of sphingolipids, free fatty acids, cholesterol, and ceramides, thus decreasing transepidermal water loss.12,38,39 The improvement of facial dyspigmentation is also likely mediated by the suppression of melanosome transfer from melanocytes to keratinocytes.40 Nicotinamide increases collagen production in fibroblast culture, and this effect may be responsible for the improvement of skin elasticity and reduction of fine wrinkles.15 All of these effects may help to reverse some of the aging skin signs, and for this purpose, it has been used in cosmeceutical products in concentrations ranging from 3.5% to 5%.15,41 Because it is nonirritating to facial skin, easily formulated, chemically stable, and compatible with other formulation components, niacinamide has been considered an ideal

Cosmeceuticals vitamins cosmeceutical agent; nevertheless, it is from one-third to one-fifth as effective as topical 0.025% tretinoin.15 There is certainly opportunity and interest to optimize use of this agent to achieve a higher performance.

473 such as promoting collagen synthesis, lightening hyperpigmentation, and anti-inflammatory and photoprotective properties.6,48,49 data confirming these benefits and its diverse biologic activity in the skin makes topical vitamin C a valuable and useful agent for the dermatologist practice.

Vitamin C Vitamin C, or L-ascorbic acid, is the most plentiful antioxidant in human skin. Most animals and plants have the capacity to synthesize vitamin C. Humans are an exception, because we have lost the ability to produce L-gulonogamma-lactone-oxidase, the enzyme necessary for its production.42 Vitamin C must be obtained from dietary sources. Even with massive oral supplementation, the increase of vitamin C in skin concentration is limited.43 Topical application of L-ascorbic acid is the only way to further increase skin concentration, and therefore, vitamin C has become a popular topically applied cosmeceutical. Much of the recent research on vitamin C has focused on its role as a free radical scavenger. Vitamin C is water-soluble and functions in the aqueous compartment of the cell by donating electrons, neutralizing free radicals, and protecting intracellular structures from oxidative stress.44 L-ascorbic acid is essential for collagen biosynthesis. It serves as a cofactor for prolyl and lysyl hydroxylases, enzymes that hydroxylate proline and lysine in collagen, stabilizing its triple helical structure. Recent studies have demonstrated that vitamin C also influences collagen synthesis independently of hydroxylation by activating its transcription and stabilizing procollagen messenger ribonucleic acid.45 Ascorbate also inhibits elastin biosynthesis, further supporting treatment of photoaged skin.46 The first cosmeceutical creams used vitamin C in its active form, L-ascorbic acid. Early formulations of L-ascorbic acid were very unstable due to the oxidation of the vitamin exposed to air. For this reason, esterified derivatives of L-ascorbic acid in topical formulations have been used to improve stability. The most common derivatives are magnesium ascorbyl phosphate and ascorbyl-6-palmitate.46 Magnesium ascorbyl phosphate demonstrated a skin-lightening effect in an open study. Studies with ascorbyl-6-palmitate in hairless mice revealed percutaneous absorption but little effectiveness in an UVB photoaging model.47 In contrast, other studies48 suggest that delivery of L-ascorbic acid into skin depends on removing the ionic charge on the molecule. This is achieved at a pH of less than 3.5 The maximal concentration of the L-ascorbic acid for percutaneous acid was 20%. Higher levels failed to increase absorption.48 Daily application of a 15% solution of L-ascorbic acid increased ascorbic acid levels 20-fold and tissue levels of the vitamin were saturated after 3 days.48 Ascorbyl-6-palmitate is a free radical scavenger and has some advantages over L-ascorbic acid.49 Despite these discussions, all the researchers agree that topically applied vitamin C has many benefits,

Conclusions Cosmeceuticals containing topically applied vitamins have an increasing place in the dermatologist's armamentarium. The growing demand for combating the signs of aging has had a profound effect in society. In the dermatologist's practice, requests have grown considerably for aesthetic medical treatments, such as chemical peelings, botulinum toxin, laser, and soft tissue augmentation. The first step to initiate an aesthetic treatment, no matter the choice, is to prepare and recommend a daily skin care regimen. Dermatologists have a responsibility to help achieve a healthy appearance of their patient's skin through proper skin care guidance. It is important for us to understand the science behind cosmeceuticals as they are increasingly being incorporated into the skin by daily use of skin care products.

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M. Manela-Azulay, E. Bagatin 34. Lin JY, Selim MA, Shea CR, et al. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol 2003;48:866-74. 35. Maia Campos PM, Gianeti MD, Kanashiro A, et al. In vitro antioxidant and in vivo photoprotective effects of an association of bioflavonoids with liposoluble vitamins. Photochem Photobiol 2006;82:683-8. 36. Lin FH, Lin JY, Gupta RD, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol 2005;125:826-32. 37. Shalita AR, Smith JG, Parish LC, et al. Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol 1995;34:434-7. 38. Tanno O, Ota Y, Kitamura N, et al. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol 2000;143:524-31. 39. Bisset DL, Oblong JE, Saud A, et al. Topical niacinamide provides skin aging benefits while enhancing barrier function. J Clin Dermatol 2003;32:S9-S18. 40. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 2002;147:20-31. 41. Bisset DL, Oblong JE. Cosmeceuticals vitamins: vitamin B. In: Draelos ZD, editor. Cosmeceuticals. 1st ed. Philadelphia: Elsevier Saunders; 2005. p. 63-8. 42. Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K. Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J Biol Chem 1994;269:13685-8. 43. Levine M, Wang YH, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A 2001;98:9842-6. 44. Farris PK. Cosmeceuticals Vitamins: Vitamin C. In: Draelos ZD, editor. Cosmeceuticals. 1st ed. Philadelphia: Elsevier Saunders; 2005. p. 51-6. 45. Nusgens BV, Humbert P, Rougier A, et al. Topically applied vitamin C enhances the mRNA level of collagen I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase I in the human dermis. J Invest Dermatol 2001;116:853-9. 46. Farris PK. Topical Vitamin C: a useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg 2005;31:814-8. 47. Kobayashi S, Takeana M, Kanke M, Itoh S, Ogata E. Postadministration protective effect of magnesium-L-ascorbyl-phosphate on the development of UVB-induced cutaneous damage in mice. Photochem Photobiol 1998;67:669-75. 48. Pinnell SR, Yang HS, Omar M, et al. Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg 2001;27:137-42. 49. Perricone NV. The photoprotective and anti-inflammatory effects of topical ascorbyl palmitate. J Geriatr Dermatol 1993;1:5-10.

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