Basically, I would be interested to know how much you can realistically screw Spain during the reign of Philip II, starting with the defeat of the Spanish Armada.
Lets make the Drake-Norris expedition succeed as much as realistic and Henri III of France survive is OTL assasination, therefore not giving the French League and the Spaniards that respite coming from the anti-royalists backlash coming from the accession to the french throne of a protestant and probably making for an early fall of Paris.
How much can you make Spain unlucky-inefficient in the ensuing years while boosting her opponents? Will it be possible to end Spain as the greatest power in Europe right then and now?