## 2 Materials and Methods
### Intervention and Study Procedures  
Participants were randomized with a computer program (Epidat 4.1) and were distributed according to a simple randomization procedure to the active or experimental treatment group (cucumber extract supplement) or to the control group (placebo supplementation). An independent investigator performed the randomization process. Neither patients nor investigators were aware of whether the assigned study arm corresponded to the active treatment or placebo. The active product was an extract of _Cucumis sativus_ L. (CuberUp(r), Euromed S.A., Mollet del Valles, Barcelona, Spain), the composition of which included 80% _Cucumis sativus_ L., 18% maltodextrin and 2% anhydrous colloidal silica recipient. The percentage of maltodextrin and the excipient only represented 20% of each capsule, and these components were necessary to prevent the agglomeration of the product and to increase the bioavailability. The part of the cucumber used was the whole cucumber fruit, and the varieties and maturation stage were those used applied in extensive cucumber food production. The methodology for obtaining the natural extract was based on an eco-friendly ultrapure continuous water extraction method and refinement by a proprietary tangential flow filtration process (Pure-Hydro Process(r)). This procedure gave a total concentration of amino derivatives expressed as L-Citrulline of not less than 50%, the concentration of the extract being 80% of the total. The nutritional value of the cucumber is shown in Table 1.  
Subjects randomized to the experimental arm were instructed to take two capsules a day (10 mg per capsule) at the time of breakfast for 8 consecutive weeks (60 days). Participants assigned to the placebo (control) arm ingested the capsules in the same pattern as the experimental group. The capsules, based on maltodextrin, were identical in appearance. All subjects were instructed regarding the importance of maintaining their eating habits, particularly to consume the same amount of foods containing flavonoids (coffee, tea, chocolate, nuts, etc.). In addition, they were not allowed to consume cucumber throughout the study. A diary card (24-h dietary recall) was provided to collect data for a period of 3 days (two weekdays and one weekend) at the beginning and at the end of the intervention. Dietary data were analyzed with the Dietsource(r) (v3.0) software package. Moreover, if a new treatment was started, it had to be reported to the principal investigator. Any analgesic or other medications taken during the study period had to be recorded on the diary card. \begin{table}
\begin{tabular}{l c c} \hline \hline \multicolumn{1}{c}{**Component**} & **Value** & **Unit** \\ \hline Energy & 50 (12) & kJ (Kcal) \\ \hline Total lipids & 0.1 & g \\ \hline Total protein & 0.7 & g \\ \hline Water & 95.7 & g \\ \hline Carbohydrates & & \\ \hline Total fiber & 0.8 & g \\ \hline Carbohydrates & 2 & g \\ \hline Vitamins & & \\ \hline Vitamin A & 2 & \(\mu\)g \\ \hline Vitamin D & 0 & \(\mu\)g \\ \hline Vitamin D & 0.09 & mg \\ \hline Folic acid & 13 & \(\mu\)g \\ \hline Riboflavin & 0.02 & mg \\ \hline Niacin & 0.23 & mg \\ \hline Thiamine & 0.02 & mg \\ \hline Vitamin B12 & 0 & \(\mu\)g \\ \hline Vitamin B6 & 0.04 & mg \\ \hline Minerals & & \\ \hline Calcium & 19 & mg \\ \hline Iron & 0.3 & mg \\ \hline Potassium & 150 & mg \\ \hline Magnesium & 12 & mg \\ \hline Sodium & 3 & mg \\ \hline Phosphorus & 23 & mg \\ \hline Iodure & 0.3 & \(\mu\)g \\ \hline Selenium & 0.8 & \(\mu\)g \\ \hline Zinc & 0.1 & mg \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Nutritional value of the cucumber. Participants were assessed twice, at baseline (visit 1) and after product consumption for 60 days (visit 2). At the baseline visit, a signed informed consent form was collected, the satisfaction of the inclusion criteria was confirmed, and all subjects were provided with the corresponding study product.