ISMH » Erectile Dysfunction International Society for Men's Health Tue, 14 May 2013 08:53:36 +0000 en-US hourly 1 Udenafil in the Management of ED Wed, 01 May 2013 12:03:29 +0000 Daniela Udenafil is a novel PDE5-inhibitor approved for treatment of ED in Korea.  It has an onset of action of 1-1.5 hours and a half-life of 11-13 hours, suitable for both on-demand and daily use.  It has been tested across various levels of trials (through Phase III studies) in subjects with ED and concomitant diabetes mellitus, hypertension, and BPH.  It appears to be safe and well-tolerated, resulting in significant improvements in men with ED according to IIEF parameters.

Commonly reported adverse effects include headache, facial flushing, and febrile sensation, and none were considered to be of moderate or severe intensity.  In a multiple-dose study, a color discrimination abnormality was reported that affected the blue-green region of the visual spectrum, yet this adverse effect spontaneously resolved upon successive testing defined as 1.5 hours after the fourth dose.  There were no clinically significant findings in routine laboratory parameters including platelet aggregation tests, bleeding time, or semen analysis.

Udenafil appears to have a longer onset time compared with vardenafil and a shorter duration compared to tadalafil.  Larger cohort, multi-ethnic trials will be required to more accurately assess its efficacy for worldwide use.

Reference: Kang SG, Kim JJ.  Udenafil: efficacy and tolerability in the management of erectile dysfunction.  Ther Adv Urol 2013;5(2):101-110.

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Effects of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction Thu, 18 Apr 2013 16:30:20 +0000 Daniela Testosterone is a major regulator of sexual desire, spontaneous sexual thoughts, motivation, attentiveness to erotic stimuli, and sexual activity in men. Experimental studies show that testosterone regulates penile nitric oxide synthase and blood flow. These data lead to speculation that, in men with erectile dysfunction (ED), normal testosterone level is necessary to achieve an optimum response to phosphodiesterase type 5 (PDE5) inhibitors.

This randomized, parallel group trial was performed in 140 men aged 40 to 70 with ED and low levels of total or free testosterone levels (<330 ng/dl or <50 pg/ml, respectively). First, dose of sildenafil was optimized for 3 to 7 weeks (25-100 mg/d). Then, participants were randomized (1:1) to testosterone (Testim, Auxilium Pharmaceuticals, Malvern) or placebo gel. Men were treated for 14 weeks and testosterone was adjusted on the basis of testosterone measurements. During the treatment, erectile and sexual functions as well as ED-related quality of life were assessed using standardized and validated questionnaires.

During the first phase, sildenafil administered alone increased testosterone levels by ~100 ng/dl. Later on, in the testosterone-treated group, testosterone levels increased further to the average level of 649 ng/dl. Sildenafil alone induced a substantial increase in all domains of the International Index of Erectile Function (IIEF) such as erectile function, sexual desire, orgasmic function, or intercourse satisfaction. Sildenafil alone also improved substantially all domains of the Sexual Encounter Profile (SEP), e.g. frequency of sexual encounters, vaginal penetration or ejaculation. Further, sildenafil also improved the ED-related quality of life. Importantly, there was no difference between men who did or did not take testosterone (in addition to sildenafil) as concerns the evaluated parameters of sexual function. The analysis limited to men who completed 14 weeks of treatment provided similar results. The effect of testosterone on ED did not vary by the testosterone levels, age or body mass index.

Thus, sildenafil plus testosterone did not improve sexual function compared with sildenafil plus placebo. This may seem surprising in light of preclinical data. However, sildenafil may have increased testosterone levels higher than the upper limit of dose-response relationship of testosterone for erectile function. Testosterone and sildenafil may share common mechanistic pathways and the optimized dose of sildenafil may have maximally induced these pathways. The results are not related to methodological problems: this was a randomized, double-blind and placebo-controlled trial, dropout rate was low, patients responded robustly to sildenafil, duration of testosterone treatment was sufficient to induce a therapeutic response.

Thus, in summary, these results do not support the routine addition of testosterone therapy for improving erectile response to selective PDE5 inhibitors in men with ED who have low testosterone levels.

Reference: Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, KNapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, DeRogatis L, Bhasin S. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 157(10):681-91.

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Erectile dysfunction is associated with higher cardiovascular risk and all cause mortality Wed, 20 Feb 2013 17:10:58 +0000 Daniela Cardiovascular (CV) disease and erectile dysfunction (ED) share common risk factors, whereas evidence-based studies have identified pathophysiological links as endothelial dysfunction and inflammation. Thus, identifying ED may be a useful predictor of future CV events.

Vlachopoulos et al. (1) performed the meta-analysis of 14 studies including jointly 92757 men (various outcomes have not necessarily been studied in all men). Total CV events were defined as CV death, myocardial infarction, revascularization, cerebrovascular events (stroke, transient ischemic attacks, intracranial hemorrhage), peripheral vascular disease, angina, heart failure and arrhythmia. ED was associated with a significantly higher (by 44%) risk of total CV events. The risk was significantly increased in the intermediate-risk group (by 51%) and in the high-risk group (by 30%), but not in the low-risk group. In an analysis performed in the studies in which the analyses were adjusted for main CV confounders, the increase in the risk of total CV event associated with ED was similar to the overall combined estimated risk. It shows that the higher CV risk in men with ED was independent of their higher baseline CV risk. The increase in the CV risk associated with ED was higher in studies in which ED was diagnosed with a validated questionnaire (by 61%) compared with a single question (by 27%).

ED was also associated with a significantly higher risk of myocardial infarction (by 62%) and of cerebrovascular event (by 39%). ED was associated with a significantly higher all-cause mortality (by 25%), mainly in men with known CV disease, but not with CV mortality. The findings of the meta-analyses were not related to the publication bias. Finally, meta-regression analyses showed that ED was predictive of CV events mainly in younger men, smokers as well as in men with higher total cholesterol and lower HDL-cholesterol levels.

Thus, screening and diagnosing ED can be important for primary prevention in the clinical practice because ED assessment offers an easy, low-cost alternative for CV biomarkers. The risk conferred by ED on the CV events is of a magnitude similar to that of the risk conferred by established risk predictors such as hypertension or dyslipidemia. ED can describe the CV risk particularly in men belonging to the intermediate-risk category. This group requires further risk reclassification and ED may be an additional predictor permitting to better assess the individual CV risk. Furthermore, the use of a validated questionnaire improves the diagnosis of ED and provides a stronger association between ED and the CV risk.

Overall these findings show that the assessment of ED using a validated method may help to estimate the CV risk in the clinical practice.

Reference: Vlachopoulos CV, Terentes-Printzios DG, Ioakeimidis NK, Aznaouridis KA, Stefanadis CI. Prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohort studies. Circ Cardiovasc Qual Outcomes. 2013 6:99-109.

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Viagra on the Internet: Is It Real? Mon, 10 Dec 2012 12:55:55 +0000 ismh The rate of availability of counterfeit medications is increasing dramatically worldwide, a substantial portion of which is attributable to the purchase of medications via the Internet.  A recent study sought to assess the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the PDE5 inhibitor sildenafil citrate (VIAGRA®, Pfizer Inc, New York, NY, USA).

The World Health Organization (WHO) estimates that medicines purchased over the Internet from sites that conceal their physical address are counterfeit ≥ 50% of the time.  In a European study, 62% of medicines ordered via the Internet and without a prescription were substandard or counterfeit.  In an analysis of samples seized worldwide for suspicion of being counterfeit Viagra, 83% of the samples ordered via the Internet were found to be counterfeit.  Recreational users and abusers of PDE5 inhibitor medication also report using the Internet as a source channel.

In this trial, Pfizer monitored top search results for the query “buy Viagra” on two leading Internet search engines in March 2011.  Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer.  Tablets received were assessed for chemical composition.  No website examined required a prescription for purchase or a health screening survey; 90% offered illegal “generic Viagra.”  Cost per tablet ranged from $3.28–$33.00.  Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each).  Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address.  

Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim.  Contaminants such as talcum powder, commercial paint, printer ink, and other active pharmaceutical entities have been found in counterfeit Viagra.  Although non-genuine “fillers” were not further assessed in this study, filler ingredients are associated with significant risk because they generally comprise the majority of tablet weight.

This study provides additional evidence that online sites claiming to sell authentic Viagra are not often legitimate. Besides the health risks possible from ingesting counterfeit products, credit card fraud and identity theft are also concerns with Internet ordering of medications.  There is evidence that Web sites that illegally supply POM without a prescription manipulate web searching to preferentially direct consumers to their fraudulent sites.  Consumers should use extreme caution when purchasing Viagra, as well as any other medications, via the Internet.

Reference: Campbell N, Clark JP, Stecher VJ, Goldstein I.  Internet-ordered Viagra (sildenafil citrate) is rarely genuine.  J Sex Med 2012;9(11):2943-2951.

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Recent review on the erectile dysfunction in Lancet Tue, 30 Oct 2012 20:50:31 +0000 ismh This paper describes several aspects of erectile dysfunction (ED). The ED incidence increases with age and the number of older men is on the rise due to the increasing life expectancy. Therefore, the number of men with ED increases and ED became a problem of public health. Vasculogenic ED is particularly important. Symptomatic cardiovascular diseases (CVD), such as ischemic heart disease or hypertension, are often associated with ED. It is partly related to cardiovascular risk factors (smoking, sedentary lifestyle, obesity, diabetes, dyslipidaemia) and to medications (thiazides, b-blockers, quinidine, amiodrone). In men aged <60 without known CVD, ED may be a marker of cardiovascular status. A man in his forties who reports an onset of ED should be considered a “cardiac patient” until proven otherwise.

The most important part of the diagnosis of ED is history taking. In case of psychogenic ED it helps to establish predisposing, precipitating and maintaining factors. In some cases, it may reveal severe psychosocial disorders necessitating psychiatric therapy. It also helps to identify the presence of factors increasing the risk of ED (lifestyle, concomitant diseases, drugs). The assessment of the patient's opinions on his sexual performance, masculinity, penile length and on his attitude to sex should be a part of history taking. Interviewing the patient's partner is also advisable. Local physical examination permits to assess organic congenital and acquired diseases. Laboratory investigations should comprise fasting blood sugar, lipid profile and testosterone. The patient's cardiovascular risk should be also assessed.

The therapeutic choice should be based on the specific problems of the patient. Psychosexual therapy (of the patient or of the couple) is recommended in the psychogenic ED. However, the efficacy of this treatment has not been appropriately investigated. Smoking cessation, weight loss and physical exercise improve erectile function and augment the efficacy of other types of therapy. Selective phosphodiesterase type 5 inhibitors (PDE5-Is) are the mainstay of the treatment of ED. However, their efficacy is 65% and they are contraindicated in men with severe CVD or taking some types of drugs. The failure of PDE5-Is may be related to the underlying diseases (e.g. diabetes, severe CVD, hypogonadism). Thus, its management should include the treatment of the underlying disease. Decision on other options (intracavernosal injection, vacuum constrictive device, penile prosthesis) depends on the health status of the patient, his preferences and on the failure or side effects of other therapeutic methods.

This paper presents useful hints for the management of ED. It will probably elicit a discussion of experts in the field which may be interesting for physicians in charge of patients with ED.

Reference: Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2012 Oct 4. pii: S0140-6736(12)60520-0. doi: 10.1016/S0140-6736(12)60520-0.

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ED in HIV-Positive Men Fri, 24 Aug 2012 09:03:09 +0000 ismh While prevalence of ED in men in the general population has varied from 2-70% in many reports, most studies have examined men older than 40 years of age; few studies have examined ED in younger men.  A recent trial hypothesized that both HIV and antiretroviral therapy may be pathogenetically linked to ED. 

A cross-sectional, observational, controlled study of 444 HIV-positive and 71 HIV-negative Italian men used the IIEF-5 questionnaire to assess degree of ED.  All degrees of ED were higher in the HIV-positive group, with an odds ratio greater than 34.  HIV infection was the strongest predictor of ED, to a greater degree than hypogonadism.  Desire was the only measured parameter on the IIEF-15 that was not confirmed as an independent risk predictor of HIV-related ED, yet this characteristic is also closely associated with hypogonadism and various psychological factors, thus making this factor more challenging to accurately assess.

This study is the first to highlight a clear association between HIV-positive status and ED, after adjusting for both age and BMI.  One possible confounder was that the HIV-negative group was significantly younger than the HIV-positive group.  A limitation of the study was that the authors did not identify anti-retroviral therapy exposure associated with ED, and the immunologic status of the HIV-negative group was unknown. 

Importantly, this trial demonstrated an increased prevalence of ED in HIV-infected men, thought to be intrinsic to the clinical presentation of HIV.  The authors posit that HIV should be added to the list of chronic medical conditions that contribute to ED.

Reference: Zona S, Guaraldi G, Luzi K, et al.  Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV-uninfected men.  J Sex Med 2012;9:1923-1930.

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Sexual Self-Confidence and Treatment Outcomes with PDE5 Inhibitors Sun, 10 Jun 2012 19:41:40 +0000 ismh Researchers from Mexico, the US, and Europe collaborated to compare Sexual Self-Confidence and other treatment outcomes following 8 weeks of treatment with tadalafil 5 mg daily versus tadalafil 20mg or sildenafil 100mg as needed in men with erectile dysfunction (ED).  This study was a randomized, open-label, crossover study in men >= 18 years of age with history of ED and satisfactory response to phosphodiesterase type 5 inhibitors (PDE5Is).  The primary objective was to test the hypothesis that tadalafil daily would provide superior psychosocial outcomes to sildenafil as needed in men with ED who had reported a previous satisfactory response to on demand PDE5I therapy.  Secondary objectives included comparison of daily tadalafil, on demand tadalafil, and on demand sildenafil comparing other outcomes to Sexual Self-Confidence, Time Concerns, and Spontaneity scales (PAIRS domains).

A total of 378 men naïve to daily tadalafil treatment were randomized to the various treatment arms.  A significant improvement was noticed in all PAIRS domains from baseline when comparing daily tadalafil and on demand tadalafil and sildenafil.  There was no observable difference in Sexual Self-Confidence between daily versus on demand tadalafil.  Changes in SEAR (Self-Esteem and Relationship), the erectile function domain of the International Index of Erectile Function, and Erectile Dysfunction Inventory of Treatment Satisfaction scores from baseline to post-treatment endpoint were statistically similar.  One advantage of the crossover design methodology was that each individual patient could serve as their own pre- and post-treatment control with respect to treatment effect.  Open-label design may have introduced some degree of bias in treatment outcomes, given the highly subjective treatment outcome measures.  Nonetheless, this study is the first comparative trial between daily tadalafil therapy and on demand PDE5Is, and most notably, there was no statistically significant difference in Sexual Self-Confidence improvement between daily and on demand tadalafil.

Reference: Rubio-Aurioles E, Porst H, Kim ED, et al.  A randomized open-label trial with a crossover comparison of sexual self-confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on-demand in men with erectile dysfunction.  J Sex Med 2012;9:1418-1429.

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Higher Risk of Erectile Dysfunction in Hypertensive Men Fri, 27 Apr 2012 19:01:17 +0000 ismh Arterial hypertension is a major public health problem worldwide, as well as an important risk factor for cardiovascular diseases, especially coronary heart disease and stroke. In addition, erectile dysfunction (ED) is more frequent in hypertensive patients compared with general population. In this context, two important points need to be addressed, recently evaluated in a study by Nunes and colleagues.

On one hand, ED may be a consequence of hypertension per se. High blood pressure and atherosclerotic disease (whose incidence is higher and progression is faster in hypertension) induce morphological changes in the penile vascular bed. They influence vascular smooth muscle (VSM) tone and cause endothelial dysfunction. The small diameter of cavernosal arteries and the high content of endothelium and VSM make penile vascular bed particularly susceptible to damage induced by systemic vascular disease. The mechanism of erection is relaxation of VSM induced by nitric oxide that activates guanylate cyclase. The subsequent decrease in cytosolic calcium leads to dilation of penile arteries, higher blood flow into the corpora cavernosa and penile erection. Therefore, in hypertensive men, higher levels of vasoconstrictors (angiotensin II, endothelin 1) contribute to the development of ED. Angiotensin II stimulates constriction of penile arteries through activation of AT1 receptor. Endothelin 1 induces vasoconstriction in the cavernosal arteries and in the internal pudendal artery, which provides blood flow to the penis. In addition, hypertension is associated with progressive collagen deposition, decrease in elastic fibers and increase in amyelinated nerves in the connective tissue surrounding cavernosal arteries, VSM hypertrophy as well as decreased nitric oxide bioavailability and responsiveness. These factors also decrease blood flow in the penile vasculature and impair erectile function.

On the other hand, ED can be a side effect of some drugs used in the pharmacotherapy of hypertension. This is the case of beta-blockers and diuretics which are the first line drugs for hypertension. Treatment with beta-blockers or diuretics, alone or added to other therapy, has been shown to induce or worsen sexual dysfunction. A new generation beta-blocker, nevibolol, was shown to dilate penile arteries and to improve erectile function; however, available data are limited. Other vasodilators (calcium channel blockers, angiotensin-converting enzyme inhibitors, hydralazine, minoxidil) have been rarely reported to cause ED. Finally, angiotensin II receptor antagonists have been reported to improve endothelial function in the cavernosal tissue and to improve sexual activity and erectile function.

In summary, in hypertensive men, ED is frequent and may be the effect of hypertension itself or a side effect of anti-hypertensive drugs. The physician should address this point in the contact with a hypertensive male patient and account for the risk of ED in the choice of the anti-hypertensive medication.

Reference:  Nunes KP, Labazi H, Webb RC. New insights into hypertension-associated erectile dysfunction. Curr Opin Nephrol Hypertens 2012;21:163-170.

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Erectile dysfunction in men on chronic haemodialysis Tue, 20 Mar 2012 15:16:07 +0000 ismh Erectile dysfunction (ED) is a very frequent, but under-diagnosed and under-studied health problem in men with chronic kidney disease (CKD).  ED has been reported in up to 70% of men with CKD, occuring more frequently in dialysis patients (both peritoneal and haemodialysis) compared with CKD patients who were not on dialysis and with kidney transplant recipients.  However, few of them received any treatment for ED, what may reflect the reticence of men to discuss sexual issues with their doctors.

Data on the risk factors for ED in patients with CKD and/or chronic heamodialysis have been obtained mainly in small groups of patients with insufficient statistical power, as most of the analyses were not adequately adjusted for confounders.  In this context, the recent paper by the Collaborative Depression and Sexual Dysfunction in Haemodialysis Working Group, a cross-sectional study, evaluated 946 men aged 18 years and older, who were representative of men on haemodialysis. ED was assessed using a validated detailed questionnaire. This study evaluated a large number of potential risk factors using multivariable analyses.

In this group, 83% of men reported experiencing ED.  Among them, 445 men (47% of the cohort) reported severe erectile problems. However, only 2% of men with severe ED reported use of phosphodiesterase type-5 inhibitor treatment. The risk of ED increased with age, and being married and employed was associated with lower risk of ED. Diabetic nephropathy and hypertensive nephrosclerosis were associated with higher risk of ED compared with other kidney diseases. Greater interdialytic weight gain and co-existent endocrine abnormalities were associated with a significantly higher risk of ED, whereas being on the waiting list for kidney transplant was associated with better sexual function. Importantly, more severe depression was strongly associated with higher prevalence and greater severity of ED.

Thus, ED is a very frequent and neglected problem in men on haemodialysis. Of note, men who declined to participate were older and more likely to be retired. Greater age and lack of professional activity were associated with higher risk of ED. Thus, real prevalence of ED in men on haemodialysis may be higher than that reported in the paper. The results of this study suggest role of generalized microvascular disease due to diabetes, hypertension or hormonal dysregulation in the development of ED. However, the results of this cross-sectional study should be interpreted cautiously. More severe depression was associated with more severe ED; however, these results do not permit to conclude on the causal relationship. Unmarried men on haemodialysis had more severe ED; however, they may have had some erectile problems before CKD developed and therefore, they were less likely to get married.

In conclusion, ED is a frequent problem in men on haemodialysis, but they rarely speak about sexual issues to their doctors. Therefore, clinicians in charge of these patients should address this problem themselves. All the men on haemodialysis, especially those at high risk of ED, should be asked about ED using easily available validated questionnaires.

Reference:  Collaborative Depression and Sexual Dysfunction in Haemodialysis Working Group – Prevalence and correlates of erectile dysfunction in men on chronic haemodialysis: a multinational cross-sectional study.  Nephrol Dial Transplant, published 2011 Dec 29 online at: doi: 10.1093/ndt/gfr635.

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HIGH RISK OF ERECTILE DYSFUNCTION IN MEN WITH COLORECTAL CANCER Tue, 07 Feb 2012 12:47:05 +0000 ismh In patients with colorectal cancer, especially those with rectal cancer, quality of life can be affected by bowel, bladder and sexual problems. Erectile dysfunction (ED) is often reported among men who have been treated for rectal cancer. It may result mainly from injury to pelvic nerves by surgery, radiation or chemotherapy. In addition, in every patient, individual risk factors have to be considered (age, co-morbidities).

In a recent study, Dowswell and colleagues assessed 28 men aged 34 to 80 years who had been treated for colorectal cancer. Despite some limitations (e.g., small group, descriptive approach), the study provides several interesting pieces of information. In survivors of colorectal cancer, ED is frequent. However, many patients do not seek help for ED for various reasons (e.g., unawareness of the association between experienced symptoms and colorectal cancer or cancer therapy, lack of knowledge about the possible treatment for ED, embarrassment, lack of confidence, perception of ED as a subject which is inappropriate for the medical office).

Even more importantly, among those who sought help for ED, almost none were receiving adequate, effective and affordable care. The patients emphasized lack or inadequacy of information about the risk of ED, inability or unwillingness of health care providers to speak about sexual function or even unintentionally offensive remarks, especially in regard to older men. In some cases, patients did not obtain any help from professional healthcare providers and sought medication on the internet.

Thus, from the practical point of view, three points are important. First, neither information about ED nor treatment for ED are incorporated into routine care of men with colorectal cancer.  Second, in these men, it may be necessary to explore problem of sexual function sensitively but routinely. Third, in case of older men, making assumptions about their sexual behavior or motivation (in particular, about lack thereof) may be inadvertently offensive.

Dowswell G, Ismail T, Greenfield S, Clifford S, Hancock B, Wilson S. Men’s experience of erectile dysfunction after treatment for colorectal cancer: qualitative interview study. BMJ. 2011 Oct 18;343:d5824. doi: 10.1136/bmj.d5824.

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