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How does sildenafil citrate work? Definition Sidenafil Wikipedia

Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was developed and is being marketed by the pharmaceutical company Pfizer. It acts by inhibiting cGMP specific phosphodiesterase type 5, an enzyme that regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea. Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the US Food and Drug Administration on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes. Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.

about history sildenafil citrate

Even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on U.S. TV (famously being endorsed by former United States Senator Bob Dole and soccer star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire. The "Viagra" name has become so well known that many fake aphrodisiacs now call themselves "herbal viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", as well as various other nicknames.
In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills. By 2007, Viagra's global share had plunged to about 50 percent[9] due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors.
In February 2007, it was announced that Boots, the UK pharmacy chain, would try over the counter sales of Viagra in stores in Manchester, England. Men aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.
Pfizer's worldwide patents on sildenafil citrate will expire in 2010–2013. The UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

Mechanism of action sildenafil citrate 

The mechanism of action of sildenafil involves the protection of cyclic guanosine monophosphate (cGMP) from degradation by cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to the receptors of an enzyme called guanylate cyclase which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis causing an erection.[16] Robert F. Furchgott won the Nobel Prize in Physiology or Medicine in 1998 for his discovery and analysis of endothelium-derived relaxing factor or "EDRF", later identified with NO itself or a closely-related compound.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).

Sildenafil is metabolised by liver enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.


Uses
Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.

People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation. Following up to earlier reports from 1999, the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.[22]

Altitude sickness

Sildenafil has been shown to be useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers.[23][24] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.[25]



Professional athletes have been documented using sildenafil believing the opening of their blood vessels will enrich their muscles. In turn, they believe that it will enhance their performance.[26]
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Non-medical use
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Recreational use

Sildenafil's popularity with young adults has increased over the years. Sildenafil's trade name "Viagra" is widely recognized in popular culture, and the drug's association with treating erectile dysfunction has led to its recreational use. The reasons behind such use include the belief that the drug increases libido, improves sexual performance, or permanently increases penis size Studies on the effects of viagra when used recreationally are limited, but suggest that it has little effect when used by those not suffering from erectile dysfunction, and having sex within a stable relationship. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the post-ejaculatory refractory time. This study also noted a significant placebo effect in the control group.

Unprescribed recreational use of sildenafil and other PDE-5 Inhibitors is noted as particularly high among users of illegal drugs. Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[28] Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as "sextasy", "rockin' and rollin'," or "trail mix.Mixing with amyl nitrite is particularly dangerous, and is potentially fatal.[28]

Jet lag research

The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina, for their discovery that Viagra aids jet lag recovery in hamsters.[32] Their research was published in the Proceedings of the National Academy of Sciences.[33]

Analogues sildenafil citrate 

Acetildenafil is a structural analogue of sildenafil, one of the PDE5 inhibitors found in a number of "herbal" aphrodisiac products sold over-the-counter. This class of analogues have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have an unknown side effect profile. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.
Dosage sildenafil citrate

Viagra

Viagra pills are blue and diamond-shaped with the word "Pfizer" engraved on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) engraved on the other. The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse.

The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.[36]

Contraindications

Contraindications include:[citation needed]
When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers") In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors
Severe hepatic impairment (decreased liver function)
Severe impairment in renal function
Hypotension (low blood pressure)
Recent stroke or heart attack
Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

Side effects sildenafil citrate

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision. Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment in rare cases and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.

Rare but serious adverse effects found through postmarketing surveillance include priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.[38] As a result of these postmarketing reports, in October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.

Interactions sildenafil citrate

Care should be exercised by patients that are also taking protease inhibitors for the treatment of HIV. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25 mg dose every 48 hours.

Concomitant use of sildenafil and an alpha blocker may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantitated in plasma, serum or whole blood in order to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.

Chemical synthesis sildenafil citrate


The preparation steps for synthesis of sildenafil are as follows:
Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate.
Hydrolysis with aqueous NaOH to free acid.
Nitration with oleum/fuming nitric acid.
Carboxamide formation with refluxing thionyl chloride/NH4OH.
Reduction of nitro group to amino.
Acylation with 2-ethoxybenzoyl chloride.
Cyclization.
Sulfonation to the chlorosulfonyl derivative.
Condensation with 1-methylpiperazine.

source Wiki 

Los Angeles Times about sildenafil citrate (viagra)

A randomized trial of the blood vessel relaxant sildenafil in patients with pulmonary fibrosis has disappointed researchers by failing to improve patients' ability to walk, but the drug did provide a small but statistically significant improvement in other outcomes that are related to quality of life, researchers reported Tuesday. The benefits on quality of life were strong enough to justify a broader and longer trial of the drug, the researchers reported in the New England Journal of Medicine and at a New Orleans meeting of the American Thoracic Society.

Pulmonary fibrosis is a scarring of the lungs that interferes with their ability to take in oxygen. Its cause is unknown, and there are no drugs presently approved to treat it. An estimated 200,000 Americans ages 50 to 70 have the condition, and about 50,000 are newly diagnosed each year. Most patients die within three to five years after diagnosis.

A small pilot study conducted at UCLA by Dr. David A. Zisman in 2007 found that sildenafil improved the ability of patients in a six-minute walking test. Twelve patients were given the drug for three months. At the end of the trial, 57% of the patients had improved the distance they could walk during the period by 20% or more.

Based on those findings, the National Institutes of Health organized a large trial headed by Zisman, who is now at the Sansum Clinic in Santa Barbara. The trial involved 180 patients at 14 centers. Half were given sildenafil three times daily and half a placebo. At the end of the 12-week period, nine of the 89 patients in the treatment group had a 20% increase in the distance they could walk in the six-minute trial, but so did six of the 91 in the placebo group. The patients in the treatment group, however, had less shortness of breath, better arterial oxygenation and a better quality of life. The presence of these benefits "creates clinical equipoise for further research," the team wrote.

Two deaths occurred during the study in the treatment group and four in the control group. Acute exacerbations of disease also occurred in two of the treatment group and four of the placebo group.

The authors acknowledged several limitations of the study, including the shortness of follow-up, the failure to test patients with less advanced disease and possible problems in the blinding of the groups.

Sildenafil is the active ingredient in Viagra. It is also sold by Pfizer under the brand name Revatio for treatment of high blood pressure in the pulmonary arteries, which is the form used in the study.

The study was funded by NIH, but Pfizer donated the drug.

source LAtimes

About Generic Brands of Sildenafil Citrate

There has definitely been a good deal of controversy over Viagra®, it's use and more recently, it's side effects among some unfortunate patients however, apart from the specific drug itself and the effects, reasons and results of it's use, there has been another controversy of which only those involved would probably be aware. I am referring to the purchase and use of Generic Brands of Sildenafil Citrate.

Those involved being those who operate online generic Pharmacies, those who purchase through them and, by no means least, the thousands of Affiliates who market these.

Did you notice a moment ago when I called it Sildenafil Citrate and not Viagra®? It is, and has been referred to as Viagra®, regardless of whether Pfizer's(TM) original brand or a generic version is being talked about, since it's introduction to the Pharmacy industry, not to mention the public.

Although I thoroughly respect Pfizer's(TM) right to guard it's own trade mark with jealousy and, especially make sure that website domains are not being registered using their 'property', I can't help thinking that, at least in many cases, most people's use of the Viagra® moniker is more part of our social and language set than any deliberate attempt to profit by using the name, albeit in a legally questionable way.

There are plenty of examples, where what was originally a 'brand' or 'trade name' has become the popular means of identifying an object, product or other such item. Obviously, the use of these brand names and their becoming part of our descriptive language generally applies to the 'first' or 'original' of the given item in question. I can't give too many examples, being Australian; mine would only mean something to my countrymen. I am only familiar with a couple of examples from say... the US or the UK but I'm sure everyone gets the picture.

Having said this however, I think the crux of the matter lies not so much in the 'name' itself, but the use of the Viagra® name to describe and market the generic equivalents - and they are equivalents, PROVIDED they do contain the same active ingredients and if they are made and packaged with the care and controls that most people from developed countries expect from such products.

The name 'Viagra®' belongs to Pfizer(TM) and there's no doubt or argument that can circumvent that fact however, to use the term 'Generic Viagra', provided it's not used in a company name or exclusive website domain, is simply a means to describe to visitors and potential customers what you are offering. For instance, if I were to advertise 'Generic Levis', people would know that I am not selling Levi Strauss(TM) jeans. The word 'generic' makes that quite clear and I'm sure there is no way any misunderstanding could result.

In fact, if there were any misunderstanding, it would be in favor of Levis(TM) because, although it's totally untrue technically and in reality, generic still means 'inferior' to many people. Of course, generic means 'non-brand name'. There is nothing to suggest that the word does, or ever has meant anything else. Although realistically, in terms of some products that are generic, there are definitely cases where 'generic' has become a little 'synonymous' with 'not as good as the original'. A number of generic or 'no-name' food items come to mind.

Not so, with generic medications. They either have the active ingredients, in the prescribed quantities, or they don't. If they don't, they are not generic they are forgeries! Forgery means forgery but generic does not. Generic means 'the same but not the original', (and more often much cheaper!).

The controversy, as long-winded as it has been, could be coming to a close, for a couple of good reasons. I predict that the close of the issue and consequent legal approval of a number of generic drugs will occur sooner rather than later. After all, in the 'generic drug' category, it has been progressing for some time now. How many different brands (and 'no name' versions) of aspirin or acetaminophen can you now choose from?

The patent which allows Pfizer(TM) to claim exclusivity with regard to the chemical is enforceable until 2013 however, one of the patents concerning the discovery of its positive effects on impotence, has been withdrawn in the UK (where Viagra® was first discovered). According to a report of the court case, it was determined that the information forming the basis of the patent was already in the 'Public Domain' at the time of the patent application.

It remains to be seen whether this decision and other challenges, which have been hinted at, will have any effect on Pfizer's(TM) hold on the exclusivity of the Viagra® drug. Obviously, the active ingredient has been ruled in the public domain at some point, as it's use is widespread.

There is also to be considered the fact that Levitra®, a treatment for erectile dysfunction, which works in a different way to Sildenafil, has just received approval to be supplied en masse in Europe virtually ensuring it's survival outside of the U.S., where it has already been approved.

Because of these developments, and I know many who would agree, I personally think that approval from the FDA, and the regulating authorities of other countries, of generic versions of all the ED type medications won't be too far off. The simple fact that there are so many medications for this type of problem is testimony enough that the market is expected only to grow and grow. Examples of Viagra® equivalents alone are: Zenegra®, Kamagra®, Caverta® and Silagra® and each of the other medications like Levitra® and Cialis® all have their generic versions too.

So, given that these types of generic prescription medications can be basically the life blood of the online Pharmacy, especially the Affiliate driven ones and the affiliates themselves, the future is looking a fair bit brighter than it was say... 12 months ago, when questions of the legality, rumored legislation and even morality were being bandied about regarding the online pharmacy industry.

The question seems not to be whether these generic medications will receive the recognition of official approval in the 'developed' countries but more so, when it will be. This leaves only the concept of importation from countries in Europe, India and, of course, Mexico as a matter for controversy. This practice doesn't sit well with a number of people and in some cases; there is good reason why.

Personally, I know that the generic versions shipped through the online pharmacy that I affiliate with are reliable and W.H.O. (World Health Organization) approved. I can't speak for any operations, which use Mexican or Indian sources however. I assume, as with everything, the good and bad exist.

I am the first to admit that there are definitely 'forged' drugs being sold and imported. There are also probably generic medications, which may well have the prescribed amount of active ingredient, but may be manufactured and/or packaged under conditions, which leave them less than perfectly safe.
There are ways to determine if the Pharmacy through which you want to purchase generic medications is 'bonafide' (in terms of the quality of the drug and the conditions under which it is manufactured and packaged).

The World Health Organization (W.H.O) has a set of such guidelines, which must be adhered to in order for their approval to be given. A number of the generic drugs in question, i.e. those that are being touted as 'possibly' impure or 'useless' have this approval. I can only imagine that W.H.O. ensure this certification doesn't come too easily and it is in some way monitored.

Of course, there are other ways to check an online Pharmacy. Contact information is always a good means to ascertain if you're dealing with an organization that will be there tomorrow and has a good reputation and supplies reliable product, even if it is imported directly to the client (the cheapest and most expedient way). A polite email or phone call asking a few questions like: 'Where do the drugs come from?' or 'what is your refund or guarantee policy?', will usually elicit the signals you would normally be wary of.



All that those who choose to take advantage of the HUGE savings that can be made through online pharmacies selling generic medications need to do is to be aware of their own health and any conditions they may have, read the supplied information carefully and complete the online consultation form honestly. If the required information is not available on the pharmacy website, I would certainly advise finding another.

Having become disabled, I am fortunate enough to be able to earn a comfortable living from home through Affiliate Marketing. Having a number of websites, the generic online pharmacy component represents only part of my activities however; I do feel that this area of affiliate marketing does contribute in a large way towards helping people who are in need of a product, which unfortunately, isn't within the financial reach of everyone that it should be. A sad indictment for developed nations like the US, Canada, the UK and Australia (although Australia does have a very generous Pharmaceutical Benefits Scheme, it doesn't cover 'luxury' drugs like Viagra® - and maybe it shouldn't...).

If I can be responsible for one person being able to access a much-needed medication through one of my generic medication websites, which they wouldn't normally be able to access because of financial constraints, then I am a happy man...
Stephen Brennan is an accomplished Affiliate and Internet Author. He operates several affiliate websites including Quit Smoking OnlinePlus and The Diet & Weight Loss Place. He has written ‘The Affiliate Guide Book’ - The Definitive guide to Affiliate SUCCESS.

source ezinearticles

FDA Warns Consumers To Avoid TimeOut Capsules

The U.S. Food and Drug Administration is warning consumers not to take TimeOut Capsules because it contains an active drug ingredient that can dangerously lower blood pressure. The product is marketed as a dietary supplement for sexual enhancement.

TimeOut is labeled as "100% natural" and consumers may mistakenly assume the product is harmless and poses no health risk. TimeOut is distributed on Internet sites and online marketplaces as 2,500 mg capsules.

Consumers who have TimeOut Capsules should stop using them immediately. Sexual enhancement products that claim to work as well as prescription products are likely to expose consumers to unpredictable risks and the potential for injury or death.

The FDA analyzed TimeOut and determined that it contains hydroxythiohomosildenafil, a chemical similar to sildenafil, the active ingredient in Viagra. Like sildenafil, this chemical may interact with prescription drugs such as nitrates, including nitroglycerin, and cause dangerously low blood pressure. When blood pressure drops suddenly, the brain is deprived of an adequate blood supply which can lead to dizziness or lightheadedness.

To date, the FDA is not aware of any adverse events associated with the use of this product.

The FDA advises consumers who have experienced any negative side effects from sexual enhancement products to consult a health care professional and to safely discard the product.

Source: U.S. Food and Drug Administration

View drug information on Viagra.

Faculty Of Sexual And Reproductive Healthcare Response To ONS Statistics On Teenage Conceptions

Following the release of teenage conception statistics, the Faculty of Sexual and Reproductive Health highlights the importance of high quality contraception, and calls for sexual and reproductive health services to be a public health priority.

In light of new ONS teenage conception statistics released today, the Faculty of Sexual and Reproductive Healthcare issued the following statement:

Whilst today's statistics highlight that there has been a very small increase in teenage conceptions over the past quarter, the overall teenage pregnancy rate is nevertheless still in decline.

What today's figures highlight is that it is as important as ever that sexual and reproductive health services are a public health priority and investment is maintained. With 11 per cent of the female population aged between 13 and 44 attending contraceptive clinics each year*, sexual and reproductive health services play a vital role in health and well being.

Furthermore, the economic benefits of high quality, sexual and reproductive health services are well documented; the Department of Health estimates that for every £1 spent on contraceptive services, £11 is saved and the NHS in England could save over £100m each year by increasing the use of long acting reversible contraception.

However, future achievements rely on our ability to maintain a skilled workforce that is fully trained to provide this full range of contraceptive choices. Therefore, in this challenging economic climate, and in light of today's statistics, it is crucial that sexual and reproductive health remains a public health priority, so that we can build on these achievements, continue to innovate our services, and maintain a skilled workforce capable of delivering high quality services that provide a full range of contraceptive choices for all women.

Notes

- *in 2008-09

- Office of National Statistics data released on 24th August 2010, revealed that the teenage pregnancy rate has increased from 9,781 in March 2009, to 10,050 in June 2009. However, these data sets represent a decrease in the previous rate of 10,145 in December 2008. ONS data tables can be found on the ONS website.

- The Faculty of Sexual and Reproductive Healthcare (formerly called the Faculty of Family Planning and Reproductive Healthcare) of the Royal College of Obstetricians and Gynaecologists was established on the 26th March 1993.

- It grants diplomas, certificates, fellowships and equivalent recognition of specialist knowledge and skills in family planning and reproductive health care.

- It has approximately 12,000 medical members in the UK of whom 8,000 are general practitioners.

- As a body it promotes conferences and lectures, provides members with an advisory service and publishes The Journal of Family Planning and Reproductive Health Care.

Source:
Faculty of Sexual and Reproductive Health

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