Erectile Dysfunction: Pathophysiology, Evaluation and Treatment
Authors: B. Robert Bamshad, MD, Chief Resident, Urology, Loma Linda University Medical Center, and Steven C. Stewart, MD, Associate Professor of Surgery, Division of Urology, Loma Linda University Medical Center, Loma Linda, CA.
Peer Reviewer: Robert D. McClure, MD, Department of Urology, Virginia Mason Medical Center, Seattle, WA.
Editor's Note-With the release of Viagra, treatment of impotence has captured the attention of a nation. From scientific literature to the target of jokes by Jay Leno, Viagra has been catapulted into the headlines. Male patients, who heretofore have never brought up the subject, are mentioning to their physicians their plight of impotence and asking if Viagra is the answer.
This issue deals with the rational approach to impotence, from the initial work-up to providing appropriate treatment. It puts into proper perspective the role of Viagra as well as the non-pharmacological modalities available to the clinician. The role of the primary care physician is to provide an open atmosphere that will allow his or her patients to address their concerns and to proactively pursue questioning in the history taking which will identify patients who might otherwise have been reluctant or embarrassed to bring out the problem. Perhaps this renewed interest in an old problem will undoubtedly lead to yet further advances in effective intervention.
Introduction
Erectile dysfunction is a potentially devastating ailment that affects not only men, but also their sexual partners. The Massachusetts Male Aging Study revealed that age is the single most important variable associated with erectile difficulty.1 Currently, about 20-30 million American men are impotent, with projections of up to 47 million by the year 2020.2 This can be a rather difficult and embarrassing topic for most of these individuals to discuss. Moreover, most patients and health care professionals do not have an adequate understanding of the available treatment options. Hence, it has been estimated that only 5-10% of men with erectile dysfunction will seek medical intervention.2 Since this is one of the most undertreated conditions in the United States, the evaluation and management of impotence has become an emerging market, resulting in the expansion of numerous men's impotence clinics.3
Over the past few years, there has been an increased understanding of the physiology of erection and the pathophysiology of erectile dysfunction. We are beginning to understand the events leading to tumescence and detumescence at the cellular and molecular level. Combined with the advent of sophisticated diagnostic modalities, more and more of these patients are diagnosed with treatable organic causes of erectile dysfunction. Currently, there are a multitude of treatment options available, ranging from oral to injectable medications and various surgical treatments. A thorough understanding of penile physiology as well as current diagnostic and treatment modalities is necessary for proper evaluation and treatment of patients with erectile dysfunction.
Anatomy of the Penis and Physiology of Erection
Erectile function is a complex interplay of humoral, neuronal, and vascular events. Adequate androgen (testosterone) levels are usually required for libido. However, the exact role of testosterone in the erectile process is not known, and only certain types of stimuli causing erection are androgen dependent. For instance, nocturnal erections have been reported to be testosterone-dependent.4 More than 95% of circulating testosterone is secreted by the testes in response to stimulation from the hypothalamic-pituitary axis (the adrenals are another source). Pulsatile release of hypothalamic luteinizing hormone releasing hormone (LHRH) stimulates the pituitary to release luteinizing hormone (LH), which, in turn, causes testicular secretion of testosterone in a diurnal pattern. Although it is the unbound free testosterone that is effective, the majority of circulating testosterone is protein-bound.
The penis is composed of three cylindrical structures: the paired, dorsally positioned corpora cavernosa (CC) and the ventrally positioned corpus spongiosum (CS), which surrounds the urethra. Each structure is surrounded by its own fascial sheath, or tunica albuginea, and all are surrounded by the outer Buck's fascia. The CC, primarily composed of venous sinusoids covered with smooth muscle cells, are the main structures responsible for erectile function and essentially serve as reservoirs for the storage of blood during erection. The paired internal pudendal arteries are the principal blood supply to the penis. These vessels arise from the internal iliac (hypogastric) artery and form the penile arteries which, in turn, divide into three main branches. The bulbourethral artery supplies the CS, and the dorsal artery of the penis nourishes the penile skin and glans. The paired cavernous arteries, coursing through the center of the CC, are the principal blood supply to the erectile tissue and are important for corporal engorgement. It should be noted that there can be considerable variation in the penile arterial supply. The principal venous drainage of the CC are the subtunical and emissary veins, which drain into the deep dorsal vein, while the superficial dorsal vein provides for cutaneous drainage of the penis. The other major venous drainage system is the cavernous and crural veins, which form the pudendal vein. The venous drainage of the penis is also complex and variable.
The penis receives both somatic and autonomic (sympathetic and parasympathetic) innervation. The somatic component (S2 to S4) is the dorsal nerve of the penis, a terminal branch of the pudendal nerve carrying penile sensory afferent fibers. Sympathetic (T10 to L2) and parsasympathetic (S2 toS4) fibers form the pelvic plexus and cavernosal nerves. These fibers run posterior and lateral to the tips of the seminal vesicles and prostate, and penetrate the genitourinary diaphragm at the 3 and 9 o'clock positions. The nerves are located at the 1 and 11 o'clock position relative to the bulbar urethra before entering the CC. Cholinergic parasympathetic fibers are the primary neuronal system involved in the erectile process and are involved in both tactile and psychogenic erection. The role of the sympathetic nervous system is less defined. It is generally agreed that adrenergic stimulation results in penile detumescence; however, sympathetic fibers may have a role in psychic erection.4 Recent evidence also points to the presence of noncholinergic, nonadrenergic neurons in the CC that cause penile tumescence through release of an endothelium-derived relaxation factor, nitric oxide. This compound, which is also released in response to cholinergic stimulation, is believed to be the principal mediator of CC smooth muscle relaxation. Nitric oxide appears to exert its effect through increased intracellular levels of cyclic guanosine monophosphate (GMP).
With cavernosal artery smooth muscle relaxation, blood engorges the sinusoids resulting in tumescence.5 To maintain an erection, the corporal venous outflow has to be occluded. When the CC engorge with blood, they enlarge and stretch the surrounding tunica albuginea. This, in turn, compresses the small venules running through the tunica and blocks the venous outflow of the penis. Corporal smooth muscle constriction and the opening of venous channels allows for drainage of corporal blood resulting in detumescence.
Pathophysiology of Erectile Dysfunction
Up until 10-15 years ago, erectile dysfunction was, for the most part, attributed to psychogenic factors such as life stressors, performance anxiety, etc. However, current studies show that up to 90% of these men have underlying organic pathology as the principal cause or contributing factor to their condition.6 The common denominator in all organic impotence is either humoral, vascular, neurogenic, or anatomic derangements, but probably a combination of these factors. Chaabouni and associates rated the organic causes of impotence in decreasing order of frequency: arterial, venous, neurological, and endocrine.7 This discussion will focus on organic causes of erectile dysfunction. (See Table 1.)
The overall incidence of endocrine abnormalities in impotent patients is variable. Buvat and associates recently reported on a large series of impotent patients with an overall 6.6% incidence of endocrinopathy.8 Decreased or deficient testosterone is the main hormonal imbalance that can cause impotence. It is unclear exactly how testosterone is involved in the erectile process; however, it is generally agreed that adequate testosterone levels are needed to maintain normal libido. The cause of hypogonadism can be at different levels. Although hypothalamic or pituitary failure is possible, primary testicular failure is probably the most common cause of hypogonadism. Hyperprolactinemia, most commonly secondary to a pituitary adenoma, can also result in hypogonadism and erectile dysfunction by interfering with the hypothalamic-pituitary axis. Hyperthyroidism and uremia have also been associated with impotence.
Vascular impotence can be secondary to arterial or venous pathology. Arterial causes are usually encountered in older men with a history of diabetes mellitus (DM) and peripheral vascular disease, or in young men with penile vascular injury secondary to perineal trauma.9 Thus, a problem in either small or large vessels can cause inadequate inflow of blood to the penis, with resultant inability to engorge the CC. Venous "leak" impotence is secondary to abnormal venous drainage of the corpora, and/or inadequate corporal smooth muscle relaxation. Thus, the penis receives adequate inflow of blood but is unable to trap enough volume into the CC for tumescence. This condition may present as a life-long problem.
Neurogenic impotence can be secondary to central (CNS) or peripheral nervous system (PNS) dysfunction. The classic and most common PNS lesion is peripheral neuropathy in patients with longstanding DM. Bemelmans and associates reported that neuropathy played a greater role than angiopathy in diabetic patients with erectile dysfunction.10 Patients with spinal cord injury have varying degrees of erectile dysfunction, depending on the level and completeness of the cord lesion. Patients with other spinal cord diseases and lesions of the cerebral hemispheres also have varying degrees of impotence. Another category of neurogenic erectile dysfunction is iatrogenic (i.e., in patients after radical pelvic or lower bowel surgery with resultant interruption of the erectile nerves).
Finally, an important and frequent cause of erectile dysfunction is drug-induced, which can potentially affect the erectile process at any level. The two most common classes of medication responsible are the antihypertensives and antidepressants. Other commonly used medications that can potentially induce impotence include cimetidine and tranquilizers.
Evaluation of Erectile Dysfunction
As with any medical condition, the initial evaluation relies on a detailed history and physical examination. An important aspect of the preliminary assessment is to determine if psychogenic factors are the principal causes of erectile dysfunction.11,12 A thorough medical and sexual history should be taken. The physician must try to elicit social or psychological factors that could be potential causes of the problem. Particular attention should be given to medical conditions, medications, and history of prior pelvic surgical procedures. Physical examination should focus on abnormalities of sexual characteristics and inspection of the genitalia for evidence of trauma, plaques, or testicular abnormalities. A careful neurologic examination must be performed as well.
With respect to laboratory testing, there are differing views as to the recommended extent of testing. Some authors have advocated a complete laboratory work-up, including complete blood count, chemistries, and hormonal tests (testosterone, prolactin, etc.). Most clinicians, however, only obtain basic labs and pursue hormonal testing based on clinical suspicion.13 In a recent study, Buvat and associates recommended serum testosterone measurement in all impotent patients over age 50.8 However, in patients younger than 50 years, they advocated serum testosterone determination only in cases of low sexual desire and abnormal physical findings They also advocated serum prolactin measurement only in patients with low sexual desire, gynecomastia, and/or testosterone less than 4 ng/mL.8
Table 1. Broad Categories of Organic Erectile Dysfunction
· Hormonal
· Vascular
- Arterial insufficiency
- Venous "leak"
- Corporal sinusoidal pathology
· Neurogenic
- Peripheral neuronal dysfunction
- Central neuronal dysfunction
- Iatrogenic
· Drug-induced
Nocturnal penile tumescence (NPT) studies have been advocated as a method to differentiate between psychogenic and organic impotence. Although traditionally this has been a difficult test to perform (requiring the patient to stay in a sleep lab), machines like the Rigiscan allow for ambulatory monitoring of erections and rigidity. There is no consensus to the utility and validity of NPT studies, and numerous studies have deemed it unreliable.14,15 Currently, this study is not as widely used as in previous years.
Most urologists now initiate diagnostic testing by injection of vasoactive substances, such as alprostadil, allowing for relaxation of arterial and sinusoidal smooth muscle with resultant increase in penile blood flow. The ability to obtain an erection with pharmacologic injection will, for the most part, rule out significant vascular causes of impotence. According to Raifer, no further diagnostic testing is necessary if the patient responds to injection therapy.6 Failure to respond to intracavernous injection of vasodilating or relaxing substances raises the possibility of vascular impotence (arterial, venous, or sinusoidal). At this point, penile duplex Doppler sonography, in conjunction with intracavernous injection of vasoactive agents, can be used to evaluate the arterial inflow to the penis. Arterial insufficiency is suspected with poor blood flow, while veno-occlusive dysfunction is inferred in the face of adequate blood flow and poor erectile response.16
Occasionally, pudendal angiography and cavernosography/cavernosometry are done to evaluate the arterial and venous leak status of the penis, respectively.17 The latter tests, which are performed in conjunction with the injection of vasoactive substances, involve radiologic studies to localize penile venous leakage and measurement of intracorporal pressures with respect to engorgement. It should be emphasized that these tests should only be performed if the patient is a candidate for arterial or venous penile surgery (approximately 1% of all patients). A summary of the evaluation algorithm is shown in Figure 1.
Treatment of Erectile Dysfunction
There are multiple modalities for the treatment of erectile dysfunction. (See Figure 2.) Lue et al have introduced the concept of goal-directed therapy, in which the patient and his sexual partner have an active role in the decision-making process with respect to treatment.18 A recent report by Jarow and associates revealed that most patients prefer the least invasive therapy even when the more invasive options are more effective.19 There are essentially seven choices for impotence treatment as described by Lewis and Barrett: 1) accepting the loss of vaginal penetration with a rigid penis and using alternative sexual gratification methods; 2) medical therapy (hormonal and oral drugs); 3) psychological sex therapy counseling; 4) vacuum/constriction devices; 5) home pharmacological penile injection therapy or urethral suppositories; 6) penile prosthesis; and 7) vascular surgery.20
Although most physicians often fail to mention this option, every patient should be given the choice of alternative sexual gratification methods without vaginal penetration. If a patient and his partner are thus satisfied, the need for further unnecessary and expensive diagnostic tests and treatments would be obviated. On the other hand, if it is felt that a patient's erectile dysfunction is essentially psychological in nature, then psychological counseling is a viable option. Yaman and associates advocated acupuncture as an alternative modality for management of purely psychogenic impotence.21
Medical management involves many treatment choices based on the specific abnormality. In the face of low serum free testosterone (< 9 ng/dL), a trial of parenteral testosterone (200 mg IM q 2 weeks) or testosterone patches may be quite beneficial. Caution should be exercised in older males (> 50 years) at risk for development of prostate cancer, thereby necessitating careful rectal examination and PSA testing prior to institution of, and during, testosterone therapy. With respect to other modes of administration, treatment of hypogonadal men with oral androgens is essentially ineffective22 and can occasionally cause hepatic damage. Patients with elevated prolactin who, upon work-up, are found to have pituitary secreting tumors should be referred to an endocrinologist or neurosurgeon for bromocriptine treatment or surgical ablation. Other treatable conditions that can potentially cause impotence include history of urinary tract infections or prostatitis and sleep disorders.
Until the introduction of sildenafil (Viagra), there was no highly effective oral medication for treatment of erectile dysfunction. Medicines commonly tried in the past include yohimbine and trazadone. However, the American Urological Association (AUA) impotence guidelines panel concluded that yohimbine has no therapeutic value.23 Although they have no proven clinical efficacy, yohimbine and trazadone have been used as first-line therapy in patients with mild or intermittent erectile dysfunction with occasional benefit (probable placebo effect).
Currently, sildenafil is the only FDA-approved oral medication available for the treatment of erectile dysfunction. Sildenafil has received tremendous publicity in the United States, as well as internationally, and is quickly becoming one of the most prescribed medications in the United States. A type 5 phosphodiesterase inhibitor, the drug potentiates the effects of nitrous oxide on sinusoidal smooth muscle by causing increased intracellular cyclic GMP. It is important to realize that local release of nitric oxide secondary to sexual stimulation is necessary for sildenafil to exert its effect. The medication comes in 25, 50, and 100 mg tablets and should be taken about 1-1.5 hours prior to anticipated intercourse. Most patients are started at the 50 mg dose at a maximum frequency of one per day. However, the dose can be increased up to 100 mg depending on the response. Since the drug can potentiate the hypotensive effects of nitrates, concomitant administration of sildenafil to patients already on organic nitrates is an absolute contraindication. Some adverse reactions include headache (most common) and changes in vision. Other emerging oral medications awaiting FDA approval include phentolamine (Vasomax) and apomorphine.
Vacuum constriction devices (VCD) are a popular and effective treatment alternative for erectile dysfunction. The basic design involves a plastic cylinder that is placed on the penis down to the base, with negative pressure created inside the cylinder by a manual or electric vacuum pump allowing for penile engorgement with blood. Once an adequate erection is obtained, a constriction band is placed at the base of the penis (hence preventing outflow of blood) in order to maintain the erection once the cylinder is removed. Most patients can learn to use a VCD with relative ease since instructional videos are readily available and most manufacturers provide for over-the-phone assistance if necessary. It should be noted that almost every patient can be a candidate for these devices. Although some younger couples are less enthusiastic about using VCD, studies have shown that the overall long-term patient and partner satisfaction rate is high.24 Some contraindications to the use of VCD include patients with severe penile angulation deformity, prior history of priapism, and patients prone to capillary fragility or who are taking anticoagulants. These devices are manufactured by several different companies and cost roughly $150-500.
Pharmacologic injection therapy is another commonly used treatment for erectile dysfunction. This form of therapy involves direct injection of pharmacologic agents, namely smooth muscle relaxants or dilators, into the CC. The agents most commonly used are papaverine, phentolamine, and prostaglandin E-1 (PGE-1) either as single agents or in combination therapy. Although urologists have been administering these agents for many years, currently the only FDA-approved medications for injection are Caverject and Edex (both are prostaglandin-based). The goal is to achieve a rigid erection that occurs within 20 minutes of injection and lasts for about 20-90 minutes. The dose necessary to obtain such a result is different for each individual, and patients should be started on the minimal dose and titrated up until the desired result is achieved. An adequate response rate to injection therapy is achieved in about 70% of patients. It is imperative that the initial dose adjustments be done in the physician's office under close supervision. When the minimum dose suitable for an erection is determined, the patient may administer the medication at home. Patients with evidence of neurogenic impotence tend to require lower doses than those with vascular impotence and, therefore, should be started on a lower initial dose. The most common side effect is penile pain, while the most serious side effect is priapism (frequency of about 1%). In fact, the most common cause of priapism in the United States currently is pharmacologic injection therapy. Fortunately, most of these cases of priapism respond to low-dose injection of phenylepherine (200-400 mcg) or other alpha agonists. However, penile shunting surgery is occasionally necessary. Patients on injection therapy should have a 24-hour telephone number available to them in case of a priapism episode. Patients should be encouraged to alternate the site of injection (on dorsolateral sides of the penis) and should probably not inject themselves more than twice weekly. Some contraindications to injection therapy include patients on anticoagulation therapy, penile plaque, and history of sickle cell trait or disease. The cost of pharmacologic injection therapy is dose-dependent but averages about $20 per use.
Another advance is the introduction of intraurethral prostaglandin suppositories (MUSE), which became FDA-approved in January 1997. The advantage of MUSE is that penile injection is not necessary (the medication is deposited per meatus into the distal urethra using a disposable plastic applicator). MUSE comes in four dosages-125, 250, 500, and 1000 mcg. As with Caverject, the initial dosing adjustment should be done under medical supervision, and penile pain appears to be the most common side effect. MUSE is contraindicated in men with abnormal penile anatomy, and a condom should be used for intercourse with a pregnant female. The maximum frequency of use is no more than two systems per day, and each system costs about $20-30. Preliminary results have shown a response rate of about 40-60%.
The principal surgical treatment of erectile dysfunction is placement of a penile prosthesis. This therapy should only be considered if all other less invasive treatment options have been explored, since surgery may irreversibly effect any potential response to them. Devices available include two broad categories: semirigid or inflatable prostheses. Semirigid prostheses have the advantage of ease of placement and minimal risk of mechanical breakdown. Their inherent disadvantage is lack of variable rigidity and potentially difficult concealment. In comparison, inflatable devices are slightly harder to place and carry a higher risk of mechanical failure over the long term. They do, however, provide for variable rigidity, better concealment, and a decreased chance of erosion compared to semirigid devices. The inflatable devices come in three varieties: self-contained, two-piece, and three-piece models. In the self-contained prosthesis, fluid is stored in the crural end of the penile cylinders, and rigidity is obtained by activation of a pump in the glandular end. The two-piece model has a combination scrotal pump and reservoir plus two cylinders. The three-piece model has a separate scrotal pump, abdominal fluid reservoir (which is placed behind the rectus muscle in the prevesical space), and two cylinders. This model provides for better flaccidity, rigidity, and girth but requires more extensive surgery (need to make abdominal insertion). As with surgical implantation of any foreign material, infection of the device almost always requires complete removal of all hardware. The overall cost of penile prosthesis implantation is approximately $10,000.
Finally, an occasionally indicated treatment option is vascular surgery, either arterial or venous. It should be emphasized that these procedures are only intended for a select group of patients and should probably be performed at experienced centers. Moreover, the AUA guideline panel on impotence has deemed these procedures experimental.23 Prior to arterial surgery, internal pudendal angiography should be performed, and only patients displaying focal lesions in the internal pudendal or deep penile arteries are candidates for surgery. The most suitable candidate would be a young patient with a history of pelvic trauma. Patients with a history of peripheral vascular disease, hyperlipidemia, and smokers are not good surgical candidates. Venous surgery involves deep dissection and ligation of penile veins with the intent of minimizing venous drainage of the penis. The immediate success rate of these procedures is about 50-60%, and 20% over the long term.
Conclusion
Erectile dysfunction affects a significant portion of the male population and is probably one of the most undertreated conditions in the United States. Thanks to aggressive research, vital improvements in the diagnosis and treatment of this ailment have occurred, with more options soon to be available. Health professionals should familiarize themselves with the new diagnostic and treatment modalities available and should encourage patients to seek medical intervention. Major advances in the understanding, evaluation, and treatment of erectile dysfunction are continuing to emerge.
References
1. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychological correlates: Results of the Massachusetts male aging study. J Urol 1994;151:54-61.
2. Gillenwater JY. International impotence education month, November 1997. AUA News 1997;2:11.
3. Overmyer M. Impotence clinics find what medicine has overlooked. Urology Times 1996;24:1.
4. Benson GS, Boileau MA. The penis: Sexual function and dysfunction. In: Gillenwater JY, Grayhack JT, Howards SS, Duckett JW, (eds): Adult and Pediatric Urology, Third Ed. St. Louis: Mosby; 1996:1951-1995.
5. Carrier S, Brock G, Kour NW, et al. Pathophysiology of erectile dysfunction. Urology 1993:42:468-481.
6. Raifer J. Impotence: The quick work-up (editorial). J Urol 1996;156:1951.
7. Chaabouni MN, Mhiri MN, Hassan T, et al. Diagnostic and therapeutic approach in organic impotence. Ann Urol (Paris) 1994;28:148-156.
8. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile dysfunction: Clinical significance and cost-effective strategy. J Urol 1997;158:1764-1767.
9. Lehmann K, Schopke W, Hauri D. Subclinical trauma to perineum: A possible etiology of erectile dysfunction in young men. Eur Urol 1995;27:306-310.
10. Bemelmans BL, Meuleman EJ, Doesburg WH, et al. Erectile dysfunction in diabetic men: The neurological factor revisited. J Urol 1994;151:884-889.
11. O'Keefe M, Hunt DK. Assessment and treatment of impotence. Med Clin North Am 1995;79:415-434.
12. Butler RN, Lewis MI, Hoffman E, et al. Love and sex after 60: How to evaluate and treat the impotent older man. A roundtable discussion: Part 2. Geriatrics 1994;49:27-32.
13. Johnson AR 3d, Jarow JP. Is routine endocrine testing of impotent men necessary? J Urol 1992;147:1542-1543.
14. Djamilian M, Stief CG, Hartmann U, et al. Predictive value of real-time RigiScan monitoring for the etiology of organogenic impotence. J Urol 1993;149:1269-1271.
15. Steers WD. Impotence evaluation (editorial). J Urol 1993;149:1284.
16. Borirakchanyavat S, Lue TF. Evaluation of impotence. Infec Urol 1997;10:12-23.
17. Kaufman JM, Borges FD, Fitch WP 3d, et al. Evaluation of erectile dysfunction by dynamic infusion cavernosometry and cavernosography (DICC). Multi-institutional study. Urology 1993;41:445-451.
18. Lue TF. Impotence: A patient's goal-directed approach to treatment. World J Urol 1990;8:67-72.
19. Jarow JP, Nana-Sinkam P, Sabbagh M, et al. Outcome analysis of goal directed therapy for impotence. J Urol 1996;155:1609-1612.
20. Lewis RW, Barrett DM. Modern management of male erectile dysfunction. AUA Update Series, 1995, Vol XIV, Lesson 20, pp 162-167.
21. Yaman LS, Kilic S, Sarica K, et al. The place of acupuncture in the management of psychogenic impotence. Eur Urol 1994;26:52-55.
22. Morales A, Johnston B, Heaton JW, et al. Oral androgens in the treatment of hypogonadal impotent men. J Urol 1994;152:1115-1118.
23. Montague DK, Barada JH, Belker AM, et al. Clinical guidelines panel on erectile dysfunction: Summary report on the treatment of organic erectile dysfunction. J Urol 1996;156:2007-2011.
24. Cookson MS, Nadif PW. Long-term results with vacuum constriction device. J Urol 1993;149:290-294.
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