Papaya

Scientific Name(s): Carica papaya L. Family: Caricaceae

Common Name(s): Papaya , papaw , pawpaw (not to be confused with North American pawpaw [ Asimina triloba (L.) Dunal]), mamao , melon tree , chichput , fan kua , kavunagaci , lechoso , lohong si phle , maoaza , mu kua , papailler , papaya , papayer , pepol , tinti , wan shou , kuo , betik petik , gandul , katela , gantung , kates , kepaya , kuntaia 1 , 2

Uses

In some developing countries, the traditional use of papaya is being investigated as an alternative to standard treatments for a range of ailments. C. papaya has a wide range of purported medicinal properties including antiseptic, antimicrobial, antiparasitic, anti-inflammatory, antihypertensive, diuretic, antihyperlipidemic, antidiabetic, and contraceptive activity. While there are only limited data to support most of these uses, there is some evidence for use in healing decubitus ulcers and other wounds and in treating intestinal worms in humans.

Dosing

A commercially produced debriding ointment is available by prescription in the United States. Each 1 g contains 8.3 × 10 5 USP units papain and 100 mg of urea. 3 , 4 There are very little data available to make specific recommendations regarding systemic doses of papaya. One study used a 4 g dose of air-dried papaya seeds in 20 mL of honey to treat helminthiasis. 2 In the United States, the fruit is generally recognized as safe (GRAS status) when used as a food.

Contraindications

Papaya may cause severe allergic reactions and is therefore contraindicated in sensitive people. 5

Pregnancy/Lactation

Possibly unsafe depending on the part of the plant being used and dose administered. Avoid use.

Interactions

None documented.

Adverse Reactions

Papaya may cause severe allergic reactions in sensitive people. 5 Topically, papaya latex can be a severe irritant and vesicant. 1 Papaya juice and papaya seeds are unlikely to cause adverse effects when taken orally 2 , 6 ; however, papaya leaves at high doses may cause gastric irritation. 7

Toxicology

There are parts of the plant (eg, seeds) that contain benzyl isothiocyanate, which may cause toxicity at high doses. 8

Botany

Papaya grows as small, bushy trees 4 to 8 m in height with a hollow trunk, large palmate leaves, and oblong smooth-skinned fruits (melons). The melons are usually picked in a mature green state and allowed to ripen. When ripe, the flesh is sweet and juicy and similar in taste to other melons. 9

History

Papaya, a tropical plant believed to have originated in southern Mexico and central America, is now cultivated in tropical and subtropical regions worldwide. 9 , 10 C. papaya is cultivated for its edible ripe fruit; its juice is a popular beverage, and its young leaves, shoots, and fruits are cooked as a vegetable. 1 The fruits are a source of flavoring used in candies, jellies, preserves, and ice cream. Shallow cuts on the surface of fully grown but unripe fruits cause the exudation of a milky sap or latex that is collected, dried, and termed crude papain. 11 Papain, a proteolytic enzyme, has a wealth of industrial uses: it has milk-clotting (rennet) and protein-digesting properties. Nearly 80% of American beer is treated with papain, which digests the precipitable protein fragments, and causes the beer to remain clear upon cooling. 1 Papain is most commonly used commercially in meat tenderizers and chewing gums. 1 , 11 Cosmetically, papain is used in some dentifrices, shampoos, and facial creams. 1

Papaya has been used widely in folk medicine for many ailments: the juice for warts, corns, cancers, tumors, and indurations of the skin; the roots or their extracts for tumors of the uterus, syphilis, yaws, hemorrhoids, and to remove urine concretions; the unripe fruit as a mild laxative or diuretic, and to stimulate lactation, labor, or abortion; the ripe fruit for rheumatism and alkalinizing the urine; the seeds as an anthelmintic or to stimulate menstruation or abortion; the leaves as a poultice on nervous pains and elephantoid growths, or smoked for asthma relief; and the latex for psoriasis, ringworm, dyspepsia, or applied externally as an antiseptic or to heal burns or scalds, or smeared on the cervix as an ecbolic. 1 , 12 , 13

The Tropical Plant Database lists the following as documented properties and actions of C. papaya : analgesic, amebicide, antibiotic, antibacterial, cardiotonic, cholagogue, digestive, emmenagogue, febrifuge, hypotensive, laxative, stomachic, and vermifuge. 1

Chemistry

The stems, leaves, and fruits of papaya contain copious amounts of latex. 9 , 13

The latex from unripe papaya fruit is rich in 2 enzymes: papain (also known as vegetable pepsin) and chymopapain. 9 Other constituents include a mixture of other cysteine endopeptidases, such as papaya endopeptidase II (also known as caricain), papaya endopeptidase IV, omega endopeptidase, 14 chinitases, protease inhibitors, linamarase, and proteins without known functions. 15 , 16 As the fruit ripens, papain and chymopapain dissipate and neither is present in the ripe fruit. 17 Papain is primarily a mixture of protein-degrading enzymes, 18 but other components of papain can degrade carbohydrates and fats. Chymopapain has been fractionated into subcomponents designated “A” and “B.” 19 It is very similar to papain in the spectrum of its proteolytic activity, although it is less potent with respect to protein degradation. 20 Carpaine, an alkaloid compound, is also found in the unripe fruit and young leaves of papaya. 9 , 21 The leaves contain the glycoside carposide. 1

The seeds contain sinigrin and caricin, both glycosides, and the enzyme myrosin. 1 When caricin is combined with myrosin, it produces a mustard-like odor. 1 , 22 Papaya seeds and pulp contain benzyl glucosinolate that is hydrolyzed by the enzyme myrosinase to produce benzyl isothiocyanate. 23

A preliminary phytochemical analysis of C. papaya leaves revealed the presence of alkaloids, flavonoids, saponins, tannins, cardiac glycosides, anthraquinones, reducing sugars, steroids, phenolics, and cardenolides. 7

Uses and Pharmacology

C. papaya has a wide range of purported pharmacological effects, including antiseptic, antimicrobial, antiparasitic, anti-inflammatory, antihypertensive, diuretic, antihyperlipidemic, antidiabetic, and contraceptive activity. While limited data exists for most of these effects, there is some evidence for its use in healing decubitus ulcers and other wounds and for treating intestinal worms in humans.

In the early 1980s, chymopapain was approved for intradiscal injection in patients with documented herniated lumbar intervertebral discs and who had not responded to conservative therapy. 24 This procedure is effective 25 , 26 but remains the focus of controversy, particularly regarding the safety of the administration of the enzyme. 27

Decubitus ulcers, burns, and wound healing

Papain has the ability to dissolve dead tissue without damaging living cells. 9 An ointment, each 1 g containing 8.3 × 10 5 USP units papain and 100 mg of urea, 3 , 4 is available by prescription in the United States to debride necrotic tissue and liquefy slough in a variety of short- and long-term lesions, including pressure ulcers.

Chymopapain has also been used to aid in the healing and recovery of surgical wounds. 17 A home treatment for pressure ulcers that involved soaking gauze in the “milk” that comes from the trunk or unripe fruit of the papaya plant and packing this into the pressure sore 3 times daily has been described. 28

Animal data

Although papaya fruit is known to possess wound healing properties, no systematic clinical evaluations have been carried out until recently.

A study investigated the efficiency of papaya latex on burns induced in Swiss albino mice and concluded that 1% and 2.5% dried papaya latex formulated in carbogel are both effective in the treatment of burns. 29 There was an increase in the percentage of wound contraction observed from day 12 in the 2.5% papaya-treated group, and from day 20 in the 1% papaya-treated group and the standard treatment (silver sulfadiazine/chlorhexidine cream) group. The epithelization time was shorter in the 2.5% group. 29

This supports the promising results from previous studies in rats. In 1 study, burns were either treated with papaya gel or not. In the treated group, the wounds became much less inflamed and healed more quickly (noticeable on day 8), and by day 12, the wound area was half the size in the treated group compared with the untreated group. 30

In another study in streptozotocin-induced diabetic rats, aqueous extracts of C. papaya fruit (100 mg/kg for 10 days) applied to excision and dead space wound models exhibited a 77% reduction in wound area compared with controls (59%). The extract-treated wounds were found to epithelize faster. 31 A study compared the effects of aqueous extracts of unripe versus ripe papaya on wound healing. Unripe papaya induced complete healing in shorter periods than that required by ripe papaya (13 vs 17 days). 32 A study examining the effects of fermented papaya preparation oral supplementation on wound healing in adult obese diabetic mice has provided the first evidence that this may specifically influence the response of wound site macrophages and subsequent angiogenic response. 33

Clinical data

Healing remedies in Belize have reported that sliced fruit or crushed papaya seeds applied to wounds, cuts, and topical infections assisted with healing. 34

C. papaya is used in the pediatric unit at the Royal Victoria Teaching Hospital, located in The Gambia in West Africa, as a major component of burn dressings. The pulp of the papaya fruit is mashed and applied daily to full thickness and infected burns. It appears to be effective in sloughing necrotic tissue, preventing burn wound infection, and providing a granulating wound suitable for split thickness skin grafting. 35 Mechanisms of action postulated include activity of the proteolytic enzymes, papain, and chymopapain, and antimicrobial activity. Further studies are needed.

In an attempt to document papaya's use, a 15-item questionnaire was used to interview 9 nurses in Jamaica who used papaya to treat pressure ulcers. 9 They found that the nurses used grated unripe papaya blended into a paste and applied this twice daily, once daily, or on alternate days to the ulcers. The ulcers were cleaned with normal saline, Eusol , or soap and water 4 , 9 prior to application and then covered with gauze to keep the papaya in place. 9 , 36 The interviewees reported that the slough was easily removed from the ulcer after the papaya had been applied for about a week, at which time granulation tissue was evident. When healing was slow, papaya was used in conjunction with systemic antibiotics or topical Eusol , tetracycline, or mupirocin. 4 , 9 All participants interviewed were convinced that applying unripe papaya to pressure sores was effective. 9

Contraceptive properties

Anecdotal evidence suggests that eating unripe papaya for 3 consecutive days may induce abortion and that the papain in ripe fruit may have contraceptive-like activity when consumed daily. It has been suggested that papain suppresses progesterone, which is needed for conception and pregnancy. 37

More recently, the seeds of C. papaya are being considered in the development of an antifertility agent for men. 38 , 39

Animal data

Various investigators have reported remarkable antifertility effects of C. papaya seeds in laboratory mammals.

Abortifacient properties have been reported in female rats, 40 , 41 while a decrease in sperm motility and count have been reported in male rats 39 , 42 , 43 , 44 , 45 , 46 , 47 and rabbits. 48

Histologic examination of sections of pituitary gonadotrophs (follicle-stimulating hormone and luteinizing hormone cells) in male Wistar rats treated with C. papaya extract 200 mg/kg/day for 1 and 8 weeks revealed pronounced hypertrophy, while those treated with 50 mg/kg showed mild hypertrophy and hyperplasia. The testes of rats treated with C. papaya revealed gradual degeneration of the germ cells, Sertoli cells, and Leydig cells, as well as germinal epithelium. Tubules of epididymis of rats treated with 200 mg/kg of extract appeared empty, indicating the degeneration of sperm cells in the lumina. These results suggest C. papaya extract interfered with the pituitary-gonadal axis to influence male reproductive functions. 49

This is supported by the results of another study in which rats were given oral doses of 50, 100, 250, and 500 mg/kg methanolic extract of papaya seeds for 28- and 90-day periods. Sperm density showed a decrease in all 28- and 90-day treated animals, whereas total sperm motility inhibition was observed at 250 and 500 mg/kg dose levels at the 28-day interval and in all dose groups at the 90-day interval. 39

Studies are also being performed to evaluate the toxicological effects of seed extract and whether this effect is reversible even after high concentrations of the extract and long-term administration.

One such study in mice revealed a dose-dependent suppression of sperm motility coinciding with a decrease in sperm count and viability with high dosages of aqueous C. papaya seed extract. Forty-five days after withdrawal of treatment, complete normalcy was restored. 38 Another study in mice administered 50 mg/kg/day showed 100% sterility after 60 days, and safety was evidenced after 360 days by unaltered health status, organ weight, hematology, and clinical chemistry, and by an increase in body weight. All altered parameters, including percent fertility, were restored to control levels 120 days after treatment withdrawal. 47

In other studies, no signs of toxicity were observed in rats receiving a single oral dose of a methanolic extract of papaya seeds at 2,000 mg/kg 39 or in those receiving 5,000 mg/kg aqueous and methanolic extracts of whole, unripe C. papaya fruit. 50

Recently, another study in albino rats concluded that long-term daily oral administration of methanolic extract of C. papaya seeds affects sperm parameters (count, viability, motility) so as to be effective as a male contraceptive without causing adverse effects. 51

Clinical data

There are no clinical data regarding the use of papaya as a contraceptive agent in men and women.

Anthelmintic activity

C. papaya contains proven anthelmintic chemical agents such as benzyl isothiocyanate and papain. 1 , 23 , 52 , 53 However, papain is unstable in the presence of digestive juices, which may account for its lack of efficacy as an anthelmintic in clinical studies. 11 Benzyl isothiocyanate is therefore considered to be the chief or sole anthelmintic in papaya seed extracts. 19 , 23 , 53

Animal data

Various studies in animals confirm the effectiveness of C. papaya seeds as an anthelmintic effective against nematodes found in animals. 54 , 55 , 56 , 57 , 58 , 59

Clinical data

In a study of 60 asymptomatic Nigerian children with microscopic evidence of intestinal parasites in their stools, patients were randomized to either treatment with 20 mL elixir containing air-dried C. papaya seeds and honey (0.2 g/mL) or 20 mL honey alone (placebo). More subjects given C. papaya seeds and honey elixir than those given placebo had their stools cleared of parasites (76.7% vs 16.7%). 2 The high stool clearance rates of between 71.4% and 100% affirm the effectiveness of C. papaya seeds against intestinal parasites. Organisms cleared included Ascaris lumbricoides (84.6%), Strongyloides stercoralis (100%), Trichuris trichiura (100%), Giardia lamblia (100%), Taenia saginata (100%), Entamoeba histolytica (71.4%), and Necator americanus (80%). 2

Other antiparasitic/antiprotozoal activity
Animal data

C. papaya has documented activity against protozoa in addition to intestinal parasites in animal models. These include antiamebic, 60 antitrichomonal, 61 antimalarial, 62 , 63 , 64 and leishmanicidal 65 properties.

Clinical data

There are no clinical data regarding the use of papaya in these other parasitic/protozoal infections.

Antimicrobial activity

Papaya may exert a proteolytic effect on bacteria resulting from the production of a coagulum that immobilizes microorganisms and protects the host against bacterial infections. 66 In addition, papaya may improve the efficiency of phagocytic cells that destroy bacteria. 29 Papaya also contains the alkaloid, carpaine, which has antibacterial properties. 9

In laboratory tests, extracts from skin, flesh, and seeds of both ripe and unripe papaya showed in vitro antibacterial activity against several microorganisms, including Bacillus cereus , Bacillus subtilis , Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae , Proteus vulgaris , Pseudomonas aeruginosa , Salmonella typhi , Shigella flexneri , and Staphylococcus aureus . 67 , 68 , 69

Animal data

There are no in vivo animal data regarding the use of papaya as an antimicrobial agent. 69

Clinical data

There are no clinical data regarding the use of papaya as an antimicrobial agent in humans, although it is postulated that its antimicrobial activity may play a role in its efficacy in treating ulcers, burns, and wounds. 35

Anti-inflammatory activity

Papain has been used to control edema and inflammation associated with surgical or accidental trauma. 30 Papain solutions have produced therapeutic effects in patients with inflammatory disorders of the genitals, intestine, liver, and eye. 70 The leaves of papaya have been used for the treatment of inflammatory conditions such as asthma, rheumatism, arthritis, and wound healing. 7 However, there have been few studies investigating the biological activity of the dried leaves, which are used traditionally for the treatment of inflammatory conditions. 7

Animal data

The results of a Nigerian study in rats showed that the ethanolic extract of C. papaya leaves reduced carrageenan-induced paw edema and also produced a reduction in the amount of granuloma formed. Likewise the extract produced a reduction in the edema in the formaldehyde-induced arthritis model. 7 Further studies are required to identify the exact active ingredient(s) or mechanism responsible for the anti-inflammatory action.

Clinical data

There are no clinical data regarding the use of papaya in inflammatory conditions in humans.

Antiulcer activity
Animal data

A study revealed the antiulcer potential of aqueous and methanolic extracts of unripe papaya fruit in experimental rat models. The extracts reduced the ulcer index; the methanolic extract demonstrated better protection against indomethacin-induced ulcers, the ethanol extract against ethanol-induced gastric ulcers. 50 The cytoprotective and antimotility properties may account for the antiulcer properties of unripe fruit. 50

Clinical data

There are no clinical data regarding the use of papaya as an antiulcer agent.

Diuretic activity
Animal data

Diuretic activity is associated with the aqueous extracts of C. papaya . Adult male Sprague-Dawley rats were given an oral dose of 10 mg/kg of C. papaya root extracts. The demonstrated increased urine output ( P < 0.01) was similar to receiving hydrochlorothiazide 10 mg/kg. 71

Clinical data

There are no clinical data regarding the use of papaya as a diuretic.

Antihypertensive activity
Animal data

Antihypertensive activity is associated with ethanolic extracts from the unripened fruit of C. papaya . Both hydralazine (200 mcg per 100 g intravenously [IV]) and C. papaya extract (20 mg/kg IV) produced a depression in mean arterial pressure in renal hypertensive, DOCA-salt hypertensive and normotensive rats. The papaya extract decreased mean arterial pressure 28% more than hydralazine in the hypertensive groups. 72 The papaya extract produced relaxation of vascular tone that was attenuated by phentolamine. It was concluded that the fruit of C. papaya probably contains antihypertensive agent(s) that exhibit mainly alpha-adrenoceptor activity. 72

Clinical data

There are no clinical data regarding the use of papaya as an antihypertensive agent.

Antihyperlipidemic activity
Animal data

The raw fruit of C. papaya displayed potential as an antihyperlipidemic agent in Sprague-Dawley rats with hyperlipidemia induced by IV injection of triton WR1339 or a high-fat diet. 73 The fresh juice of C. papaya exerted a lowering of serum cholesterol and triglycerides within the first 24 hours in the triton model. Similarly, the aqueous and methanolic extracts of C. papaya markedly reduced the levels after 7 days of repeated oral treatment when compared with the control (atorvastatin and fenofibrate-treated) group. 73

Clinical data

There are no clinical data regarding the use of papaya as an antihyperlipidemic agent.

Antidiabetic activity

A recent survey of traditional medical practitioners, herbalists, and herb sellers in selected local government areas in Lagos State in Nigeria identified C. papaya as a popular traditional antidiabetic herbal remedy. 74 A recent study revealed that papaya is an intermediate glycemic index food. 75

Animal data

There are no animal data supporting the use of papaya as an antidiabetic agent.

Clinical data

A study compared the effects of fermented papaya preparation in a group of type 2 diabetic patients who were being treated with the hypoglycemic agent glibenclamide and a group of healthy subjects. All participants were given 3 g of fermented papaya preparation daily during lunch for 2 months. The results of this study confirmed the empirical experience that fermented papaya use can induce a decrease in plasma glucose levels in both healthy subjects and type 2 diabetic patients. This hypoglycemic effect, associated with clinical signs, induced the diabetic patients to reduce the dosage of their oral glibenclamide therapy; 1 patient stopped completely. 76

Antioxidant activity

Papaya contains antioxidant components such as vitamin C, malic acid, and citric acid 66 , 77 ; a limited number of studies have examined the antioxidant potential of papaya.

Animal data

In a study of Wistar rats, the rats were divided into a control group or 1 of 4 treatment groups. The treatment groups received 100, 200, or 400 mg/kg/day of C. papaya juice or vitamin E (alpha-tocopherol). The study demonstrated that the antioxidative stress potential of the juice was comparable with alpha-tocopherol. 6

Clinical data

A study of elderly patients supplemented with fermented papaya preparation exhibited an enhancement in antioxidant protection, suggesting that fermented papaya preparations may improve antioxidant-defense in elderly patients even without overt antioxidant deficiency states. 78

Another study in patients with hepatitis C suggested a potential supportive role of fermented papaya preparation or vitamin E. Both treatments improved redox status, however, only fermented papaya preparation decreased 8-hydroxy-deoxy-guanidine. The improvement of cytokine balance with fermented papaya preparation was better than with vitamin E treatment. 79

Miscellaneous uses

Papain and chymopapain have strong digestive properties and are used as digestive aids. 20

Caricain, and to a lesser extent, chymopapain, from papaya latex are gluten-detoxifying enzymes that might provide a basis for suitable enzyme therapy in gluten intolerance. 80

Benzyl isothiocyanate found in the pulp and seeds of papaya is a potent inducer of glutathione S-transferase, a phase 2 enzyme involved in the cellular detoxification of xenobiotics and reactive metabolites. 81 Aqueous extracts of C. papaya caused a concentration-dependent and statistically significant inhibition of root growth in onion bulbs. The extracts exhibited mitodepressive effects on cell division and mitotic spindle disturbance in Allium cepa . 82

Another study reported that aqueous extract of C. papaya leaves exhibits antitumor activity and immunodulatory effects, suggesting that the C. papaya leaf extract may provide the means for the treatment of cancer and various allergic disorders. 83

Dosage

An ointment for topical use, to debride necrotic tissue and liquefy slough in a variety of short- and long-term lesions, including pressure ulcers, is available as a prescription in the United States. Each 1 g contains 8.3 × 10 5 USP units papain and 100 mg of urea. 3 , 4

There are very little data available to make specific recommendations regarding systemic doses of papaya. One study used 20 mL of an elixir containing air-dried papaya seeds in 0.2 g/mL of honey to treat helminthiasis in children. 2

The papaya fruit has GRAS status when used as food.

Pregnancy/Lactation

Possibly unsafe. A 1978 report suggested that papain was teratogenic and embryotoxic in rats. 84 Several studies have investigated whether papaya consumption is safe during pregnancy. Rats given a ripe papaya blend in place of water showed no difference in the number of implantation sites and viable fetuses. However, unripe or semi-ripe papaya, which contains a higher concentration of latex, could be unsafe during pregnancy. 85 The crude papaya latex induced spasmodic contraction of the uterine muscles 85 similar to oxytocin and prostaglandin F2-alpha. 86 No adverse effects on prenatal development were observed in female Sprague-Dawley rats administered a low-dose, crude, aqueous extract of papaya seeds. 12 Some authors have postulated that papain may affect a vital membrane involved in the development of the fetus. 37

Interactions

None documented. It is possible that papain, which is found in the papaya leaves and unripe fruit, may effect the international normalized ratio in patients maintained on warfarin. 87

Adverse Reactions

Papaya is contraindicated in patients with known hypersensitivity to any of its components (eg, papain).

Papaya may induce severe allergic responses in sensitive people. A case report of immediate hypersensitivity reaction after contact with C. papaya has been reported. A total serum immunoglobulin E of 2,500 units/mL was found in this patient, and prick tests with papaya extracts were positive. 5 Cross-sensitivity between papain and papaya latex has been described, suggesting patients who exhibit an allergic reaction to papaya latex may have a similar reaction to papain. 88 , 89

Topically, the papaya latex can be a severe irritant and vesicant. 1

Orally, high-dose extracts from the leaves may cause gastric irritation (extracts from unripe fruit have shown antiulcer activity in animal models 50 ). The results of an ulcerogenic study showed an ethanolic extract of C. papaya leaves produced gastric mucosal irritation at high doses (200 mg/kg in rats). A dose of 800 mg/kg produced a comparable ulcerogenic effect with a standard ulcerogenic dose of indomethacin (20 mg/kg). 7 However, in another study investigating the anthelmintic efficacy of C. papaya seeds in a honey elixir, no adverse effects occurred. 2 Two of the 30 children complained of transient nausea and an episode of loose stools was reported on the day treatment was given. All participants in this study had intestinal parasitosis that may have caused these symptoms.

Toxicology

An acute toxicity test (median lethal dose) in adult male Wistar rats demonstrated that papaya juice (from the ripe fruit) was not lethal and no sign of toxicity was observed in rats receiving up to and including doses as high as 1,500 mg/kg after oral administration. Thus, papaya juice is considered nontoxic. 6

Oral administration of aqueous and methanolic extracts of whole, unripe C. papaya fruit of up to 5,000 mg/kg in mice did not produce lethality or signs of acute toxicity after 24 hours. 50

Papaya seed extract may exert potentially toxic effects on mammalian vascular smooth muscle. Benzyl isothiocyanate, the chief bioactive ingredient in seeds, irreversibly inhibits the contraction of dog carotid artery. 8 Papaya extract, when present in high concentration, was found to be cytotoxic by increasing the membrane permeability to calcium. 8

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