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Segunda B strugglers L'Hospitalet battled to a 3-2 victory at home to fourth-tier outfit Izarra, who started well at the Estadio Municipal Feixa Llarga.
Pito Camacho struck twice in the opening 22 minutes for promotion-chasing Izarra.
Former Athletic Bilbao and Brighton and Hove Albion midfielder David Lopez skied Lugo's fifth penalty over the bar before Alvaro Cejudo sent Betis through.
Alcoyano edged Lleida Esportiu 1-0 thanks to Juan Vich's 71st-minute goal and Real Oviedo needed extra time to overcome a nine-man UCAM Murcia 1-0.
