VOL. 66 . N.4 . DICEMBRE 2014

A PROSPECTIVE STUDY TO EVALUATE THE EFFICACY OF CISTIQUER IN IMPROVING LOWER URINARY TRACT SYMPTOMS IN FEMALES WITH URETHRAL SYNDROME Anno: 2014 Lavoro: Mese: December titolo breve: Efficacy of Cistiquer in improving lower urinary tract symptoms Volume: 66 primo autore: PALLESCHI No: 4 pagine: 1-8 Rivista: MINERVA UROLOGICA E NEFROLOGICA Cod Rivista: MINERVA UROL NEFROL



MINERVA UROL NEFROL 2014;66:1-8

A prospective study to evaluate the efficacy of Cistiquer in improving lower urinary tract symptoms in females with urethral syndrome

G. PALLESCHI 1, A. CARBONE 1, A. RIPOLI 1, L. SILVESTRI 1 V. PETROZZA 2, P. P. ZANELLO 3, A. L. PASTORE 1

Aim. The aim of the study was to compare 1Unit of , Uroresearch Association Cistiquer, a new phytotherapeutic product Department of Sciences and developed for chronic bladder inflammatory Medico‑Surgical Biotechnologies diseases, and intra-vesical administration of Sapienza University of Rome gentamicin plus betametasone, in females I.C.O.T. Hospital, Latina, Italy with urethral syndrome. 2Unit of Pathology, Department of Sciences and Methods. Between september 2013 and may Medico‑Surgical Biotechnologies 2014, 60 women with urethral syndrome and Sapienza University of Rome were incuded in this study. Patients I.C.O.T. Hospital, Latina, Italy 3 were randomly assigned to treatment with Microbiology and Virology intra-vesical administration of betametasone Deakos Scientific Consultant 8 mg plus gentamicin 80 mg (group A), and oral administration of Cistiquer (group B) for 7 weeks. Before and after the therapeutic protocol, symptoms were assessed by three betametasone. However, treatment adherence days voiding diary, the resulted higher for patients treated by oral questionnaire short form and a ten points therapy and rate of adverse events resulted visual analogic scale adopted to assess the higher for those submitted to endovesical micturition discomfort. Histologic findings treatment. were assessed by the examination of speci- Key words: Lower urinary tract symptoms - Ure- mens obtained by cold bladder biopsies of thral syndrome. the bladder trigone at baseline in all the sub- jects. Results. The two groups had significant and rethral syndrome is an ill-understood comparable symptoms improvement. How- ever, the score obtained from the visual ana- Udisease affecting females and respon- logic scale decreased significantly only in the sible for lower urinary tract symptoms group submitted to oral therapy. Further- (LUTS), as urinary frequency, urinary ur- more, in the group treated with endovesical gency, burning micturition, hematuria, and approach, higher drop out rate and higher pelvic pain associated with negative urine incidence of urinary infection were observed. 1 Conclusion. Patients with urethral syndrome cultures. Cystoscopic examination of indi- and trigonitis improved symptoms either viduals suffering from urethral syndrome with oral therapy with Cistiquer and with in- reveals an inflammatory status of the blad- tra-vesical administration of gentamicin plus der neck and trigone, described as trigoni- tis, whose histologic pattern reveals many Corresponding author: A.L. Pastore, MD, Phd, Urology layers of stratified squamous epithelium.2 Unit, Department of Medico-Surgical Sciences and Biotech- nologies, ICOT, Sapienza University of Rome, corso della To cure urethral syndrome, therapies today Repubblica 79, Latina, Italy. E-mail: [email protected] available are symptomatic but most of them

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are not effective and do not contribute to degenerate nucleus.7 Similar findings have significantly improve quality of life of- pa been reported by our pathologists in pa- tients. This is also the consequence of the tients enrolled in this protocol. These al- fact that urethral syndrome has had several terations are usually not found in the lateral sobriquets, which have led to much confu- wall of the bladder, as clearly showed by sion over its existence and the useful op- Pacchioni et al., who showed also clear cor- tions in the care of the afflicted patients.3 respondence between the presence of ster- Urethral syndrome is refractory to antibiosis oid receptors at the squamous metaplasia of and patients often do not respond to oral the trigonum speculating about a possible administration of conventional therapy, endocrine pathogenesis of trigonitis.8 This represented by steroidal and non-steroidal observation is also supported by Stephen- anti-inflammatory drugs. son TJ et al. who found the selective ex- However Tait J. et al. identified a micro- pression of nuclear estrogen receptor in biological cause in 4 patients of a cohort trigonal epithelium of 10 women affected of 31 individuals referred to their attention by trigonitis, in a distribution similar to that with a diagnosis of recurrent urethral syn- reported in vaginal epithelium by other drome.4 hardly contributes to workers. In this case the authors suggest an diagnosis cause it reveals hyperemia and oestrogen mediated aetiology of trigonitis squamous aspect of the bladder mucosa at speculating that it could be consistent with trigone level. In his population, Tait noted an embryological derivation of the trigone, trigonitis at cystoscopy in 26 of the 31 pa- distinct from that of the rest of the blad- tients and bladder biopsies showed squa- der.9 An association has been found among mous metaplasia in 15 and lymphocytic in- trigonitis, intestinal disorders, and inflam- filtration of the lamina propria in 29. These matory lesions of the genital tract (uterine findings give support to an inflammatory cervix). Since 1956 J.E. Semple of the St. aetiology of this enigmatic condition and Paul’s Hospital, London, reporting his ex- confirm the hard association between ure- perience in 43 females with trigonitis, has thral syndrome and trigonitis5. Further evi- described that 11 subjects presented with dence of this association is provided by Car- lesions of the large intestine (diverticula reras, who reported 68% of alone and radiologic appearances of inflamma- or combined with trigonitis in a cohort of tion).10 However, he suggested that the cor- 350 women presenting LUTS.6 In addition, relations between bowel inflammation and this author specified that urine examination trigonitis was not so strong as the associa- and cultures resulted negative in 80% of tion that he found with alteration of the cer- this population. Bladder histology in these vix and genital tract (in 66% of patients). patients shows pathological findings. Nor- In his experience, Semple firstly suggested mal trigonal urothelium consists of 3 cell the chance of treating these patients by layers (basal, intermediate and superficial), endoscopic fulguration of the bladder or whereas trigonitis constitutes many lay- urethral calibration.10-12 However, urethral ers of stratified squamous epithelium. The calibration is not useful in patients with basal cells contain prominent nuclei with normal micturition parameters as the pa- condensed chromatin, nucleoli and nuclear tients enrolled in our protocol. Endoscopic bodies. The cytoplasm of these cells is rich treatment is considered invasive but it is in mitochondria. The profiles of the urothe- still widely used for treating this condition lial cells become progressively elongated, by monopolar or bipolar fulguration of the their nuclei increasingly smaller and their inflammatory area of the bladder trigone. content of cell organelles gradually reduced However, no randomized prospective trials as the luminal surface is approached. The have been developed on this therapeutic squamous surface cells, linked by desmo- option and no level of evidence is therefore somes, retain many longitudinally arranged available regarding its efficacy and safety. fine filaments, together with an occasional Only Costantini et al. reported the results of

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a prospective randomized study on surgical contribute to reduce inflammation and pain, treatment using Nd:YAG laser in 62 patients and to preserve the integrity of urothelium with trigonitis refractory to drugs.1 This and connective tissue of the bladder. Quer- study concluded that side-firing laser, which citin, the principal, is a flavonoid, a plant produces necrotic coagulation followed by pigment with a molecular structure like or reconstitution of normal functional epithe- derived from flavone. It is found in fruits, lium, was significantly more successful than vegetables, leaves and grains. It can be used end-firing and was associated with a 78% as an ingredient in supplements, beverages, success rate. These results are encourag- or foods. Several laboratory studies show ing in patients who are usually refractory quercetin may have anti-inflammatory prop- to medical therapy. Medical therapy options erties and it is being investigated for a wide are represented by oral anti-inflammatory range of potential health benefits.16, 17 A drugs which determine short-time relief of study with rats showed that quercetin effec- symptoms and are very often followed by tively reduced immediate-release niacin (vi- recurrence. One of the most used treatment tamin B3) flush, in part by means of reduc- is represented by topic administration of ing prostaglandin D2 production.18 A pilot drugs. Shirley SW et al. reported favorable clinical study of four humans gave prelimi- outcomes using Dimethyl sulfoxide. How- nary data supporting this.19 Quercetin may ever, this study included a large population have properties of a calcineurin inhibitor, of both sexes and suffering from various similar to cyclosporin A and tacrolimus, ac- disorders, as , intractable intersti- cording to one laboratory study.20 Moreover, tial cystitis, radiation cystitis, chronic pros- Quercetin has been found to provide sig- tatitis, and chronic female trigonitis.13 Many nificant symptomatic improvement in most physicians use topic administration of cor- men with chronic prostatitis, a condition tisone reporting satisfying results. However, also known as male chronic pelvic pain syn- for all these therapeutic options there are drome.21 Cistiquer contains also Condroitin no large randomized trials available and Sulphate, a glycosaminoglycan (GAG) acting some data come from old studies.14 by the inibition of NO synthesis providing ef- Since many years various authors expe- fective outcome on inflammatory symptoms, rienced the effects on urethral syndrome and glucosamine, which contributes both to symptoms exerted by drugs capable of re- restore physiological properties and ana- ducing inflammation of the bladder.15 The tomical integrity of urothelium, as already high incidence of symptoms recurrence and shown by previous studies which also dem- the poor efficacy of these therapeutic choic- onstrated efficacy and safety of these agents es, induce patients to receive mini-invasive on chronic bladder conditions, as trigonitis treatments, consisting of intravesical instilla- and interstitial cistytis.22 Another agent con- tion of drugs, or surgical approaches, such tained in Cistiquer is bromelin, which is an as endoscopic resection or coagulation of extract derived from the stems of pineap- the pathologic bladder mucosa. Obviously, ples, although it exists in all parts of the invasive treatments are not well tolerated fresh plant and fruit, which has many uses and furthermore they have variable efficacy, and also anti-inflammatory properties.23-25 thus to prompt patients to search for alter- An antioxidant and anti-inflammatory activ- native options. ity has been also shown for another compo- Several reports show encouraging out- nent of Cistiquer, Centella, a genus of 2 or 3 comes provided by phytotherapic agents species of flowering plants in the subfamily on chronic lower urinary tract inflammatory Mackinlayaceae which has also revealed im- disorders. Recurrent cystitis and chronic portant antibacterial properties in microbio- prostatitis are the most important diseases logical studies.26, 27 Other extracts included that benefit from these therapies. in Cistiquer are from Rhodiola, a plant of the Cistiquer is a phytotherapeutic agent Crassulaceae family which has shown effects composed by natural elements which may on relieving mental and physical fatigue,28

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and from Scutellaria barbata, a species of cruited for this study after informed consent flowering plants in the mint family whose was read by the investigator, signed and dat- English common name is Barbed skullcap. It ed by the patients. All subjects were evalu- is used as a herbal remedy for inflammation ated at the Urology Unit of the Department and traumatic injury and has been tested in of Medico-Surgical Sciences and Biotech- clinical trials for the treatment of metastatic nologies of Sapienza University of Rome, breast cancer; moreover, its extracts induced by means of history, comorbidities assess- apoptosis in cancer cells in labo- ment, physical and genital examination in- ratory studies.29 The properties of all these cluding stress test, microbiological tests on natural agents appear intriguing for treating vaginal swab to exclude genital infections bladder modifications observed in urethral (Chlamydia, Mycoplasma, Ureaplasma, Tri- syndrome associated with trigonitis. The ac- chomonas), urinanalysis and urine culture, tion of quercetin combined with the other renal and pelvic ultrasound, three days void- natural extracts and the precious contribute ing diary, urinary cytology, pregnancy test, of condroitin sulphate and glucosamine may uroflowmetry with ultrasound evaluation of provide hard synergic favorable effects re- bladder residual volume, and flexible cys- ducing irritative symptoms as a consequence toscopy combined with multiple cold biop- of lower inflammation and of better bladder sies of bladder mucosa at trigone level (six mucosa integrity. Considering these charac- for each patient). Symptoms were assessed teristics, the aim of this investigation was to by the overactive bladder questionnaire compare the efficacy and tolerability of oral screener short form (OAB-SF, Figure 1). Fur- administration of Cistiquer with intravesical thermore, all patients were invited to indi- administration of gentamicin and betameta- cate the grade of micturition discomfort on sone in females with urethral syndrome. a ten visual analogic scale (VAS), from 0=no discomfort to 10=severe discomfort. Inclu- sion criteria were represented by presence Materials and methods of irritative symptoms as urinary urgency and urinary frequency combined with a his- A total of 98 females with urgency-fre- tological diagnosis of trigonitis. Exclusion quency syndrome were prospectively re- criteria were considered: urinary and/or

Figure 1.—The overactive bladder questionnaire short form (OABq SF). This questionnaire has been specifically developed to diagnose OAB, is easy to fill and is self-administered.

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genital tract infection, evidence of organic Results disease at renal and pelvic ultrasound, geni- tal prolapse, stress at Clinical findings history or revealed by physical examination, neurogenic diagnosis, previous genital and/ Mean age, mean body mass index, meno- or urological surgery, previous pelvic ra- pausal status and comorbidities distribution diotherapy, maximum flow rate <18 mL/s, did not significantly differ between the two bladder residual volume >50 mL, any evi- groups compared in the study (Table I). In dence of genital dystrophy, or any anatomic order of prevalence, comorbidities were alteration at genital assessment such as hyp- represented by: type II diabetes, dyslipi- ospadias, positive pregnancy test. Basing on demia, blood hypertension, dysthyroidism. these criteria, from the preliminary cohort, All diabetic patients assumed only oral 61 patients were histologically diagnosed therapy. None of these patients presented suffering from trigonitis and satisfied the polyuria at voiding diary examination. inclusion criteria. The histological diagnosis was achieved by optical microscopy. Two Protocol development different pathologists evaluated independ- ently the specimens and provided the same Three patients of group A spontaneously diagnosis. Patients eligible for the protocol dropped out from the protocol. One of them basing on inclusion and exclusion criteria due to severe hematuria cured in 48 hours were randomized 1:1 to two different treat- with bladder catheterism; 2 patients refused ments: 30 individuals were submitted to en- further catheterism after 6 and 8 procedures do-vesical administration of gentamicin 80 respectively due to pain; furthermore, these mg plus betametasone 8 mg (twice/week 2 patients reported no symptom improve- for 7 weeks, group A) while the other 30 as- ment. One patient of the group A and 2 pa- sumed oral therapy with Cistiquer, one tab- tients of group B needed antibiosis due to let/day/7 weeks (group B). One patient was acute urinary infection during the first week excluded from the protocol to obtain the of treatment and were therefore excluded same number of individuals in both groups. from the study. Final evaluable cohort at the The outcomes provided by the reported in- end of protocol resulted of 26 patients in vestigational measures were assessed 7 days group A and 28 patients of group B. 19/26 before and 7 days afer therapeutic protocol. subjects of group A and 19/28 subjects of Statistical analysis was performed to evalu- group B reported to be sexually active. Base- ate the outcomes: c2 test and odds ratios for line data achieved by three days voiding di- categorical variables, and Student’s t test to ary showed severe increase of micturition evaluate differences of continuous measure- episodes in the population and significant ments. number of urinary urgency episodes. None

Table I.—Demographic and clinical features two groups enroled. The results show that the two cohorts do not present significant difference about sex, age, BMI and comorbidities distribution. Diabetes, dyslipidemia and OSAS were the most represented disorders associated with obesity. Group A Group B Number of pts (26) (28) Age: range, mean and SD (27-57 years, 42.4±8.24) (31-55 years, 44±6.34) BMI: mean and SD 22±4.9 21±5.5 Diabetes 8 7 Dylsipdemia 6 7 Hypertension 11 11 Dysthyroidism 6 3 Menopausal status 12 13 Comment: clinical features of the population. The table shows that women of two groups were comparable in terms of mean age, mean BMI, comorbidities distribution, and menopausal status.

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Table II.—Comparison of baseline and control parameters in group A and B. Data regard patients with OAB diagnosis. P value was considered statistically significant when <0.005. Before treatment After treatment P Group A Total fluid intake per 24 h (mL 1280 ± 67.9 1309 ± 68.4 NS* Total micturitions per 24 h 9.6 ± 1.2 6.6 ± 1.7 <0.0010 Urgency episodes per 24 h 3.5 ± 1.1 0.4 ± 1.9 <0.0010 UUI episodes per 24 h 1.2 ± 0.7 1 NS Nocturnal micturitions 24 h 1.1 ± 1.2 1.1 ± 1.3 NS Mean voided volume (mL) 189 ± 57 233 ± 26 <0.0100 OAB-q score 18.69 ± 8.9 12.18 ± 3.2 <0.0001 Group B Total fluid intake per 24 h (mL) 1190 ± 37.4 1201 ± 33.2 NS* Total micturitions per 24 h 9.2 ± 1.4 5.6 ± 1.1 <0.0010 Urgency episodes per 24 h 3.3 ± 0.9 1.4 ± 1.0 <0.0010 UUI episodes per 24 h 1.4 ± 0.8 1.4 ± 0.3 NS Nocturnal micturitions per 24 h 1,0 ± 1.3 1.0 ± 1.1 NS Mean voided volume (mL) 212 ± 44 232 ± 39 NS OAB-q score 16.4 ± 1.5 12.3 ± 1.1 <0.0010 N.S.: not significant; UUI: urge urinary incontinence. patient suffered from polyuria (considered and urgency episodes in both groups. Al- as voided urine volume > 3000 mls per 24 though the results appeared better for the hours). VAS scores did not significantly dif- group B, this outcome did not reach sta- fer between the two groups at baseline. Par- tistical significance (Table II). None of the ticularly, patients in group A scored at VAS patients of group B reported any adverse a median 8, mean 6.5±2.3; patients in group event secondary to drug assumption. A sig- B scored a median 8, mean 6.3±2.2. nificant decrease of VAS score was reported Three patients of group A and 2 patients by females of group B, whilst no signifi- of group B presented also urinary urgency cant modification of this parameter was ob- incontinence episodes. After the protocol served in patients of group A. In fact, after was concluded, the examination of voiding treatment, patients in group A scored at VAS diary data and of OAB-q SF scores showed a median 5, mean 3.5±2.3, while patients in a significant improvement of symptoms and group B scored a median 0.8, mean 1.1±1.7 significant reduction of urinary frequency (P=0.001, Figure 2). In group B, 55% of

Figure 2.—Comparison of VAS before and after treatment between the two groups shows a significant higher decrease of score in group B respect to group A.

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patients referred no micturition discom- restoring urothelium integrity. Cistiquer is a fort (VAS=0) while all patients in the other phytotherapeutic product containing various groups experience the persistence of some agents capable of reducing bladder inflam- degree of discomfort. At the end of the pro- mation and protecting urothelium. These tocol the number of individuals who re- possible advantages provided by Cistiquer ported to be sexually active increased only seem to be supported by the outcomes of in group B, from 19 to 21 women. Urinary this investigation, which showed good symp- urgency incontinence episodes disappeared toms improvement of patients with favora- in 1 patient of group A and 1 of group B. ble effects also on sexual activity. The results confirm that oral therapy is better tolerated than catheterism, as revealed by the higher Discussion rate of adverse events and higher drop-out rate observed in group A. In fact, as shown Women with urethral syndrome present by VAS outcomes, urinary discomfort did not irritative symptoms which hardly lower their significantly change in patients submitted to quality of life, limiting daily practises, social intravesical therapy, although urinary fre- interaction and sexual activity. These pa- quency and urinary urgency were improved. tients present negative urine examinations Moreover, it has to be considered that natu- and cultures and are consequently refrac- ral agents are characterized by a low rate of tory to antibiosis. However, despite this evi- side effects inducing patients to well tolerate dence, they come to the attention of urolo- also long-term therapies, especially if associ- gists and gynecologists after many attempts ated with symptoms improvement, as shown of treatment with different antibiotics. Of by Cistiquer in our experience. course, urinary and genital tract infections (sexually transmitted diseases) must be ex- Limitations of the study cluded to diagnose an inflammatory chronic abacterial condition of the bladder. In our Limits of the study are represented by the clinical practice we use local administration small population included and the absence of cortisone after endoscopic and histologic of a placebo-controlled group. It should diagnosis of trigonitis: patients are submit- also be noticed that some data about ef- ted to 14 local instillations of betametasone ficacy and therapeutical properties of some 8 mg associated with gentamicin 80 mg to natural agents included in Cistiquer com- prevent acute urinary infection secondary position are lacking of rigorously-designed, to bladder catheterism. Patients who have well-controlled randomized control trials. no clinical improvement are then treated by However, in the Literature the use of con- bipolar electrovaporization of the inflamma- ventional drugs to treat trigonitis is also not tory area of the trigone. In our experience, commonly considered. Therefore, surely either catheterisms and endoscopic surgical this topic needs better consideration with treatment are not well tolerated by the pa- the aim to improve our knowledge on etio- tients, so much that we need to find alterna- pathoegeteic mechanisms and explore bet- tive therapeutic strategies to improve symp- ter therapeutic options. Basing also on this toms. Furthermore, many patients are willing pilot experience, Cistiquer should be taken to use therapeutic strategies derived from into consideration as one of the therapeutic natural/herbal extracts, capable of lowering options for treating urethral syndrome be- symptoms and curing chronic conditions as fore choosing invasive procedures. alternative and/or complementary therapy to glucocorticoids, non-steroidal antirheu- matics, and immunomodulators. Goals of Conclusions therapy in trigonitis are: reducing the inflam- mation of the bladder, protecting the blad- Both oral treatment with Cistiquer and der wall from damage of deeper layers and intravesical administration of betameta-

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sone plus gentamicin improved symptoms 16. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a prelimi- of patients with urethral syndrome. How- nary prospective, double-blind, placebo-controlled ever, in the group treated with Cistiquer a trial. Urol 1999;960-3. lower rate of adverse events was observed 17. Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, Madhappan B et al. Role of Quercitin in al- and patients reported better improvement lergy and inflammation. J Biol Regul Homeost Agents of urinary discomfort. 2006;20:47-52. 18. Papaliodis D, Boucher W, Kempuraj D, Theoharides TC. The flavonoid luteolin inhibits niacin-induced flush. Brit J Pharmacol 2008;153:1382-7. References 19. Kalogeromitros D, Makris M, Chliva C, Aggelides X, Kempuraj D, Theoharides TC. A quercetin containing supplement reduces niacin-induced flush in humans. 1. 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J thro-trigonitis caused by intestinal infection. Med J Microbiol Immunol Infect 2014 [In press]. 1956;2:696-7. 28. Ishaque S, Shamseer L, Bukutu C, Vohra S. Rhodiola 11. Miola L. Trigonitis secondary to inflammatory proc- rosea for physical and mental fatigue: a systematic esses of the uterine cervix. G Ital Chir 1953;9:770-8. review. BMC Complem and Altern Med 2012;12:70. 12. Sandes GM. The aetiology and treatment of trigonitis 29. Muluye RA, Bian Y, Alemu PN. Anti-inflammatory and in the female. Med Press 1948;3:220:365. antimicrobial effects of heat-clearing chinese herbs: a 13. Schulte TL, Reynolds LR, Hammer HJ. Topical use of current review. J Tradit Complement Med 2014;4:93- cortisone in urology. Calif Med 1954;80:380-1. 8. 14. Shirley SW, Stewart BH, Mirelman S. Dimethyl sulfox- ide in treatment of inflammatory genitourinary disor- Conflicts of interest.—Dr. Zanello is a scientific consult- ders. Urol 1978;11:215-20. ant for Deakos. The other authors do not have conflicts of 15. Aragona F, Serretta V, Marconi A, De Angelis M. Our interest to declare. experience in the medical therapy of chronic cervico- Received on July 6, 2014. trigonitis. Clin Ter 1985;114:323-30. Accepted for publication on July 10, 2014.

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