## 2 Materials and Methods  
The study used six Beagle dogs who were about one year old and weighed approximately 14 to 15 kg. The Animal Research Ethics Committee of the State University of Murcia, Spain, following the guidelines established by the European Union Council Directive of 1 February 2013/53/EEC, approved the protocol. The dogs were placed in quarantine and vaccinated against rabies, as well as given essential vitamins. Throughout the study, the dogs were kept in cages and provided with veterinary care, water, and nurture. The experiment was a split-mouth study design (Figure 1). The dogs were pre-anesthetized with 10% Zelazol at 0.15 mL/kg and acepromazine maleate 0.10-0.25 mg/kg (Calmo-Nesional; Pfizer, Madrid, Spain) and Domtor 30 mg/kg (Medetor 1 mg, Virbac, CPPharma Handelsgesellschaft GmbH, Burgdorf, Germany). Afterwards, the animals were taken to the operating room where an intravenous catheter (diameter 20 G) was placed in the cephalic vein, and propofol was infused at a rate of 0.4 mg/kg/min. Volatile anesthetics were used, and the dogs were given tracheal intubation to administer the anesthetic (isoflurane diluted in oxygen 2V%). In addition, the dogs were injected with local anesthesia Artinisba (articaine 40 mg/mL + 0.01% epinephrine, Inibsa, Barcelona, Spain) in the surgical sites. A veterinarian supervised the entire procedure. Lower premolars (2P2,3P3, and 4P4) and first molars (1M1) were extracted bilaterally under general anesthesia. The multi-radicular teeth were divided using a multilayer tungsten-carbide bur, and the roots were removed one by one, to reduce the damage that could be exerted to the buccal and lingual cortical areas (Figure 2a,b). Figure 1: Apigenin K was placed on the right side and melatonin M5250 was placed on the opposite side of the dog’s mandible. P2 second premolar, P3 third premolar, P4 forth preomolar and M1 first molar. Figure 2: (**a**) Premolars and molar sectioned in buccal-lingual direction before extraction; (**b**) Empty alveolar sockets of mandibular P2, P3, P4, and M1 (premolars and first molar). A collagen sponge soaked in apigenin K (Nuttrafur, Alcantarilla, Murcia, Spain) was introduced into the lower right premolars (\({}_{3}\)P\({}_{3}\) and \({}_{4}\)P\({}_{4}\)) and the right first molars (1M\({}_{1}\)); empty sockets at the right side were done in second premolars sockets \({}_{2}\)P\({}_{2}\), Meanwhile, at the left side at the same premolar and molar sites, a collagen sponge containing melatonin M5250 (Sigma Aldrich, Merck Life Science SL, Madrid, Spain) was inserted. Second premolar sockets were used as controls (Figure 3a,b and Figure 4a,b). Resorbable sutures S90 (Lorca Marin, Lorca, Murcia, Spain) were used to close the wound. No incisors or canines were removed so that the animals could chew with the remaining teeth. The entire process was carried out under the supervision of the University's Animal Research Department veterinarian. During the whole surgical procedure, glycoside saline (200 cm\({}^{3}\)) was used for the hydration of the venous line, so that the dogs would have a better post-operative period. Once the surgery was finished, the animals received the following anti-inflammatory, analgesic, and antibiotic  
Figure 4: (**a**) Apigenin K placed in all sockets except Premolar 2; (**b**) melatonin sponges in place, leaving the P2 area empty as a control. Figure 3: (**a**) A collagen sponge soaked into yellow apigenin; (**b**) white collagen sponge soaked in melatonin. medication: anti-inflammatory Voren(r) 2 mL intramuscularly (Boehringer Ingelheim Espana, S.A. Sant Cugat del Valles, Barcelona) and antibiotic Bivamox(r) 2 mL intramuscularly (Boehringer Ingelheim Espana, S.A. Sant Cugat del Valles, Barcelona) for one week. The dogs were re-evaluated to check their post-extraction wounds and general health. After the surgery, the dogs were fed ad-libitum for 15 days with a soft diet and water. Oral cleaning of the wound and adjacent teeth was done with gauze soaked in SEA 4 (Blue Sea Laboratories, Alicante, Spain).