117Archivio Italiano di Urologia e Andrologia 2018; 90, 2 ORIGINAL PAPER Tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for < 10 mm distal and proximal ureteral stones Serdar Celik 1, Firat Akdeniz 1, Muge Afsar Yildirim 2, Ozan Bozkurt 3, Merve Gursoy Bulut 2, Mehmet Levent Hacihasanoglu 1, Omer Demir 3 1 Gaziemir Nevvar Salih Isgoren Hospital, Department of Urology, Izmir, Turkey; 2 Gaziemir Nevvar Salih Isgoren Hospital, Department of Radiology, Izmir, Turkey; 3 Dokuz Eylul University, School of Medicine, Department of Urology, Izmir, Turkey. Objectives: To evaluate the effect of tadalafil compared with four alpha blockers (alfu- zosin, doxazosin, tamsulosin and silodosin) as medical expul- sive treatment for ureteral stones in male adults. Materials and methods: Male adults who were admitted to urol- ogy clinic with flank pain and diagnosed with non complicated < 10 mm ureteral stone on non-contrast computed tomography (NCCT) between June 2014-September 2015 were retrospec- tively evaluated. A total of 273 patients with ureteral stone were divided into five groups. Alfuzosin 10 mg/daily, doxazosin 8 mg/daily, tamsulosin 0.4 mg/daily, silodosin 8 mg/daily and tadalafil 5 mg/daily for 6 weeks were prescribed respectively. Stone localization, diameter, volume and Hounsfield units were noted as NCCT findings. The patients were divided into the two groups based on their stone localization as distal and mid-prox- imal stones. These two groups were evaluated separately. Expulsion rate were noted at the end of 6 weeks. NCCT and treatment findings were compared between five drug groups in distal and mid-proximal stones separately. Results: Age was higher in tadalafil group in distal stones (p = 0.032). Expulsion rate was found 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin, 88.6% for silodosin and 90% for tadalafil in distal (p = 0.44) and 21.7%, 30%, 30%, 30% and 54.5% in mid-proximal stones (p = 0.034) respectively. Conclusions: Expulsion rate was higher in silodosin and tadalafil for distal ureteral stones but the difference didn’t meet statistical significance. However the expulsion rate was signifi- cantly higher in tadalafil than in the other groups for mid-prox- imal ureteral stones. The result of this study showed that tadalafil may increases ureteric stone expulsion. KEY WORDS: Alpha blockers; Medical expulsive theraphy; tadalafil; Ureteral stone. Submitted 17 March 2018; Accepted 4 April 2018 Summary No conflict of interest declared. or pneumatic lithotripsy with ureterorenoscopy (URS) (2, 3). But these treatments include some risks such as complica- tions of treatment, failure and high cost. Therefore, some predictors were determined on non-contrast computed tomog- raphy (NCCT) of stone diameter, stone volume, Hounsfield units (HU) and Hounsfield density (HD) to reduce these risks (4). For ureteral stones, although the watchful waiting approach has been reported to be associated with sponta- neous stone expulsion for about 50% of ureteral stones, some complications may occur such as urinary tract infec- tions, hydronephrosis and colic events (3). Medical expulsive therapy (MET), another method for stone expulsion, has become routine in the treatment of obstructive ureteral cal- culi in recent years. The use of various drugs as MET, which affect the ureter via different mechanisms, can reduce symp- toms and facilitate stone expulsion. Alpha and beta adrener- gic receptors were found in the ureter (5). Alpha-1 and par- ticularly subtype alpha-1D are the most commonly observed adrenergic receptor subtypes in the ureteral smooth muscle cells (6). Alpha blockade has been proven to decrease peristaltic activity, contraction and intraureteral pressure and to improve spontaneous stone passage and decrease both the time to stone passage and analgesic requirements (7, 8). According to European Asso ciation of Urology Guidelines, alpha-blockers are recommended for MET because they should ensure well controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve (9). A phosphodiesterase-5 (PDE-5) inhibitor (tadalafil), which acts on the NO/cGMP signaling pathway of smooth muscles, causes ureteral relaxation (10). A recent study reported that tadalafil showed a high ureteral stone expulsion rate and significant pain control (11). Alpha blockers and tadalafil in MET have a proven role to promote stone passage and reduce the need for minimally invasive surgery for distal ureteral stones. However, these findings were not investigated for proximal ureteral stones. In related studies only two of three drugs were compared for MET with distal ureteral stones. Therefore we wanted to evaluate the possible effect of tadalafil compared with alpha blockers, which are alfuzosin, doxazosin, tamsulosin and silodosin, for MET in uncomplicated distal and proximal ureteral stones in male adults. DOI: 10.4081/aiua.2018.2.117 INTRODUCTION Urinary tract stone disease is most prevalent between the ages of 20 and 40 years and 3 times more common in men than women (1). Twenty percent of all urinary tract stones are found in the ureter and many of these stones should be treated with efficacious treatment modalities such as extra- corporeal shock wave lithotripsy (SWL) and endoscopic laser Celik_Stesura Seveso 28/06/18 16:54 Pagina 117 Archivio Italiano di Urologia e Andrologia 2018; 90, 2 S. Celika, F. Akdeniza, M. Afsar Yildirimb, O. Bozkurtc, M. Gursoy Bulutb, M. Levent Hacihasanoglua, O. Demirc 118 MATERIAL AND METHODS After approval obtained from the Local Ethics Committee, we retrospectively reviewed the records of > 18 year old male patients with uncomplicated ureteral stones of < 10 mm diameter on NCCT images between June 2014 and September 2015. After the informed consent, only male patients were included in the study to standardize patients and to eliminate the differences in expulsion time depend- ing on anatomical differences between female and male patients. There is also an indication problem for tamsu- losin, silodosin and tadalafil treatment for female patients in our country. Therefore only male patients were selected for the study. Patients who had not previously received any alpha blocker or tadalafil treatment were treated with alpha blockers or PDE-5 inhibitor for 6 weeks. Patients who had only ureteral stone and were treated with one of four alpha- blockers (alfuzosin 10 mg/daily (Xatral, Sanofi Aventis), doxazosin 8 mg/daily (Cardura, Pfizer), tamsulosin 0.4 mg/daily (Tamprost, Zentiva), silodosin 8 mg/daily (Urorec, Recordati)) as MET were included in the study. Patients who had concomitant erectile dysfunction and did not accept the use of alpha blockers were treated with tadalafil 5 mg/daily (Cialis, Lilly and Lifta, Abdi Ibrahim) for possible effect of ureteral stones expulsion and erectile dysfunction treatment. Patients who were diagnosed with nephrolithia- sis, > 10 mm ureteral stones, bilateral ureteral stones, ureteral stones requiring drainage or obstructive, grade 3 hydronephrosis, multiple ureteral stones and any anatom- ical abnormalities on NCCT examination were excluded from the study. Patients with urinary tract infection, fever and elevated creatinine level were also excluded. All patients who had unsuccessful MET underwent shock wave lithotripsy (SWL) or ureterorenoscopic (URS) treatment. Demographic data of included patients (age, height, weight and body mass index (BMI)) were noted. Before MET, NCCT images using 2 mm sections with the liver's dome as cranial border and pubis joint as caudal border at 100 mA 120 kV (Alexion TSX-034A, Toshiba®, Japan) were taken. The localization of stone, the stone diameter, the stone volume, grade of hydronephrosis, the distance of stone from ureterovesical junction (for distal stones) as described by Yuceturk CN et al. (12), the distance of stone from ureteropelvic junction (for proximal stones), Hounsfield units (HU) and Hounsfield density (HD) of the stone measured by NCCT were noted. All measurements were calculated by one radiologist. Largest stone diameters were measured on longitudinal, transverse, and axial images and mean stone diameter was calculated as the average of these three values. HU and stone volume were calculated with computed tomography viewer program. HD was calculated as the HU divided by mean stone diam- eter (13). All patients were divided into five drug groups as alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups. Drug groups were subdivided into two groups according to the stone localization on NCCT images as dis- tal and mid-proximal ureteral stones and were evaluated separately. For stone localization, the anatomical limit of ureteral parts was defined as the level of the iliac artery crossing the ureter. Below this area was defined as distal, while above this area was defined as mid-proximal. Time interval follow-up of MET was 6 weeks. Patients were instructed to take diclofenac 50 mg tablets orally during episodes of pain, and filter their urine to detect stone expulsion. Expulsion time was noted when the stone was observed in the filtered urine. Suspicious expulsions or unsuccessful expulsion of stone were confirmed with NCCT at the end of the 6th week. Treatment findings (expulsion success rate and expulsion time) were noted at the end of MET. Demographic data of patients, NCCT findings and treatment findings were compared between drug groups for distal and mid-proximal ureteral stones separately. The primary endpoint expected from the study is the expulsion rate for alpha-blockers and tadalafil groups. The secondary endpoint is expulsion times for the groups. Finally an important endpoint is the tadalafil expulsion success for mid-proximal ureteral stones. Statistical analysis Demographic data of patients were analyzed and com- pared for all groups. The parameters measured on NCCT (the stone diameter, grade of hydronephrosis, the stone volume, the distance of stone from ureterovesical junc- tion, the distance of stone from ureteropelvic junction, HU and HD) were compared between all 5 groups. The Pearson χ2 test and Kruskal-Wallis test were applied between the groups for nonparametric statistical analysis using commercially available software (Statistical Package for the Social Sciences, Version 20.0; SPSS, Chicago, III). The alpha level of statistical significance was set at .05. RESULTS Male adults who were admitted to the urology clinic with flank pain and diagnosed with uncomplicated ureteral Table 1. Demographic data, tomography findings and expulsion findings of the study population. Variables All patients (n = 273) Age, year; mean ± SD (range) 41 ± 11.3 (20.3-80) Height, cm; mean ± SD (range) 1.74 ± 6 (161-190) Weight, kg; mean ± SD (range) 82.7 ± 13.7 (56-125) BMI, kg/m2; mean ± SD (range) 27.2 ± 4.1 (18.3-39.9) Percentage of stone localization Distal 61.5 Mid-Proximal 38.5 Mean stone diameter, mm; mean ± SD (range) 4.9 ± 1.7 (1-10) Stone volume, mm3; mean ± SD (range) 80.3 ± 83.5 (0.5-502) The distance of distal ureteral stone from ureterovesical junction, mm; mean ± SD (range) 9.7 ± 4.3 (1-22) The distance of mid-proximal ureteral stone from ureteropelvic junction, mm; mean ± SD (range) 84.9 ± 37.7 (29-152) HU; mean ± SD (range) 571.2 ± 307.8 (89-1384) HD, HU/mm; mean ± SD (range) 114.5 ± 40 (41.4-280.5) Percentage of hydronephrosis grade None 16.9 Grade 1 53.1 Grade 2 30 Grade 3 0 Percentage of expulsion success rate 63 Expulsion time, day; mean ± SD (range) 11.3 ± 9.5 (2-39) Abbreviations: BMI, Body Mass Index; HU, Hounsfield Units; HD, Hounsfield Density. Celik_Stesura Seveso 28/06/18 16:54 Pagina 118 stone on NCCT between June 2014 and September 2015 were retrospectively evaluated. A total of 273 male adults were included in the study. Mean age was 41 ± 11.3 (20.3-80) years and mean BMI was 27.2 ± 4.1 (18.3-39.9) kg/m2 for the whole group. Mean age, height, weight, BMI, stone localization, mean stone diameter, stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, HU, HD, grade of hydronephro- sis, stone expulsion rate and expulsion time are given in Table 1 for all patients. Considering the stone localization there were 168 patients with distal and 105 patients with mid-proximal ureteral stones. In drug groups; 55 patients were treated with alfuzosin, 57 with doxazosin, 54 with tamsulosin, 55 with silodosin and 52 with tadalafil. In the drug groups 32, 37, 34, 35 and 30 patients had distal, and 23, 20, 20, 20 and 22 patients had mid-proximal ureteral stones, respectively. There was no significant difference in the demographic data (height, weight and BMI) of the five groups for distal and mid-proximal ureteral stones (p > .05) (Table 2 and 3). Age was higher in the tadalafil group than the other groups for distal ureteral stones (p = .032) (Table 2). 119Archivio Italiano di Urologia e Andrologia 2018; 90, 2 Tadalafil as medical expulsive therapy Table 2. Comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of MET in distal ureteral stones. Table 3. Comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of MET in mid-proximal ureteral stones. Distal ureteral stones Alfuzosin Doxazosin Tamsulosin Silodosin tadalafil P value (n = 168) (n = 32) (n = 37) (n = 34) (n = 35) (n = 30) Variables a Age, year; median ± SD 41.7 ± 13.3 38.2 ± 12.8 43.9 ± 11.5 39.2 ± 11 46.3 ± 9.9 .026 Height, cm; median ± SD 172.9 ± 5.7 175.1 ± 4.8 175.2 ± 7.4 176.3 ± 5.2 178 ± 1.7 .322 Weight, kg; median ± SD 82 ± 14 82.6 ± 11 82.1 ± 12.6 82.3 ± 10.9 85.7 ± 12.2 .663 BMI, kg/m2; median ± SD 27.4 ± 3.9 26.9 ± 3.4 26.6 ± 2.8 27.2 ± 3.7 27.1 ± 4.3 .542 Stone diameter, mm; median ± SD 4.9 ± 1.4 4 ± 1.7 4.5 ± 1.8 4.5 ± 1.7 4.7 ± 1.8 .227 Stone volume, mm3; median ± SD 75.1 ± 73.1 48.6 ± 56.5 68.9 ± 94.4 66.3 ± 69.7 75.1 ± 84.5 .220 The distance of stone from ureterovesical junction, mm; median ± SD 9.5 ± 4.2 9.6 ± 4.9 9.1 ± 3.8 9.5 ±3. 6 10.9 ± 5.1 .66 Hounsfield units, HU; median ± SD 527.2 ± 270.6 442.5 ± 269.3 461.3 ± 291.6 491.8 ± 287.5 494.2 ± 268.4 .471 Hounsfield density, HU/mm; median ± SD 103.5 ± 35.9 111.1 ± 36.1 99.8 ± 34.2 104.8 ± 34.7 105.2 ± 35.9 .689 Percentage of hydronephrosis grade 2 18.7 21.6 129.4 37.1 33.3 .404 Percentage of expulsion rate 78.1 75.7 76.5 88.6 90 .44 Expulsion time, day; median ± SD 11.7 ± 5.7 11.6 ± 7.2 9.5 ± 7.6 10.9 ± 10.1 5.7 ± 3.4 .019 BMI, Body Mass Index; HU, Hounsfield Units. a Continuous variables were compared by Kruskal-Wallis test. Mid-proximal ureteral stones Alfuzosin Doxazosin Tamsulosin Silodosin Tadalafil P value (n = 105) (n = 23) (n = 20) (n = 20) (n = 20) (n = 22) Variables a Age, year; median ± SD 40.8 ± 10.7 39.6 ± 8.7 39.1 ± 10.4 37.8 ± 13.1 41.2 ± 8.3 .765 Height, cm; median ± SD 172 ± 4.9 175.3 ± 4.6 172.5 ± 6.6 173.2 ± 5.6 172.7 ± 5.7 .525 Weight, kg; median ± SD 89.6 ± 16.4 91.7 ± 19.7 77.7 ± 13 83.6 ± 15.7 79.2 ± 8.3 .177 BMI, kg/m2; median ± SD 30.3 ± 5.7 29.8 ± 5.8 26.2 ± 4.4 27.8 ± 4.9 26.6 ± 2.3 .147 Stone Diameter, mm; median ± SD 5.3 ± 1.8 5.2 ± 1.2 5.3 ± 1.6 6 ± 1.2 5.7 ± 1.6 .251 Stone Volume, mm3; median ± SD 101.8 ± 102.2 79.4 ± 52.7 100.4 ± 115.3 123.5 ± 61.2 119 ± 100.9 .207 The distance of stone from ureteropelvic junction, mm; median ± SD 84.4 ± 37.1 77.6 ±35.2 90.7 ± 36.3 81.2 ± 40.6 90.8 ± 40.8 .889 Hounsfield units, HU; median ± SD 672.6 ± 294.2 606.7 ± 241.9 775 ± 259.6 721.7 ± 344 838.7 ± 327.2 .125 Hounsfield density, HU/mm; median ± SD 127.5 ± 48.7 116.4 ± 36.9 145.7 ± 38.3 116.6 ± 42.2 143.9 ± 35 .062 Percentage of hydronephrosis grade 2 26.1 30 30 40 40.1 .185 Percentage of expulsion rate 21.7 30 30 30 54.5 .034 Expulsion time, day; median ± SD 26 ± 5.6 18 ± 20.8 10.7 ± 12.4 8.3 ± 6 18.3 ± 14.7 .191 BMI, Body Mass Index; HU, Hounsfield Units. a Continuous variables were compared by Kruskal-Wallis test. Celik_Stesura Seveso 28/06/18 16:54 Pagina 119 Archivio Italiano di Urologia e Andrologia 2018; 90, 2 S. Celika, F. Akdeniza, M. Afsar Yildirimb, O. Bozkurtc, M. Gursoy Bulutb, M. Levent Hacihasanoglua, O. Demirc 120 NCCT findings of the drug groups are given in Table 2 and 3. There was no significant difference in stone diam- eter, stone volume, the distance of stone from uretero - vesical junction, the distance of stone from ureteropelvic junction, HU, HD and grade of hydronephrosis between the five groups with distal and mid-proximal ureteral stones (p > .05). Expulsion rate was 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin 88.6% for silodosin and 90% for tadalafil for distal ureteral stones and 21.7%, 30%, 30%, 30% and 54.5% for mid-proxi- mal ureteral stones, respectively. Median expulsion time was 11.7 days for alfuzosin, 11.6 days for doxazosin, 9.5 days for tamsulosin, 10.9 days for silodosin and 5.7 days for tadalafil for distal and 26, 18, 10.7, 8.3 and 18.3 days for mid-proximal ureteral stones, respectively. Expulsion rates for silodosin and tadalafil groups with distal ureteral stones were higher than the other three groups, but this result was not sta- tistically significant (p = .44). Expulsion time for the tadalafil group was significantly lower than the other drug groups with distal ureteral stones (p = .019) (Table 2). Expulsion rate of the tadalafil group was significantly higher than the other groups with mid-proximal ureteral stones (p = .034). However, there was no statistically significant difference between the groups in terms of expulsion time for mid-proximal ureteral stones (Table 3). DISCUSSION In brief, the expulsion rate was higher in silodosin and tadalafil groups compared to the other groups for distal ureteral stones, but did not reach statistical significance between the groups (expulsion rate was 78.1%, 75.7%, 76.5%, 88.6%, and 90% for alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil, respectively). However, the expulsion rate was significantly higher in the tadalafil group compared to the other groups for mid-proximal ureteral stones (21.7%, 30%, 30%, 30% and 54.5%, respectively). Also, age was higher in the tadalafil group than in the other groups for distal ureter- al stones. In European Association of Urology (EAU) guidelines, MET, SWL and URS are recommended in the treatment of ureteral stones (9). In recent studies, some possible and accurate predictors were determined that affect the success of SWL and URS (4, 14). These predictors were stone diameter, stone volume, HU, and HD of ureteral stones and grade of hydronephrosis on NCCT. Therefore, in our study these factors were equivalent in the drug groups to reduce the effect on MET. According to previous studies, the expulsion rate of dis- tal ureteral stones during watchful waiting is 25-54% with mean expulsion time > 10 days. To increase the expulsion rate and decrease the analgesic requirements, medical therapy is recommended for distal ureteral stones (15-18). In an AUA/EAU panel, two medical ther- apies, which are calcium channel blocker and alpha- receptor antagonists, were optionally recommended for distal ureteral stones. The meta-analysis of six studies of alpha blockers (280 patients) yielded an expulsion rate of 81% (19). There are several studies that show no significant differ- ence between expulsion rates of alpha-blockers for distal ureteral stones. Alfuzosin expulsion rates were reported as 85.6% in a randomized controlled prospective study (20). In a recent randomized, placebo-controlled trial comparing placebo, tamsulosin and nifedipine as MET for distal, middle and proximal ureteral stones, there was no significant difference between the groups (21). In a recent meta-analysis, there was no statistically sig- nificant difference in stone expulsion rate and time between alfuzosin and tamsulosin (22). In a study eval- uating alfuzosin and doxazosin as MET for distal ureter- al stones, expulsion rates and time were reported as 52.9% and 7.38 ± 5.55 days with alfuzosin, 62% and 7.85 ± 5.11 days with doxazosin, respectively (23). In a prospective randomized study comparing silodosin with tamsulosin, the efficacy of silodosin (high selective antagonist of alpha-1A receptor) was shown to be supe- rior to tamsulosin (alpha-1D and alpha-1A receptors selective antagonist) (24, 25). Tadalafil, which is a smooth muscle relaxant, has recently been approved by the US Food and Drug Administration (FDA) for the treat- ment of lower urinary tract symptoms secondary to benign prostatic hyperplasia and erectile dysfunction (10). Gratzke et al. demonstrated the role of the PDE-5 inhibitors of vardanafil, sildenafil and tadalafil in relax- ation of ureteral muscles (26-29). In a recent study Kumar et al. detected significantly high- er expulsion rate and lower expulsion time in a silodosin group compared to tamsulosin and tadalafil groups for distal ureteral stones (11). In another recent study which compared the expulsion rate and expulsion time of tamsulosin with the combina- tion of tadalafil and tamsulosin, higher expulsion rate and lower expulsion time were detected in the tamsu- losin plus tadalafil group (83.6% and 14.9 ± 4.4 days) compared with the tamsulosin group (65.5% and 16.7 ± 4.8 days) (30). In this study, we divided ureteral stones into two groups according to their localization as distal and mid- proximal. For distal ureteral stones, the stone expulsion rates with silodosin and tadalafil were higher than alfu- zosin, doxazosin and tamsulosin, but the difference did not reach statistical significance. However, expulsion time in the tadalafil group was lower than in alpha blocker groups (alfuzosin, doxazosin, tamsulosin and silodosin) for distal ureteral stones. We found a higher expulsion rate in the tadalafil group compared to alpha- blockers (alfuzosin, doxazosin, tamsulosin and silo- dosin) for mid-proximal ureteral stones and that was statistically significant. However, expulsion time was not found to be statistically significant between the groups. Alpha-blockers and PDE-5 inhibitors have sep- arate mechanisms that increase the stone expulsion compared to watchful waiting. Successful combination of tamsulosin and tadalafil used by Jayant et al. opened up the potential use of a combination of silodosin with tadalafil (11, 30). The limitations of this study are that it is retrospective, non-randomized and has a limited number of patients in drug groups for ureteral stones. Due to the retrospective nature of the study, three major parameters, which were Celik_Stesura Seveso 28/06/18 16:54 Pagina 120 quantity of additional analgesic usage, frequency of acute renal colic and emergency visits of patients, could not be evaluated. Also, age was higher and expulsion time was lower in the tadalafil group than in the other groups for distal ureteral stones. The explanation of this result may be that stone expulsion was a rapid condition of the tadalafil usage or that elderly patients could expel stones more easily due to possibly more compliant ureters. Another limitation is that concomitant erectile dysfunc- tion was only present in the tadalafil group. 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Correspondence Serdar Çelik, MD, FEBU, sPhD (Corresponding Author) serdarcelik84@hotmail.com Firat Akdeniz, MD, FEBU dr.frt@mynet.com Mehmet Levent Hacihasanoglu, MD lhhasan@mynet.com Gaziemir Nevvar Salih Isgoren Hospital, Department of Urology, Izmir, Turkey Muge Afsar Yildirim, MD mugeavsar@yahoo.com Merve Gursoy Bulut, MD gursoymerve@yahoo.com Gaziemir Nevvar Salih Isgoren Hospital, Department of Radiology, Izmir, Turkey Ozan Bozkurt, Associate Professor drozanbozkurt@gmail.com Omer Demir, MD, Professor omer.demir@deu.edu.tr Dokuz Eylul University, School of Medicine, Department of Urology, Izmir, Turkey Celik_Stesura Seveso 28/06/18 16:54 Pagina 122